The tumor microenvironment is comprised of a variety of different components that includes immune cells, which are part of the body’s natural defenses against infection. However, the role that the tumor microenvironment plays in tumor growth and progression is not yet completely understood. Researchers are working to understand how to modulate or engage specific immune cells already present near tumor cells to work against them. This strategy, called immunotherapy, has been successful in some cancers but less so in breast cancer. However, immunotherapy has shown some promise in treating triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer with few treatment options. 

BCRF investigator Dr. Jean Zhao conducts research focused on integrating immunotherapy and targeted therapy to “break through” cancer, particularly for difficult-to-treat breast cancers like TNBC. In a recent article published in Nature, Dr. Zhao describes how her team targeted a pathway involving a pair of protein molecules that oppose each other’s activity in tumor cells—PTEN and PI3Kβ—and how they may be leveraged to improve immunotherapy outcomes in breast cancer. 

What is PTEN and why is it important in breast cancer?

The phosphatase and tensin homolog (PTEN) gene encodes the instructions for making an enzyme of the same name that is found in almost all tissues of the human body. The PTEN enzyme is a phosphatase that functions as a tumor suppressor, which means it keeps cells from growing and dividing rapidly or uncontrollably, a hallmark of cancer.

Those who have inherited PTEN mutations have a four-fold higher lifetime risk of developing breast cancer than those who are at average risk, which is similar to the risk profiles associated with mutations in the BRCA1/2 genes. Patients with breast cancer carrying a PTEN mutation are at increased risk of endometrial, thyroid, kidney, and colorectal cancers as well as a second breast cancer.  

The dual nature of PI3Kβ activation

The loss of the phosphatase resulting from the PTEN gene mutation activates the enzyme PI3Kβ, a kinase that governs signaling activity and can cause tumor cells to proliferate when left unchecked by the PTEN phosphatase. By using state-of-the-art PTEN-deficient breast cancer laboratory models designed by her research team, Dr. Zhao discovered that PI3Kβ activation promotes not just a pathway that fuels cancer proliferation but also controls a pathway that blocks the body’s natural immune defenses to suppress tumor growth. 

They further discovered that when a PTEN-deficient tumor was treated with an inhibitor of PI3Kβ or another protein called STAT3 (also involved in the pathway controlling the suppression of the immune system), a variety of immune cells were recruited to the tumor environment and led to destruction of tumor cells and shrinking of the tumor. When this inhibitor was combined with a pharmacological immunotherapy, breast tumors were eradicated in the research team’s breast cancer models. 

What this discovery means for patients

These findings from Dr. Zhao and her team provide scientists with a blueprint on which to base strategies to target specific molecules, pathways, and mechanisms involved in cancer progression caused by mutations in the genetic code. Already, inhibitors of PI3Kβ are being investigated in early clinical trials in those with PTEN deficiencies and are showing potential in terms of safety and preliminary efficacy. In addition, this work may open doors for the development of immunotherapy strategies that have historically been more challenging to employ in breast cancer treatments. 

Are cancers other than breast cancer impacted by this research?

The absence of the PTEN is a common driver across many different types of cancers, and those with the inherited mutation have an 85 percent lifetime risk of developing any cancer. Furthermore, the PTEN mutation is associated with a cancer diagnosis at a younger age. For people who have tested positive for a PTEN mutation, consulting a genetics expert or counselor to assess their personal and family history and assist in creating a plan to manage cancer risk may be recommended.

The insights gained from Dr. Zhao’s research will have an impact not just on breast cancer but on understanding of the fundamentals across several PTEN-deficient cancers. Her discoveries add to the growing knowledge that will help researchers develop the most effective and promising treatment strategies for the most challenging-to-treat cancers that arise as a result of these critical genetic mutations. 

References:

“PI3Kβ controls immune evasion in PTEN-deficient breast tumours” Nature 617, 139-146 (2023)

“Breast cancer risk and clinical implications for germline PTEN mutation carriers” Breast Cancer Research and Treatment 165, 1-8 (2017)

“PTEN-deficient cancers depend on PIK3CB” Proceedings of the National Academy of Sciences 105 (35) 13057-13062 (2008)

“Cancer Risk Associated with PTEN pathogenic variants identified using multigene hereditary cancer panel testing” JCO Precision Oncology 7 (2023) e2200415

“Lifetime cancer risks in individuals with germline PTEN mutations” Clinical Cancer Research 18 (2): 400-407 (2012)

Clinical trial investigators studying advanced and metastatic breast cancer presented their newest results—largely focused on emerging targeted and immunotherapies—at this year’s San Antonio Breast Cancer Symposium (SABCS).   

Read on for highlights from those trial updates, many of which involved BCRF investigators or were supported directly by BCRF.

Metastatic breast cancer

Dr. Adrienne Waks of the Dana-Farber Cancer Institute presented the first results from the phase 2 AVIATOR clinical trial, funded in part by BCRF (TBCRC 045, NCT03414658). In patients who had previously been treated for HER2-positive metastatic breast cancer (MBC), significant improvement in progression-free survival was observed—3.8 months with the addition of immune checkpoint inhibitor avelumab (Bavencio®) to chemotherapy and trastuzumab (Herceptin®) compared to two months with chemotherapy and trastuzumab alone. Results presented as part of this trial indicate that additional investigation of immune checkpoint blockade in pre-treated HER2-positive metastatic breast cancer is warranted.  

This study was chosen for a Rapid-fire Mini-Oral Presentation, a new session at this year’s SABCS that highlights thought-provoking studies in their early stages and allows other researchers to provide guidance on shaping future clinical trials.

HER2CLIMB-02 (NCT03975647) is only the second randomized study after the HER2CLIMB trial led by BCRF investigator Dr. Nancy Lin that includes patients with active or progressing brain metastases. In HER2CLIMB, researchers found that adding tucatinib (Tukysa®) to trastuzumab and capecitabine resulted in better progression-free survival and overall survival in patients with HER2-positive MBC. In the follow-up HER2CLIMB-02 trial, researchers are investigating if the addition of tucatinib to ado-trastuzumab emtansine (T-DM1) results in better outcomes for patients compared to T-DM1 alone.  

A primary analysis of this phase 3 trial was presented by Dr. Sara Hurvitz of Fred Hutchinson Cancer Center at the University of Washington, whose research team reported a 24 percent likelihood of reducing disease progression or death by adding tucatinib to T-DM1 in patients previously treated for HER2-positive locally advanced or MBC (9.5 months median time to disease progression or death for combination therapy versus 7.4 months with T-DM1 alone). For those patients with brain metastasis (40 percent of trial participants), a 36 percent reduction in disease progression or death was observed in the combined therapy (7.8 months median time to disease progression or death versus 5.7 months with T-DM1 alone). These results further support the use of the highly selective tyrosine kinase inhibitor tucatinib in patients with HER2-positive locally advanced or MBC. 

BCRF investigator Dr. Luca Gianni presented an update to the phase 3 APTneo trial (NCT03595592) in a late-breaking abstracts oral session. The study tested the role of adding the immune checkpoint inhibitor atezolizumab (Tecentriq®) to targeted HER2 treatments and chemotherapy with and without anthracyclines in HER2-positive, early high-risk, and locally advanced breast cancer. 

While the study investigators found that the addition of atezolizumab to targeted treatments and chemotherapy did not statistically increase pathologic complete response rates (pCR), adding atezolizumab to anthracyclines followed by the targeted treatments and chemotherapy did increase pCR by a statistically significant 9.9 percent compared to patients who only received targeted treatments and chemotherapy.  

HER2-negative and triple-negative breast cancer

Dr. Komal Jhaveri of Memorial Sloan Kettering Cancer Center presented the primary analysis of the phase 1 INAVO120 trial (NCT04191499). INAVO120 compared inavolisib, a highly potent and selective inhibitor of the tumor marker PI3KC⍺, plus CDK 4/6 inhibitor palbociclib (Ibrance®) and fulvestrant to palbociclib and fulvestrant alone in patients with PIK3C⍺-mutated hormone receptor (HR)–positive, HER2-negative advanced breast cancer. 

This drug combination may represent a new standard of care for patients with the PI3KC⍺ mutation facing resistance to palbociclib and fulvestrant. The addition of inavolisib demonstrated a significant improvement in progression-free survival within 12 months of adjuvant endocrine therapy. Median progression-free survival was 15 months with inavolisib versus 7.3 months with palbociclib and fulvestrant alone.

The efficacy of the newly-FDA approved capivasertib (Truqap) was evaluated in the trial CAPItello-291 (NCT04305496) and an update on patient-reported outcomes was presented by BCRF investigator Dr. Mafalda Oliveira in a poster spotlight session at this year’s meeting. Dr. Oliveira presented significantly improved progression-free survival in patients treated with capivasertib and fulvestrant as well as a manageable safety profile of the drug combination. 

Patients reported no statistically significant change in functional or symptom scores in the capivasertib plus fulvestrant group with the exception of diarrhea. These data further support a positive risk-benefit profile for capivasertib and highlight the importance of assessing quality of life in new treatments for advanced breast cancer.

Dr. Michail Ignatiadis of Institut Jules Bordet presented findings from the phase 3 ALEXANDRA/IMpassion030 trial (NCT03498716). The study investigates the value of adding immune checkpoint inhibitor atezolizumab to standard anthracycline and taxane-based adjuvant chemotherapy in TNBC. The conclusions of their interim analysis do not support the addition of atezolizumab to the chemotherapy regimen in patients who have undergone primary surgery for early TNBC. 

The knowledge gained from this research, despite the negative results, helps the research community design future studies and define the most appropriate settings for treatments. In this case, immunotherapies such as atezolizumab may work better in the neoadjuvant setting when more tumor is present. 

Read more from SABCS:

• Key Takeaways from SABCS 2023
• BCRF Investigators Honored at the 2023 San Antonio Breast Cancer Symposium
• Clinical Trial Updates from SABCS 2023: Early-Stage Breast Cancer

At this year’s San Antonio Breast Cancer Symposium (SABCS), conference attendees comprised of researchers, students, and patient advocates attended presentations reporting the results of clinical research years in the making. Read on for highlights from those trial updates in early-stage breast cancer—several of which were presented by or involved BCRF investigators.

Adjuvant CDK4/6 inhibition benefits in early-stage hormone receptor-positive/HER2-negative breast cancer

Hormone receptor (HR)–positive, HER2-negative breast cancer accounts for nearly 70 percent of all breast cancer cases in the United States, and many patients diagnosed with stage II and III disease face a high risk of recurrence. Abemaciclib (Verzenio®) and ribociclib (Kisqali®) are part of a class of drugs called CDK4/6 inhibitors; they are small molecule inhibitors targeting CDK4 and CDK6 proteins, which play a critical role in promoting growth of breast cancer cells.  

Dr. Gabriel Hortobagyi, Member Emeritus of BCRF’s Scientific Advisory Board, presented the final analysis from the phase 3 NATALEE trial (NCT03701334[PM1] ) testing the adjuvant (post-surgical) use of ribociclib in women with high-risk HR-positive, HER2-negative early stage (II or III) breast cancer. Participants were randomly assigned to receive either ribociclib for three years with hormonal therapy or hormonal therapy alone for at least five years. The overall survival endpoint data is too immature to present yet; however, the researchers reported significantly extended invasive disease-free survival, consistent across subgroups, with a 25 percent reduction in recurrence in those receiving ribociclib and hormonal therapy.   

The monarchE study (NCT03155997) is a randomized phase 3 trial testing the benefit of adding abemaciclib—another CDK 4/6 inhibitor—to endocrine therapy versus endocrine therapy alone in patients with high-risk HR-positive, HER2-negative early-stage breast cancer. In an interim analysis of overall survival, study investigators found use of abemaciclib led to sustained five-year invasive disease-free and distant relapse-free survival benefit in trial participants.   

Dr. Nicholas Turner of the Royal Marsden Hospital presented a molecular analysis of primary tumors at this year’s meeting, with the goal of associating their genomic profiles with outcomes in monarchE participants. The results supported the use of abemaciclib in HR-positive, HER2-negative high-risk early breast cancer regardless of intrinsic molecular subtypes in both high- and low-risk tumors. 

Biomarker analysis identifies patients likely to benefit from immunotherapy 

The immune system has important proteins in place to keep it from attacking normal, healthy cells. These “checkpoint” proteins can be used by breast cancer cells to avoid being targeted by the immune system. The immunotherapy drugs that target these proteins, PD-1 and PD-L1 in breast cancer, are called immune checkpoint inhibitors (ICIs).

The CheckMate 7FL (NCT04109066) and KEYNOTE-756 (NCT03725059) trials prospectively tested the benefit of anti-PD-1 agents nivolumab (Opdivo®) and pembrolizumab (Keytruda®), respectively. Study investigators previously reported an increase in rates of pathological complete response (pCR)—total disappearance of invasive disease—with the addition of either PD-1 inhibitor to neoadjuvant (pre-surgical) chemotherapy in patients with high-risk, high-grade estrogen receptor (ER)–positive HER2-negative breast cancer.  

In the analysis presented at this year’s meeting, they sought to identify biomarkers that could predict benefit of the therapy in individual patients, as adverse effects of immunotherapies can be significant. In both studies, the benefit was greater in patients with tumors positive for the PD-L1 biomarker (the drugs’ target protein) and lower ER status. 

In CheckMate 7FL, BCRF investigator Dr. Sherene Loi presented that lower progesterone receptor (PR) status and higher amounts of tumor-infiltrating lymphocytes were also identified as biomarkers that predicted a greater benefit of nivolumab. 

The KEYNOTE-522 trial (NCT03036488) tested the earlier use of immune checkpoint inhibition with pembrolizumab plus chemotherapy versus placebo plus chemotherapy followed by adjuvant pembrolizumab or placebo in patients with early-stage triple-negative breast cancer (TNBC). 

At this year’s conference, study investigators presented five-year follow-up data, which captures when most cancer recurrence is observed in patients with TNBC. The data confirmed significant improvements in pathological complete response and five-year event-free survival (81 percent with addition of pembrolizumab to chemotherapy compared to 72 percent with chemotherapy alone).  

Targeted antibody-drug conjugate improves outcomes in HER2-positive early breast cancer

Dr. Sibylle Loibl of Goethe University presented the final invasive disease-free survival and an updated overall survival analysis to the phase 3 KATHERINE trial (NCT01772472) investigating the use of pre-surgical antibody drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1, Kadcyla®) or trastuzumab (Herceptin®) in patients with invasive HER2-positive early breast cancer after neoadjuvant chemotherapy. 

The targeted therapy ado-trastuzumab emtansine (T-DM1/Kadcyla®) was found to significantly improve invasive disease-free survival (80.9 percent compared to 67.1 percent with trastuzumab) and overall survival (89.1 percent compared to 84.4 percent with trastuzumab) in trial participants after seven years of follow up. The first data from this trial was presented five years ago and has already changed the standard of care for patients with residual invasive disease. The updates presented here confirm that patients treated with TDM-1 are experiencing better outcomes.  

Pregnancy after breast cancer 

The POSITIVE study (NCT02308085[MF5] ) is a prospective international, multicenter, single-arm trial of pre-menopausal women with stage I-III HR-positive breast cancer who desired to become pregnant. After completing 18-30 months of adjuvant endocrine therapy, the women were able to take up to a two-year break from therapy to allow for conception after which they would resume endocrine therapy. Researchers found that 74 percent of patients became pregnant after pausing therapy and had similar disease outcomes as patients who didn’t suspend treatment.

In a secondary analysis, investigators focused on patients within POSITIVE who had undergone fertility preservation, such as egg freezing or other assisted reproductive technologies (ART). Dr. Hatem A. Azim, Jr. of the Monterrey Institute of Technology reported that over 82 percent of the patients in the study became pregnant and the use of ART did not increase breast cancer recurrence. Cryopreserved embryo transfer was the most effective ART for pregnancy in this patient population. Younger patients (those under 35) were able to get pregnant in a shorter time. These trial results can give HR-positive breast cancer patients confidence that using fertility preservation and ART will not increase three-year cancer recurrence. While encouraging, longer-term follow-up is warranted.

Dr. Matteo Lambertini of the University of Genova presented data from an international retrospective, hospital-based cohort study (A Multicenter Retrospective Study on the Prognostic Impact of Pregnancy in Women with History of BRCA Mutated Breast Cancer/NCT03673306) looking at cumulative incidence of pregnancy and disease-free survival in young women who are germline BRCA mutation carriers. The results showed that more than one in five BRCA carriers conceived within 10 years after breast cancer diagnosis. Importantly, for most women, pregnancy after breast cancer did not lead to negative impact on the mother’s or baby’s health.

Read more from SABCS:

• Key Takeaways from SABCS 2023
• BCRF Investigators Honored at the 2023 San Antonio Breast Cancer Symposium
• Clinical Trial Updates from SABCS 2023: Advanced and Metastatic Breast Cancer

This National Mammography Day, BCRF investigator Dr. Christopher E. Comstock delves into the details of current screening recommendations and new advances on the horizon.

There’s no question that annual mammograms save lives. Mammograms can detect potentially cancerous changes in the breast before warning signs or symptoms such as a lump appear so patients can be diagnosed earlier, when the chances of long-term survival are at their highest.

However, mammograms are not flawless. For women with dense breasts, which contain more fibrous and glandular tissue than fat, a cancerous growth or tumor can be hard to see and may be missed altogether. It’s a major area of concern in breast cancer research, and the need to develop screening improvements has become even more urgent in light of recent news that more young women—who are more likely to have dense breasts than older women—are developing the disease.

To mark National Mammography Day, Sadia Zapp, BCRF’s managing director of communications, sat down with Dr. Christopher E. Comstock, a BCRF investigator since 2019, to discuss current tests that help supplement mammography, who needs them, and a promising new screening approach he’s studying now.

Sadia Zapp: Hi, Dr. Comstock, thank you so much for joining us today.

Dr. Christopher Comstock: Thank you. Thank you for having me.

SZ: I’m so excited to speak with you because I think this conversation has the potential to not just be enlightening but also super helpful for a lot of our viewers today. I was sharing earlier that I was diagnosed with breast cancer last year at the age of 36, and I completed active treatment earlier this year. So I’m really excited to talk to you, especially because I was diagnosed at a pretty young age. But first, please introduce yourself and tell us about your work.

CC: I’m a breast imaging radiologist at Memorial Sloan Kettering Cancer Center. I’ve been just doing breast imaging and breast imaging research for nearly 27 years. And I’ve been all over—I was at the University of Chicago and Northwestern and then I was section chief at UC San Diego. I then worked my way up to Sloan Kettering, and I’ve been here for 15 years.

SZ: Will you talk a little bit about your BCRF-supported research?

CC: First, it’s so critical for researchers like me to have the support of BCRF. And [BCRF co-founder] Dr. Larry Norton, who I work with…he’s seen the power in my particular interest in contrast mammography. He’s been instrumental in making this happen and supporting the work. 

So we’ve been doing analog- or film-based mammography for quite a while, and then we moved in the mid-2000s to digital mammography, which is a little bit of an improvement. So mammography has evolved, but it’s­ been little incremental improvements—not vast improvements in screening, detection. And now the latest thing we have is 3D mammography that, again, is a bit of an incremental improvement. 

I think the biggest issue with mammographic screening is the underdiagnosis of cancer. We’ve had eight randomized control trials since the 60s that have shown that patients who mammographic screening, compared to women who don’t undergo screening, have anywhere from 20 to 40% reduction in mortality from breast cancer. But surprisingly, the test that’s used for screening mammography is probably around a 20% sensitivity. 

So it’s not a great test, but it’s fit the bill over the years because of its availability and low cost. But it’s surprising that such a poor test has managed to reduce mortality that much. What my interest is is something called vascular-based screening. It includes contrast mammography and MRI, which allow you to see the early changes of cancer from the vascularity that occur before you see a tumor that’s big enough to detect on mammography and ultrasound. So vascular-based screening can really improve sensitivity.

Despite improvements in therapy over the last 20 years, we still have over 40,000 women dying annually from breast cancer. So, I think the quickest improvement and easiest way to reduce mortality significantly is to find more cancers earlier. And vascular-based screening, such as MRI and contrast mammography, allow us to do that. 

The study I’m working on, CMIST [Contrast Enhanced Mammography Imaging Screening Trial] is supported by the BCRF. The trial is comparing our best mammographic screening, which is 3D mammography or digital breast tomosynthesis, with contrast-enhanced MRI to show how many more cancers it detects. Our early, single-institution data looks like it doubles the cancer detection rate.

SZ: That’s pretty incredible. When we’re talking contrast-enhanced and you say things like “vascular,” what does that mean?

CC: A mammographic screening or 3D mammography screening is just an X-ray of the breast. It’s basically a shadow, though 3D mammography adds a bit more information in terms of a 3D view through the breast. But it’s not true 3D like an MRI or CAT scan. 

A plain X-ray or ultrasound relies on seeing a mass in the breast tissue by its edges or its shape. And some women have more fat-dense breasts, which you can see through easily. But others have more fibroglandular tissue, and you can’t see through that as well. So in women with more fibroglandular tissue, it’s like looking for a snowman in a snowstorm—the more of a storm there is, the harder it is to see things like a mass. That’s the limitation of mammography. 

But when you have contrast mammogram, as with a [contrast] MRI, you get an injection of gadolinium [a contrast dye] and the MRI can see that area of contrast, and it’s not limited by breast density. The same is true with contrast mammography. It’s a mammogram, but you get an injection of iodine contrast beforehand, which is what we use all the time with CAT scans. That allows you to see areas that are hidden in the tissue because it’s not limited by breast density.

SZ: For a patient, it’s an injection. It’s really simple.

CC: Yes, and I think access to mammography is much easier compared to MRI.

SZ: We’re talking about improving technology but without having to roll out hundreds of new machines across mammography centers. 

So we’ve talked about mammography, MRI, and ultrasound. Can we talk a little bit about why and when you choose a particular screening for a particular patient? 

CC: How do patients and referring physicians decide? I think that’s an area we need to work on. It becomes a combination of education of the referring physicians of the pros and cons of each test, and also patients, who may have preferences for different tests. 

In general, you want a program where you have tailored screening based on the patient’s risk, their breast density, and the level of sensitivity they want, since more sensitive tests may result in some false positives. 

There are four categories of breast density: A, B, C, and D. For the top two categories, C and D, where breasts are extremely dense, the mammographic sensitivity is going to drop. So those patients should have some supplemental screening, either a contrast mammography or MRI. 

So, the decision is based on your breast density, but also on your risk of breast cancer. Let’s say you don’t have any risk factors and your breasts are not dense. You’re probably okay with just mammographic screening or mammography plus ultrasound. If you have dense breasts and you’re at intermediate risk, you probably would want to do just contrast mammography. And then if you’re really high risk, we recommend MRI. If you’re a gene carrier, which has the highest risk, you may alternate between contrast mammography and MRI.

It’s still a work in progress, but the general idea is a combination of your personal history, family history, and genetic models to assess your risk along with your breast density. Also, there is what patient wants. Some patients may not be comfortable in the MRI if they have claustrophobia, and some patients might prefer contrast mammography. 

There are other new methods being studied. Dr. Constance Lehmann, who’s also a BCRF researcher, has shown that with AI (artificial intelligence) and computer imaging, there’s certain patterns in a woman’s mammographic pattern that can infer higher risks. I think in the future, we’re going to see a whole new type of evaluating risk based on family history but also artificial intelligence, looking at the patterns of your mammogram and combining those to determine what should be the best screening program for you.

SZ: Now we’re talking about machine learning to not just detect cancer but also predict future cancer as well. I want to talk a little bit more about the basics of dense breasts, and then we’ll get into risk-based screening and what we’re hoping to do there as well, and the role that CMIST plays in that.

CC: It’s interesting that there’s no formalized pathway in breast imaging or in radiology…for adopting new technologies it’s kind of hit or miss. So the goal of CMIST is to get some basic phase two data and major publication to really foster adoption. It takes a multicenter trial and a major publication as well as the actual the community of breast imaging. This is a very hot topic. One of my frustrations is that things change very slowly. We know the power of this technology, but it’s really working on the research and the science to try to promote adoption. And that way, your referring physicians and other radiologists see that and decide, Hey, this is something we need to offer to our patients.

SZ: One thing I wanted to highlight that you’ve mentioned but I want to drive home is the success of contrast enhanced mammography as far as reducing false positives or even false negatives. I read that it could be up to 80% improvement, so we’re talking about a huge amount.

CC: Yes, it’s important information patients and referring physicians should know, whether there are high false positives and unnecessary biopsies. The first time a person has contrast mammography, you’re going to see things that might have been there before, but you don’t have a comparison. So that’s your baseline, like when a patient gets their first mammogram, and there’s obviously going to be a higher callback rate. But once you have subsequent screenings for comparison, those further rounds of testing should show fewer false positives and lead to fewer unnecessary biopsies. We already have a good sense that contrast mammography is going to nearly double—80% to 100%—increase in sensitivity. But we want to show also that it’s well tolerated and the false positives that are low.

SZ: We’re seeing an increase in incidence of breast cancer in women under the age of 50 and an 8% increase in incidence in women ages 30 to 39. We’ve long known that incidence has been on the rise, but that was the first study that really quantified that increase in risk in that younger age group. And they’re particularly vulnerable because they’re not being screened annually. 

One thing I find fascinating is that with so many of these young women, you’ll hear how patients brought the diagnosis to their doctor, or said, “I feel this lump” and the doctors will not recommend mammography. And I’ve been struggling with that because I don’t think it’s that doctors don’t care—I think a lot of it also has to do with the fact that they have less faith in the accuracy of mammography, right? They don’t want to put young patients through that screening. They’re more likely to not recommend screening because young women are more likely to have dense breasts, so there’s a higher rate of false positives and unnecessary biopsies.

I always say that when you hear about biopsies, you think, “Oh, they can’t be so bad.” But then suddenly you’re a patient who needs one, you get the biopsy, and you get that bill and realize this is really a huge financial burden. So one of the reasons I’m so hopeful about CMIST is that it will improve confidence, specifically for people with dense breasts. And that’s the majority of patients under 40. 

CC: Right, and in the 40 to 50 range. When to start screening for breast cancer is an area where there’s a fair amount of debate. Some organizations and the United States Preventive Task Force kind of left the starting age up to patients talking to their doctors. But the American Cancer Society and the American College of Radiology have, for a long time, recommended screening start at age 40. 

Regarding false positives and unnecessary biopsies, I think some of the modeling and the recommendations from the Task Force factored in the anxiety and stress of having an unnecessary biopsy or being called back. I don’t think they give women enough credit because I think women would rather have their breast cancer found than feel anxious about getting a biopsy. Yes, there’s short-term anxiety in getting a biopsy and waiting for results, but I think most women would prefer to undergo it rather than find themselves thinking later, I didn’t get screening and now I have this palpable lump that with nodes positive, I wish I had done more screening. 

So I think recommendations from at least some of the organizations and, like you say, the referring physicians, their hesitancy is because of some of that information from the Task Force, I think they overused the modeling data on anxiety and the harms of mammography. I think you’re right that some physicians are hesitant to recommend screening as often as they should. But I think CMIST may help to show that contrast mammography is a much more sensitive test that has lower false positives. So its utilization, particularly in women with dense breasts, will be a big positive.

SZ: I couldn’t agree more. There is no comparing the anxiety of screening versus being diagnosed at a later stage. And I think a lot of young patients, specifically when they go in to talk about risk factors, even that can be a longer conversation to be had with doctors—like you were saying, starting in your twenties just talking, just having that conversation with your doctor to outline what your risk factors are and when you should begin screening is really, really important. 

Let’s talk about dense breasts. What are they? The FDA just required imaging facilities to let patients know that they have dense breasts. Once you find out you have dense breasts, then what?

CC: There’s something called the Mammography Quality Standards Act, which has helped to standardize mammographic screening and the reports, so it’s more clear for physicians what they need to do and if they need to do biopsies. 

But breast density, as I mentioned, there’s four categories. And the breast is like other organs in the body like the pancreas and kidneys—its excretory. It’s made to produce milk during pregnancy. It has tubes and structures in it. Imagine it’s like the tree branches—the more leaves you have, then the more dense the breasts are. You could have just the branches and not many leaves. That’s the non-dense pattern that’s mostly fat density. So you can see through the “branches” very easily. You could see if there’s a bird sitting on a branch. But some patients have extremely dense breasts where you can’t see anything sitting on a branch anywhere.

I think back in the 60s and 70s, when mammography was rolling out during the American Cancer Society’s war on cancer, which is the time when breast imaging became a specialty and when mammography and breast cancer screening really got promoted. And I hate to say it, but I think we oversold mammography. It’s not a cholesterol test where you take a sample and you get a number. Mammography is based on the radiologist’s experience and ability to detect these patterns in the image.  

But in the last 10 years—partly through grassroots organization and a website called Are You Dense?—the importance of breast density came through because you had women who had a lump, went to their doctor, were biopsied, and told it was a cancer. And they said, Wait a minute, I had a mammogram three, four months ago. 

So there was this grassroots movement to create legislation—it’s now a federal, but it used to vary by state—that said, Hey, we need to notify patients if they’re in one of the top two density categories. So now with your report from your mammogram, you get a letter that says if you have dense breast tissue and states it’s a risk factor for breast cancer. And that’s because the more breast tissue cells you have, the higher chance of one going awry and becoming cancer. So your mammogram may not be as good at detecting cancer and you should talk to your physician about supplemental screening. 

For a long time, these letters didn’t specify which test you’d need because ultrasound was the default screening test. But again, ultrasound is based on finding the shapes of things. It’s not vascular based. MRI does improve sensitivity by maybe 40 to 50% or 30 to 40%, depending on your risk level. But it’s also fairly time consuming, expensive, and has false positives. Still, it turned out to be the default test for women who got density letters and looked into supplemental screening. 

At Sloan Kettering, in the breast imaging department where I started 12 or 13 years ago, we didn’t do many whole-breast screening ultrasounds. But when the laws changed in New York, we did 30 to 40 a day. Now, it’s been done for quite a while. But ultrasound is not an efficient mammography placeholder screening. The sensitivity is still not that great. But with MRI and contrast mammography we can double the detection rate.

SZ: How common are dense breasts? They’re more common in younger women, right?

CC: About half of the screening population falls into the dense breast category and the other into the non-dense category. But proportions change over time. Looking at women in their forties and fifties, more than half of them are in the dense category. As women get older and postmenopausal, you see breast density decrease somewhat. 

SZ: Dense breasts are a risk factor for being diagnosed with breast cancer. Is that due to the number of breast cells present, as you said earlier? 

CC: It’s kind of like lottery tickets, right? The more tickets you have, the greater the chance your number could be called. If you buy one ticket, there’s a lower chance of cancer developing. It’s related to the sheer number of breast tissue cells.

SZ: You mentioned earlier that for some women, especially those with dense breasts, they would get a combination of screenings. And you also said the screenings could be alternated. What does that mean? 

CC: There’s not a lot of data, but in general it’s accepted that some patients, instead of getting both their screenings—let’s say they’re doing mammography and ultrasound or MRI—that if you spread them out, you do one, and another six months later, you’re in essence getting a test every six months. And that approach may find something that was not visible at the time of the previous screening. But a few months later it’s seen on the second test.

Again, there are no real studies or data, but some people do alternating screening rather than having the screenings at the same time. For those who are gene carriers, BRCA carriers, for example, they’re at such a high risk—you might want to do an MRI and then contrast mammography six months later. 

SZ: What are some of the most promising areas of research you’re most excited about?

CC: As I mentioned, I think the low-hanging fruit is to reduce mortality in a way that we haven’t seen since the initiation of mammography. We really need to work on the detection side of things. In the long run, liquid biopsy would be something you could potentially do at home, but it’s not going to replace mammographic screening or MRI or contrast mammography, because it’s just not sensitive enough right now. But I think it will have a role. 

I think for now the goal is contrast mammography and then liquid biopsies further in the future, where you can detect whether a patient has cancer just by doing a quick blood test. The other thing I would bring up is vaccines for breast cancer. So I think we’re coming at screening from multiple fronts, and hopefully within the next 20 years we can significantly reduce the number of women who dying of breast cancer.

SZ: That’s what every patient wants to hear, and it leaves me quite hopeful for what the future holds. I did want to touch a little bit on CMIST, which is underway and has started to enroll patients. How soon do you think we’re bringing that to the bedside? What’s the timeframe that you think—in the next five to 10 years—that contrast enhanced will be available for patients?

CC: I think within the next five years the early results should be out, and probably three years from the first round of screening. Once that’s published, I think more and more centers will start offering it to their patients. So I don’t think it’s a long term. I think it’s a short term, five years where we see [this become available]. 

But with this mammographic screening and contrast, mammography is widely available, so it’s very easy for a center to offer that. So I can see a much more rapid uptick in offering that to patients who seek it out and say, I’m intermediate risk and I’d like I’d like something more than just ultrasound. 

If I can add here—I’ve been in breast imaging going on 30 years. And I think we’re at a time when we’re ready for a new paradigm and screening. We’ve been doing mammography, we have 3D mammography, and we’ve done ultrasound, but this is breast cancer screening 2.0. Now that we’re moving into vascular-based screening—and I think women are really ready for something new—we’ve really said, “Here’s a major change in how we can screen.”

SZ: Hallelujah.

CC: And I have to say that [CMIST] couldn’t have been done without funding from BCRF. Pretty soon, six sites will be open, and we hope to hope to have about 14 sites, despite COVID delays, FDA delays, and then staffing shortages. Larry Norton has been instrumental. He has the the vision and I think, because he uses it on his patients, he sees the power. And we could not have gotten this trial off and running without BCRF and Dr. Norton and Dorraya El-Ashry from BCRF. 

SZ: We’ll be waiting with bated breath for sure. We’re very excited to see what the results look like so then contract mammography can be adopted across the country and more patients are able to access it and see better results with screening.

CC: You can have me back on when we have the results published. 

SZ: I’d love that. Thank you so much for joining us today.

BCRF investigators Drs. Lawrence Shulman and Sonya Reid share insights this World Health Day

BCRF has long recognized that our mission is global. Around the world, an estimated 2.3 million people are diagnosed with breast cancer—and devastatingly, outcomes vary drastically depending on where patients live.

This year, BCRF is supporting 34 researchers working in 14 countries, including BCRF investigators Drs. Sonya Reid and Lawrence Shulman, who joined BCRF’s Chief Scientific Officer Dr. Dorraya El-Ashry for a conversation about the global state of breast cancer. To end breast cancer, Drs. Reid and Shulman emphasize, we must close disparities in care and outcomes and work to improve cure rates both in the U.S. and abroad. BCRF investigators since 2021 and 2013, respectively, Dr. Reid’s and Dr. Shulman’s grants are supported by The Estée Lauder Companies.

Watch the full video above or read an edited version of their conversation below this World Health Day.

Dr. Dorraya El-Ashry: We are thrilled to be here today with our leading breast cancer experts who are searching for ways to improve outcomes in low-resource communities in the US and countries around the world. … I’m very happy to introduce you to Dr. Lawrence Shulman, a specialist in the treatment of patients with breast cancer. His research includes development of new cancer therapies and implementation of cancer treatment programs in low-resource settings. He has helped establish cancer programs in Rwanda, Haiti, and Botswana—places where historically the chance for a successful outcome was greatly diminished just because of delayed and later stage breast cancer diagnosis. And I’d like to introduce Dr. Sonya Reid, who’s working to help us better understand health disparities in breast cancer, young-onset breast cancer, and hereditary breast cancer. Specifically, she is investigating genomic differences that may be contributing to the racial survival disparity in breast cancer. Dr. Reid is also focused on improving healthcare delivery to underserved communities and increasing the representation of minority patients in clinical trials. She is also actively involved in breast cancer research in Jamaica, her home country as well. Dr. Schulman, you’ve been treating breast cancer patients here and around the world for over 40 years. Can you paint a picture for us of what the global state of breast cancer is today, and how it has changed?

Dr. Lawrence Shulman: I entered Harvard Medical School in 1971. And that was the year that President Nixon signed the National Cancer Act and declared his war on cancer. And that was one of the things that got me excited about this field, because we were starting to develop tools to treat our patients who had different forms of cancer. But looking back over those 50 years, what we were doing in the 1970s was pretty primitive, frankly, [and] really hard on our patients physically and otherwise. The cure rates were still very low. One of the remarkable things for me, looking back now over half a century, is how far we’ve come. And, frankly, it’s also been through the help and vision and direction of BCRF, which is funding myself and Sonya and so many breast cancer researchers not only in the US, but around the world. And so today, 50 years later, we have remarkably better treatments; we have remarkably better survival rates. And the patients who are surviving are surviving with many fewer side effects than they had all those decades ago. But as you inferred, these advances are not available uniformly around the world. In many places, they’re not available at all. When I first went to Rwanda in 2011, there wasn’t a single cancer doctor in the country, and there was no cancer treatment. And if you got cancer, you died. That’s what the patients would tell us. And it was true. As Sonya will talk about, there are also places in the US where we’re not delivering the remarkable treatments that we’ve now discovered. We still have a lot of work to do.

DEA: Dr. Reid, we know that who survives the disease varies greatly, even right here in the US. Can you tell us about the work that you’re doing to understand why these disparities exist?

Dr. Sonya Reid: When we think about disparities it’s not just overseas in low-income areas. We see that right here in our backyard. Here in Nashville, for example, close to Vanderbilt, where I work, is a county hospital. We know that sometimes patients that receive care in certain environments don’t get the quality of care that they need to receive—and that does impact their outcome. So when we think about disparities, it’s a combination of factors. We think about access to adequate care, their social determinants of health. Where you live, are you able to access insurance? An NCI-designated site that may or may not accept the insurance that you have? What are some of your comorbidities even starting along the journey before diagnosis? Were you able to get screening at an adequate center that has the optimal screening machine? We also know that there are perhaps biological differences. We know that Black patients, for example, are more likely to have triple-negative breast cancer, and even patients that have hormone-positive breast cancer, perhaps are having even more aggressive types of hormone positive breast cancer. Then we talk about genomics. It’s an understudied area when we think about disparities, because we know that not enough Black patients are receiving genetic testing, not enough Black patients are receiving genomic assays to guide their treatment. … It’s one of those things that you really have to take layer by layer.

DEA: Larry, your career in research also includes the development of new cancer therapies and implementation of cancer treatment programs in these low-resource settings. What inspired you in the first place to focus on that area?

LS: I’ve always been interested in the delivery of cancer care … and that was a lot of my focus in the first decades of my career. But in the early 1990s, I met a guy named Paul Farmer, who was actually my intern at the Brigham, and we became friends. He was devoted to bringing health care to people around the world. He was the one who asked me to develop cancer programs and Rwanda and Haiti, which I did, and through the incredible support of BCRF have been able to develop [them] over more than a decade. There’s a humanitarian mission to this, obviously. We’re a global community. … It’s part of our responsibility in a country that does have more resources to try to figure out ways to make those resources available to other people in the world. There are two other things I’d like to mention. One, Sonya’s mentioned biologic differences. And it’s a complicated landscape. For instance, I work in East Africa and we’re now starting to learn that many of the Blacks in the U.S. came from West Africa, which is where the slave trade came from. And it turns out that breast cancer is biologically different in East Africa and West Africa. We’re just starting to learn about that. That type of knowledge, benefits everybody everywhere. The other thing I would say is that the things that we learn about how to provide complex and effective cancer care in resource constrained settings, like Rwanda, are actually applicable in lots of places in the U.S. … There’s a lot of cross-learning between some of the underserved areas in the U.S. and some elsewhere in the world.

DEA: Dr. Reid, you started your career in Jamaica, and then came to the United States. Could you share with us a little bit about that experience?

SR: Lawrence set that up very nicely, because it’s the same. That really was my lesson coming to the United States. Jamaica, beautiful island, but of course [it’s] under-resourced, a developing country. I did my medical school training there and saw a lot of unfortunate circumstances where patients were just not able to even have their cancer treated because they just did not have access to treatment. Or patients coming in with maybe a fungating mass because they didn’t know what to do in between feeling that lump and getting diagnosed because there was no infrastructure for screening and diagnostics. That weighed on me heavily. You learn the optimal treatment [in a textbook] but you’re not able to offer adequate care to patients. And then fast forward, I came to the United States and did my residency training here in Nashville working at a county hospital. It blew my mind that in a developed country, I saw so many similarities: where these patients were coming in with sometimes late-stage diseases because they didn’t have insurance, or they were underinsured, mistrusted the medical system. I almost felt I could connect more with some of these patients because of my background in Jamaica. When I think about global oncology, I really think about it more as a shared learning for us to really be able to apply what we learn here, elsewhere, and vice versa.

DEA: Yes, and Larry, maybe you could talk a little bit to that about your biggest takeaways from what you been doing there in Africa?

LS: Those are important points. And a lot of the things that make cancer care hard for patients to take advantage of, in a place like Rwanda, is poverty. Women are more worried about putting their next meal on the table for their children than they are about going and getting breast cancer screening or other medical care. Transportation is a huge issue in Rwanda. But when you look at Philadelphia, which is where I am, only a few miles from here in West Philadelphia, there are the same issues. When we ask our patients from West Philadelphia what the biggest obstacle to get coming and getting care in a timely fashion, they tell us transportation, and they’re not that far away. If you’re coming to get chemotherapy, you got to have somebody to bring you. Public transportation doesn’t work for people who are getting four hours of chemotherapy and don’t feel well. And then who’s going to take care of the kids and who’s going to bring the money in and work. Poverty, transportation, prioritization, food challenges, they’re present right down the block for me. So we have several initiatives. We are using some of the same strategies that we use in Rwanda in West Philadelphia: supplying transportation, working on food insecurity, working on housing and financial toxicity. Those are all the things we’ve done a decade in Rwanda. And we’re now just starting to do in West Philadelphia.

DEA: Sonya, let’s dive a little bit deeper into the biology and specifically the genomic differences that you’re investigating. What do we know so far?

SR: When we think of genomics, there’s tumor genomics and then there’s germline that you’re born with. Germline or somatic. A lot of the differences that I’ve been focused on as it relates to hormone receptor–positive breast cancer focuses on tumor differences. Because hormone-positive breast cancer is the most common type of breast cancer, even among Black patients. Triple-negative breast cancer is over-represented among Black patients, but hormone receptor–positive breast cancer still accounts for just around 70 percent of all breast cancer in Black patients. We think about why Black patients are still dying more frequently from HR-positive breast cancer. We’re looking at that tumor biology to try to answer some of those questions. … We found was that Black patients were more likely to have basal subtype of hormone receptor–positive breast cancer, which is actually more similar to a triple negative type of biology, so these are patients are perhaps not benefiting from hormone blockers as you would expect them to benefit and maybe should be treated more with chemotherapy, like triple-negative breast cancer is. … And then when we look at germline, it’s a struggle, because patients are still not being tested for germline mutations, despite us having so many options for prevention and treatment. What we have seen is that in certain countries, the Bahamas for example, patients have more BRCA mutations. That’s not the same in Jamaica, which has even lower rates of BRCA mutations than the United States. There’s definitely a lot of admixture when we think globally about what hereditary breast cancer looks like, even among Black patients because we know there are ancestral differences. But a lot of times, we lump everyone together when we know that there are some inherent differences. My project that’s funded by BCRF and The Estée Lauder Companies is looking at a diverse cohort for differences that may be accounting for some of these disparities among hereditary breast cancer patients, both from the tumor standpoint, as well as access to treatment.

DEA: What steps do we need to take to eliminate disparities here in the U.S. and around the world?

LS: Well, I wanted to emphasize what Sonya was just saying, because I think that’s one of the answers to your question, which is: We need to understand breast cancer in different populations. The Breast Cancer Research Foundation has been wonderful and funding the work that I do in Rwanda and allowing us to do this, but we do it in a scientific manner. We keep incredibly careful records, because it’s not clear that somebody who has hormone receptor–positive breast cancer is going to respond the same to treatments in Rwanda, as they are in the U.S. Not only do we need to figure out how to help patients have access to the treatment that they need, but we need to learn more about the biology of their disease and how they respond to the therapies. We can’t go to Rwanda and assume that the same treatments that I’m using in Philadelphia for a Caucasian white woman are going to have the same effect. That knowledge helps everybody everywhere because it expands our basic understanding of breast cancer biology.

SR: I couldn’t agree more. We need diverse representation in our trials. When we’re starting trials from the get-go, we’re asking: Are they set up in a way that’s going to accommodate patients that have transportation barriers? Are those clinical trials intentional about opening at trials sites that have diverse patients? Or are we unintentionally or maybe intentionally excluding some patients? If so, then 10 years from now, we’re not going to have these answers, because we didn’t have those patients in studies.

DEA: What impact do you expect COVID-19 to have on research and patient care around the world? And what can we do to help?

SR: I worry that disparities where I am will worsen. Across the board, there have been delays in screening. Hopefully we’re catching up some. … A lot of research funding slowed down as well, not just here but globally. I saw that even in Jamaica, where things were put on hold and haven’t started to ramp back up. … We really have to double down because we were going forward, then we went back, and hopefully we can catch up and then move forward.

LS: I would add a couple of points. I agree completely with Sonya. When the pandemic started in March of 2020, the breast cancer group at Penn was meeting every Monday, Wednesday, and Friday trying to figure out how to adjust our treatments because our hospital was full of COVID patients. It made us start to question why we did a lot of the stuff we do. We analyzed every approach that we had to every aspect of breast cancer care, and that helped us think about things with a clean slate. … The other thing that happened is that we had to think about new ways to do clinical trials, because patients were very restricted in their ability to come into our major centers. …We were using telemedicine more to communicate not only with our regular patients, but with our clinical trials patients. We were thinking about ways to have patients participate in clinical trials without the burden that we often put on them with extra visits. That has the potential to reduce some disparities in clinical trial enrollment. At Penn, we’re proud of the fact that we have higher enrollment of Blacks in our clinical trials than the percentage of Blacks in our community. That hasn’t happened by accident. We’ve tried to keep some of the things that we put in place during COVID to make clinical trials more accessible and more manageable for patients. COVID has been absolutely awful, but it made us do things in ways that were unconventional.

DEA: Let’s finish by looking ahead to the future of research. What are you most excited about?

SR: I’m most excited about discovery. Breast cancer is such a fascinating field. … It’s truly fascinating how many drugs we have; how we have discovered HER2-low. [The field] keeps evolving. What I’m excited about is not actually another drug; what I’m excited about is us figuring out how to utilize these thousands of drugs we now have to make sure that we get them to all the patients that need them.

LS: I would echo that. It’s a fascinating time in the last few years have been unbelievable [new] understanding of the biology of breast cancer, and using that to develop these new drugs and understand who they’re going to work for and who they’re not going to work for. It’s really been a paradigm shift. I’m old enough to remember what it used to be like, and things are happening very, very quickly. … The advances that we’re making now are huge, but it’s just such a strong link. And this is what BCRF does. There’s this link between what happens in the laboratory, and what gets translated into new drugs, new paradigms or treatment, and as Sonya was saying, understanding different subsets of breast cancer better than we’ve ever understood them before. Making all of those linkages. And then finally, as we’ve been talking about, [we’re] figuring out how to make sure we get those new advances and new treatments, to everybody equally, both in the U.S. and elsewhere in the world.

DEA: The progress over the last 30 years has just been tremendous. And it is right now at such a rapid pace and progressing so quickly. But our urgent goal needs to be—and this is part of what BCRF does—making sure that everybody, every patient, no matter where they are or from where they come from, that they get benefits equally.

LS: BCRF worked hard, as we’ve all worked with you, to inch up the cure rate. When we do that, we save lives. And as Sonya said earlier, and as you’ve said, the cure rates now are so much better than they were one decade ago, two decades ago, three decades ago. But if you wanted to turn around and save literally 100 times the number of lives from breast cancer, we need to make what we now know available across the globe. Because right now, every year, millions of women across the globe are dying from breast cancer. And if they lived in Philadelphia or Nashville, they would have survived.

SR: I truly want to emphasize that. A lot of resources go into the next big drug. And I’m so excited about drug discovery as well. But we know that patients, despite getting adequate care, still die from breast cancer. And it’s still a frustrating experience when you’re treating patients and you run out of options. But when we think about everything we have now, if we could get it to everyone, as Larry said, can you imagine what this conversation would look like?

Find more video interviews with BCRF investigators from our Behind the Breakthroughs series here.

Like so many medical challenges, breast cancer research reveals a long list of questions. What elements of our environment are carcinogenic? What role do factors like age, diet, and genetics play? And because cancer is biological in nature, many of us tend to think about the individual and their body as an obvious point of focus. What about, though, the larger, societal picture?

That’s what Dr. Scarlett Gomez and the field of social epidemiology are working to uncover. Dr. Gomez and her team have taken data showing that breast cancer risk in Asian Americans in the San Francisco Bay Area is rapidly rising to uncover structural and social determinants that influence that risk. And while Dr. Gomez’s work focuses on Asian American and Pacific Islander populations, that group includes people from 30 to 40 countries—each with different variables and risk factors to consider.

Dr. Gomez is professor and vice chair for faculty development in the Department of Epidemiology and Biostatistics and co-leader of the Cancer Control Program of the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco. A BCRF investigator since 2022, Dr. Gomez’s grant is supported by The Estée Lauder Companies’ Travel Retail Award.

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Read the transcript below: 

Chris Riback: Dr. Gomez, thanks for joining me. I really appreciate your time.

Dr. Scarlett Gomez: Hi Chris. Thanks for the opportunity.

Chris Riback: So I think to understand this conversation and your, we should start at the core, or at least what I believe is the core of what you do for a living. What is epidemiology?

Dr. Scarlett Gomez: The million-dollar question. I would say if you had asked me that maybe 20 years ago or even 10 years ago, most people probably wouldn’t know. But I think with the very obvious global health issue we’ve been dealing with over the past three or so years, I think the field of epidemiology has become much more apparent to the general public. So broadly speaking, epidemiology refers to the study of disease, causes of disease, and its distribution within the population. I am classically trained as an epidemiologist, specifically cancer and other chronic diseases. And I’d love to talk to you in more detail about why cancer surveillance is actually such a unique activity. It’s the only chronic disease for which we collect population level information from everybody who’s been diagnosed with cancer. So we conduct studies to [look at] how cancer occurs within population groups with a strong focus on disparities within particular groups. And we also conduct studies to try to identify risk factors for higher rates in certain groups as well as factors that contribute to worse prognosis.

Chris Riback: So I was going to ask you about that. If your focus always was cancer, and I guess it sounds like it was, and so that makes me wonder why, what attracted you to that area of the discipline?

Dr. Scarlett Gomez: Lots of reasons really. I think like many of us who have been focused on this, on cancer and trying to address this problem of cancer in our society, we come from a place with having had personal experience with cancer. So I think, again, like many, it is a fairly common problem. So I have seen family members, friends who have been diagnosed with the disease, who have struggled with the disease. So from that, a personal interest in trying to understand the structural and social drivers of why cancer may occur more in some populations than others. I have always been drawn to the field of what’s called social epidemiology. Despite that I didn’t know that there was such a field of social epidemiology when I first learned about the idea that societal factors can impact upon disease, and understanding what those associations and patterns may be can help us to design potentially more effective interventions that alleviate disparities in cancer in different populations.

I started out my research career working in a very different field within a pharmaceutical company doing bioanalysis and metabolism research. How drugs are metabolized as [they] move through the body, and it just didn’t feel particularly rewarding because I felt that there was something bigger at the population level that I could be doing. And this was actually before I even knew about the term epidemiology, and that it was actually a field of study. So I took a break and I studied, I embarked on a master’s program in public health where I focused on epidemiology.

And there was at the opportunity to train under Dr. David Schottenfeld, who literally wrote the book on cancer epidemiology. He and Dr. Joe Fraumeni authored. I think they’re now on the sixth edition of the book called Cancer Epidemiology. And that really started cementing my interests and bringing together my personal interest and personal desires to want to understand in particular what we can really do in a meaningful way to address the disparate burden of disease in different populations.

Following that exposure, I had the opportunity to do an internship at a nonprofit organization called at the time Northern California Cancer Center, which then changed its name to Cancer Prevention Institute of California. And I ended up working there for the next 25 years until I moved to my current role here at UCSF about six years ago.

Chris Riback: What an incredible and fortunate thing to have an interest and skills combined and then to be able to make a transition like that. So many of us end up in one role and sometimes feel, and I’m not just talking medicine here, obviously any role, any profession, and one can start to feel like, “Well, I chose the wrong path finding a way out becomes difficult.” I strongly believe one makes one’s own luck, so I don’t characterize it as lucky. I’m sure it was your own initiative, but what a fortunate and excellent thing to get to make a shift like that.

Dr. Scarlett Gomez: It absolutely was luck and in fact, it was really one individual at this pharmaceutical company that I had worked at. He was my informal mentor. We would be pipetting side by side along our lab bench and he would just tell me stories about the six years that he worked in the Peace Corps in rural mountainous Nepal and all the public health and hygiene issues that the populations there had to deal with. And that was when I thought, “Maybe there is a field of study that deals with these issues and its impact on health.” And I think the other way that I was able to marry those interests was in my undergraduate training, even though I was on this straight and narrow path.

Chris Riback: Molecular and cell biology, if I recall, is that right?

Dr. Scarlett Gomez: Molecular and cell biology, because I thought that’s what you needed to major in if you wanted to eventually go to medical school. But I also took a lot of classes in anthropology and social sciences and behavioral health, and I think that actually has been a really good critical foundation for the work that I do today.

Chris Riback: Well, shout out to your former lab partner or pipetting partner.

Dr. Scarlett Gomez: Larry Bowen was his name, I still remember.

Chris Riback: Shout out to Larry. Dr. Gomez, let’s talk about your current research. How and when did you learn that breast cancer risk in Asian Americans in the San Francisco Bay area is rapidly increasing?

Dr. Scarlett Gomez: Yes. So it’s essentially something that our group has been keeping an eye on for quite some time. So, this internship that I had the opportunity to do when I was working on my master’s degree in public health was at this organization that actually ran the cancer registry for the San Francisco Bay Area. Cancer, as many people may know, is a state-mandated activity. Every state, in addition to every Canadian province, has some law that mandates its collection. So if you’re a healthcare clinician provider who’s recently diagnosed or treated somebody with cancer, you are required by your state’s law to report that to your cancer registry. So I was involved and gained exposure to the cancer registry in the Greater Bay area. Much of the funding for our registry actually comes from the NCI (National Cancer Institute) as well as the State Department of Public Health.

So you can imagine what a rich resource of data that is because it is effectively every single person diagnosed with cancer in a defined attachment area. And that is what allows us to track what’s going on in cancer occurrence by different population groups. It’s also the data we use for what we call cancer cluster investigations. So the CDC also invests money into these states and regional cancer registries. So every year we undertake a thorough investigation, a deep dive into the data in our registry to look and see for whom is what’s going on with cancer in our different regions, in our different geographies and our different population groups defined by sex, race, ethnicity, age, et cetera.

And it’s through these kinds of routine surveillance activities that we started to see an interesting shift in breast cancer patterns by race and ethnicity groups in our area such that despite that breast cancer rates have been generally going down over the past about 10 or so years across almost all of our racial ethnic groups. An exception to this would be among African American women where we have been seeing a slight increase. Among Asian American women that’s actually has been rapidly increasing. So, we’re seeing something closer to at least a 10 percent increase in the incidence of breast cancer per year.

Chris Riback: Per year?

Dr. Scarlett Gomez: Yes, per year, about 10 percent increase in breast cancer.

Chris Riback: When did the curve start to shift?

Dr. Scarlett Gomez: I would say it probably started in the 2000s.

Chris Riback: 10 percent a year for a good 15-ish, 20-ish years?

Dr. Scarlett Gomez: Yes.

Chris Riback: That’s a big deal.

Dr. Scarlett Gomez: It is a big deal. I feel that this trend does not tend to get as much attention in large part because we don’t commonly report on cancer rates among Asian American populations are often combined collectively as a group, Asian American, Native Hawaiian, Pacific Islander populations, or AAPIs. When in fact these, if you consider the AAPI or API population, that represents people from 30 to 40 different countries, over 100 different languages. [It’s] highly, highly diverse. And when we start to disaggregate the data, we actually see very divergent patterns. So we’ve done a lot of work just looking within our cancer registry data to see which Asian American, Native Hawaiian, Pacific Islander groups are seeing increasing rates of breast cancer. We actually noted that it’s rapidly increasing nearly all with the interesting exception of Japanese Americans who have been here much longer than other Asian American groups.

And the other interesting finding that has been starting to emerge is that when we look at international data, so breast cancer rates in Asian countries, we’re seeing similar increases. So, it’s really not unique to Asian Americans here in the US—it’s really happening worldwide. The other interesting pattern that we’ve noted is that whereas we are used to the traditional what’s called the migrant paradigm of Asians who come from Asia, their risk is low because risk tends to be lower in Asian countries. And as they start to adopt more westernized health behaviors that are now correlated with increased breast cancer risk, their risk start starts to go up. So we see increasing risk with subsequent generations of Asian Americans.

One recent study that we did showed that, that was reverse in the Bay Area. So in fact in this particular study, we saw higher risk of breast cancer among foreign-born Asian Americans relative to their US-born counterparts. And this was not explained by the known risk factors for breast cancer. When we thought about that pattern, firstly we thought there must be something wrong with our study. We did it wrong. But when you consider the international data, the fact that breast cancer rates have been increasing really rapidly in certain Asian countries to the point that it’s projected that breast cancer in Asia will likely surpass become among the highest in the world.

So the studies in Asia have actually documented and shown that given the rapidly increasing rates of breast cancer that they’ve been seeing, these are studies that have been done with data from Taiwan, Hong Kong, Korea, Singapore, parts of China, that soon we will actually see the highest breast cancer rates among Asian women in Asia. So when we consider that vis-a-vis what we saw with this flip of breast cancer risk comparing foreign-born to U.S. foreign women in the San Francisco Bay Area, it made sense because when we consider who’s been immigrating to the Bay Area over the past 10, 20 years, they have tended to be professionals, particularly those in the tech sector, those in the health sector.

And also when you think about the high costs of living in the San Francisco Bay area, who can really afford to live here and settle here, and in fact some demographic data have documented that when you look at the most recent waves of immigrants, they have tended to have much higher levels of education than prior waves of immigrants. So that all plays into what we’re seeing in terms of rates of breast cancer and these highly dynamic populations like migrant populations in the U.S. So, we think that to the extent that we still have much to learn about what causes breast cancer, both genetically and from a risk factor standpoint, focusing studies on these highly dynamic heterogeneous populations could potentially teach us something about what some of these risk factors might be.

Chris Riback: So you might have just answered what I was going to ask, which is what are you proposing to study? What’s your hypothesis and how will you proceed?

Dr. Scarlett Gomez: Yes. We’re super excited because I think this support from the Breast Cancer Research Foundation, it really gives us the opportunity to do something to focus on this area that we, I think, may not have been able to focus on with more traditional streams of funding. So we are proposing and we are conducting what’s called a case-control study of breast cancer. This means that we are collecting information from women recently diagnosed with breast cancer, specifically Asian American women from a defined catchment area. Here, we’re starting with the Bay Area in addition to we’re expanding to LA, Southern California, and we will also recruit and collect information from matched controls—that is, Asian American women from the same regions, but without prior diagnosis of breast cancer. And by collecting information regarding their past exposures in addition to samples that will allow us to look at some genetic and molecular factors, then we can compare and see which factors are we seeing higher levels of among the cases compared to the controls.

Importantly, the way that we’re doing this study is that we’re recruiting through these cancer registries. So our sampling base is then everybody who’s been diagnosed with breast cancer within a particular defined geographic area. So that from an epidemiologic study design standpoint minimizes bias where asked if you were to recruit, for example, from one healthcare institution, patients from that given healthcare institution may be different and not represent the overall population. We hope that this will be, once women are recruited into this study, they will remain engaged and hopefully provide an opportunity for us to go back to them over time to collect additional information as the study involves and as perhaps emerging hypotheses might come out. But initially, we’re really interested in exploring hypotheses related to stress. Even just this morning, I was talking to a colleague again who had a personal struggle with breast cancer and she herself is a cancer epidemiologist, and she said, “I’m convinced that stress cause my breast cancer.”

And that’s probably the most common thing we hear from patients when we have an opportunity to talk with patients, but we don’t have good evidence. I mean, it’s been scattered and mixed in terms of what we know about stress and its impact on breast cancer risk. And to the extent that some of our Asian American communities have faced historically tremendous trauma relating to their migration experience, relating to the reasons for immigration, relating to settling into a completely new life in a different country for which they don’t speak the language, and acclimating, in addition to recent experiences with discrimination and structural racism as a result of the COVID pandemic. I think that has been understudied area, but potentially could give us some insights into the role of stress and stressors, coping resiliency as it potentially relates to breast cancer risk.

Chris Riback: And this obviously is, well, and I would assume this is out of scope, but a question that comes to my mind would be comparison to other immigrant groups, but maybe you answered that in the first place by saying, well, it’s the Asian American data that has grown so rapidly, 10 percent a year for the last 15, 20 years that’s why that’s a group of interest. We’re not seeing that with other groups. Am I both asking and answering my own question?

Dr. Scarlett Gomez: Well, I think the increase is a motivation for us to be focusing on this particular population because it’s something that’s happening, has been happening, is continuing to happen, and we need to understand why. At the same time, from a data standpoint, when you see such dynamic changes like that, it provides statistical variability for you to be able to be more likely to find patterns and associations. So it’s really a unique window of opportunity for us to potentially discover something new about breast cancer and its causes. But I think that some of the exposures that we’re focusing on are really quite unique to the Asian American diaspora.

And in fact, the challenge we’re having is how do we come up with a way to ask a certain question about a life experience that really is applicable across the diverse Asian American population. But I think the approach we need to be taking is recognizing the unique life experiences in our diverse communities and to design studies that tap into and capture those unique experiences.

Chris Riback: So what’s next? Is it literally having those conversations, starting that research and gathering the additional information?

Dr. Scarlett Gomez: Absolutely. Yes. We are starting recruitment. We have a survey that’s been finalized. We’re in the process of engaging, we have a vast network of community organizations and collaborators, and we’re really interested in hearing from women in the communities about what they think about breast cancer. We also, through some of our experiences with, we have a whole other portfolio on lung cancer among Asian American women who’ve never smoked and have learned that through the community engagement process, just getting the word out there has really allowed us to increase awareness about the issue among this community. So we’re hoping that this will provide an opportunity to do that as well.

Breast cancer remains really a stigma in our communities, and it’s not something that the community members talk about and because of that, so they’re not often aware of their risk of breast cancer. And that plays into some of our groups actually being diagnosed at later stages of disease because they are not up to date with regular screenings, do not follow up on concerning symptoms. So we hope to at least get the word out and to increase awareness about breast cancer among Asian American communities.

Chris Riback: Yes. I have heard about that problem with other groups and in other countries, not just in the U.S. but in different areas of the U.S. and in other countries. And what a wonderful initial benefit that you’re generating just by taking on the work, if you are almost as an externality, creating some initial awareness and getting people because, yes, the delayed diagnosis that can occur for a range of reasons, lack of access, cultural reasons, there are all sorts of reasons. Just to close out, I know you mentioned very briefly, but your BCRF grant is currently supported by The Estée Lauder Companies’ Travel Retail Award. What role would you characterize that BCRF has played in your research?

Dr. Scarlett Gomez: Yes. I think just to expand a bit about the comment I made earlier about this funding just being so unusual because I think this study that we’ve designed is not really something that could traditionally be funded through a grant, that one might write to, for example, the National Institutes of Health, for it to be funded. So I think just in itself, the fact that BCRF is willing to fund this, we think important work that I’ve been wanting to do for a long time and that many in our communities have been wanting to do for a long time is the major contribution.

I also had the opportunity back in October this past year at the BCRF Symposium and Luncheon to sit down and talk with some of the members from The Estée Lauder Companies’ [Travel Retail channel], which is supporting funding this research in addition to other [BCRF research projects], and hearing from them that they raised funds among their employees within [Travel Retail] and [elected to support] research on Asian American populations. So that actually was very meaningful and meant a lot to me. So, I feel especially grateful, but also responsible for the stewardship of these funds and making sure that we generate findings and data that are meaningful and impactful.

Chris Riback: I was going to say, I’m sure grateful, but also motivated. There’s another level of motivation. Dr. Gomez, thank you. Thank you for your time and thank you for the work that you do.

Dr. Scarlett Gomez: Thank you, Chris.

The San Antonio Breast Cancer Symposium (SABCS) is the world’s largest international conference devoted to breast cancer research. Held annually, it provides the optimal venue to recognize researchers for their outstanding contributions to the field. This year, three BCRF investigators received the meeting’s top honors.

Dr. Jack Cuzick received the William L. McGuire Memorial Lecture Award for his contributions to the prevention and treatment of early-stage breast cancer, commitment to collaboration, and leadership in breast cancer research. A subset of Dr. Cuzick’s accomplishments, supported in part through BCRF funding since 2011, include identifying the role of tamoxifen in the prevention of a second breast cancer after initial diagnosis, delineating the role of breast density in increasing breast cancer risk, and developing the pivotal Tyrer-Cuzick model, a breast cancer risk assessment tool that clinicians still use daily to calculate their patients’ breast cancer risk. 

In his lecture, Dr. Cuzick presented major milestones in breast cancer prevention as well as the results from his key clinical trials including the International Breast Cancer Intervention Study (IBIS-1), and the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial. His enthusiasm for research was evident as he highlighted the importance of continued investigation in this exciting and promising field.

The 16^th AACR Distinguished Lectureship in Breast Cancer Research was awarded to Dr. Kornelia Polyak for her pioneering research on the role of the tumor microenvironment and intra-tumor heterogeneity in tumor evolution. Her investigations have spearheaded major advances in our understanding of how normal cells transform into cancer cells. In addition, she has demonstrated that the immune microenvironment in ductal carcinoma in situ (DCIS) becomes suppressed during the progression to invasive cancer. In her lecture, Dr. Polyak described how years of research—supported by BCRF since 2008—have led her to conclude that cancer is a systemic disease, and that an individual’s pre-existing immunity can influence breast cancer progression.

Dr. Polyak accepted the award on behalf of the talented scientists who have worked alongside her in the laboratory. She graciously acknowledged her many collaborators who, over the course of her 25-year career, have been valued partners devoted to advancing our knowledge of breast cancer tumor biology.

Dr. Alana Welm, a BCRF investigator since 2022, was honored with the AACR Outstanding Investigator Award for Breast Cancer Research for her impactful research dedicated to understanding the fundamental biology of metastatic breast cancer and for translating these findings into new and life-changing therapeutic approaches. She has been a leader in the development of innovative human breast cancer models called patient-derived xenografts (PDXs) that accurately reflect the behavior of metastatic cancer and response to treatment. PDX models are highly regarded as the gold standard for recapitulating breast cancer in the lab. Indeed, several clinical trials have been developed based on preclinical studies that leveraged their unique characteristics, demonstrating their utility.

In her lecture, Dr. Welm highlighted the importance of PDX models, namely in ensuring the growing number of approved therapies are appropriately matched to the individual patient to achieve greater efficacy and less toxicity. She envisions that PDX models will be a vital tool for the development of novel combination strategies to treat metastatic disease—strategies that can target not just the tumor but the tumor microenvironment as well.

A BCRF investigator since 2012, Dr. Charles Swanton was invited to give a career-spanning plenary lecture to a captivated audience on the evolution of breast cancer, immune evasion, and metastasis. In his lecture, he presented a culmination of his findings highlighting the importance of chromosomal instability in cancer progression. 

In addition to the honors presented at the SABCS, BCRF investigators Drs. Olufunmilayo Olopade and Daniel Hayes were awarded the Susan G. Komen Brinker Awards at an awards event coinciding with the conference in San Antonio. 

BCRF celebrates these investigators for their meaningful contributions that have accelerated the progress of research in their respective fields. Important to recognize, the work of these researchers has provided the foundational building blocks for advances that lead to better outcomes for patients. BCRF is proud to congratulate these investigators on their honors. 

Read more from SABCS:

• Key Takeaways from SABCS 2023
• Clinical Trial Updates from SABCS 2023: Early-Stage Breast Cancer
• Clinical Trial Updates from SABCS 2023: Advanced and Metastatic Breast Cancer