Meeting Unmet Needs in Breast Cancer
Breast cancer is the second most common cancer among women in the United States, so it is critical for women to start getting regular screenings at their healthcare provider's recommendation. Screening reduces breast cancer deaths by 26% by catching the disease early.
For those diagnosed with advanced breast cancer, treatment has become more targeted and effective in the past several years and has helped improve survival rates. However, even with new, effective treatments, patients with breast cancer still grapple with quality-of-life issues, mortality inequities persist, with Black women having a higher mortality rate, and there are breast cancer subtypes that lack effective treatments.
We spoke with Stanford Cancer Institute (SCI) leaders to learn about advances in breast cancer treatment, issues affecting survivors, and bridging the racial inequities gap.
The Stanford Breast Cancer Program
SCI member Melinda Telli, MD, leads the Stanford Breast Cancer Program, which is housed within the Stanford Cancer Institute. She explains that understanding and treating breast cancer requires a multidisciplinary approach, so the program brings together more than 50 Stanford faculty members who work in breast cancer. These members come from the five core clinical groups that work together to treat breast cancer (medical oncology, surgical oncology, radiation oncology, breast imaging, and breast pathology), and members also include research faculty from the basic, translational, and population sciences.
The program’s mission is to advance and coordinate innovative research that makes a difference in the lives of breast cancer patients, train the next generation of researchers and clinicians, and deliver outstanding clinical care that improves the health and survivorship of those affected by breast cancer.
The program’s work focuses on areas of unmet need, including metastatic and hereditary breast cancer. Telli mentions that Stanford had one of the first cancer genetics clinics on the West Coast, so they see many patients and families with an inherited risk, and there’s an institutional interest in developing therapeutics for patients with hereditary breast cancer.
A notable area of the program is leveraging Stanford’s advances in detecting circulating tumor DNA (ct-DNA), the presence of which indicates that the patient is at higher risk of recurrence, and understanding how to use this tool in the clinic to make better treatment decisions. Telli explains that it could reduce overtreatment in low-risk patients and identify patients who need treatment intensification if they have an incomplete response after receiving the standard of care. Stanford is currently running clinical trials to demonstrate the clinical utility of these emerging ctDNA tests.
Cancer genomics is another important area, with SCI member Christina Curtis, PhD, having defined the integrative subtypes of breast cancer, including a group of breast cancers that are hormone receptor-positive and have a high risk of late recurrence. Currently, Curtis is partnering with Jennifer Caswell-Jin, MD, on clinical trials to move the science into the clinic to examine how doctors can best treat patients with these specific high-risk subtypes.
Teilli says that earlier detection is a priority and discusses how SCI members Bruce Daniel, MD, and Brian Hargreaves, PhD, have advanced an imaging method called a non-contrast-enhanced magnetic resonance imaging (MRI) for high-risk patients where high-quality images of the breast are developed without the need for contrast injection to create high-resolution images. Additionally, SCI member Robert West, MD, PhD, is studying the genetic events that cause ductal carcinoma in situ (DCIS), a precursor to invasive ductal cancer, to progress to invasive cancer. Telli explains there is a lot of opportunity around prevention with this work and determining what lesions require treatment and which do not.
Developing targeted treatments
Telli says that the last decade of breast cancer research has centered on appreciating the genomic heterogeneity of the disease, with precision oncology, the right drug(s) for the right patient at the right time, taking center stage because it maximizes efficiency and minimizes toxicity and overtreatment.
“We have seen successes in precision oncology. There are now approved therapies for patients with specific genetic alterations in their tumors, and there have been impactful advances for patients with hereditary cancer.”
She cites the development of PARP inhibitors, which is the first class of therapeutics approved for hereditary breast cancer resulting from inherited BRCA1 and BRCA2 mutations. Telli describes the therapeutic success seen in targeting PIK3CA, a gene that has been historically hard to target and that is altered in approximately 40% of breast cancers. A drug has been approved that shows benefit for patients with this gene mutation in their tumor, and further drug discovery efforts are underway to develop drugs that have a better toxicity profile to target this gene.
She also remarks that the past few years have seen an explosion in antibody-drug conjugates (ADCs) for breast cancer, which are antibodies used to carry a drug directly to the tumor site. Telli says that they’re seeing phenomenal results in HER2-positive breast cancer. While the data currently supports use primarily in metastatic tumors, they have activity across the main cancer subtypes, which is a big advance. Clinical trials with several of the new ADCs in high-risk localized breast cancer are ongoing.
There’s also been interest in bringing cellular therapies, such as chimeric antigen receptor (CAR) T-cell therapy used in liquid tumors such as leukemia and lymphoma, to see if it can produce durable remissions in solid tumor cancer patients.
These advances make Telli optimistic for future therapies.
“What we hope for the future is the opportunity to offer patients treatments to cure disease even when their disease is advanced. With the recent advances, I can tell in my practice that patients are doing better. Fewer patients are recurring, and more patients have complete responses to their therapy. It’s been great to see.”
Addressing survivorship issues
Breast cancer survivors include patients and those who have completed treatment, which accounts for 3.8 million in the U.S. SCI member Lidia Schapira, MD, director of Stanford’s cancer survivorship program After Cancer, says that many things could happen between diagnosis and the end of treatment that could have a lasting impact on a survivor’s physical, emotional, and financial health.
Schapira says that a survivor’s quality of life depends a lot on the treatment someone receives, their experience, and if they have long-term side effects from treatment. Some people are at risk for late effects of treatment, like cardiovascular disease, that won’t occur until years after treatment has concluded. Five to ten years of adjuvant hormonal therapy is recommended for women with hormonally sensitive breast cancer, many of whom have intensified symptoms of natural menopause. Additionally, the psychosocial impact may impact quality of life, as survivors may feel distressed, anxious, and worry that the disease may recur. Cancer treatment can also interrupt the survivors’ careers and cause relationship shifts. According to her research with young women, Schapiro says that age can impact quality of life.
“Treatment can have a huge impact for many women diagnosed during the years of their life associated with childbearing, parenting, and building their careers, especially as a lot of treatment impacts reproductive health.”
For survivorship care, the first step is to assess and identify any problems and connect survivors to the right specialists, such as reproductive experts and physical therapists, who are needed if mobility issues are present after surgery. After Care has this umbrella of supportive services that includes everything from psycho-oncology, nutrition, physical therapy, and sexual and reproductive health, such as the Stanford Fertility and Reproductive Medicine Center, to women who face a long period of hormonal therapy and wish to have a biological child. She also explains that interventions exist to teach survivors to support their own needs better.
“The most important thing is that there are a variety of ways that the disease and treatment can impact a survivor’s future health, such as body image, relationships, pain, sexual health, and fear of reoccurrence. We have good evidence-based interventions to support survivors in these areas, so we should assess and refer them to the right specialists.”
Reducing health inequities through research
While there is no longer a significant disparity between Black and white women in breast cancer diagnosis, Black women are five times more likely to die from breast cancer. Dinah Trevil, MPA, executive director of the SCI Office of Cancer Health Equity, says this inequity is because Black women are more likely to be diagnosed at a later stage, which she attributes to a lack of or inconsistent screening due to being underinsured or uninsured. She also notes that Black women with a family or personal history of breast cancer could benefit from starting screening earlier.
Trevil points out that treatment disparities exist that could lead to increased mortality. Some treatments aren’t tailored to Black women, and Black women are not offered the range of treatment options compared to white women, such as chemotherapy alone or chemotherapy and radiation therapy together.
Black women are also at risk for more aggressive forms of breast cancer. Telli says that the Stanford Breast Cancer Program has a big focus area on triple-negative breast cancer, as it has the poorest outcomes and occurs in 15% of breast cancer patients but is overrepresented in young women, Black women, and to a degree in Hispanic women. Triple-negative breast cancer is an aggressive subtype that lacks the expression of the three markers used to target breast cancer therapy, and it tends to be a very high-grade tumor. An important finding is that women from Africa also run a higher risk of being diagnosed with triple-negative breast cancer.
“People are interested in the epidemiology and risk factors behind this disease. The biology of breast cancer clearly varies by race and ethnicity and likely contributes to the disparity in outcomes by race, but that’s only part of the story. It’s certainly not the whole story.”
Telli explains that historically there was no targeted therapy for triple-negative breast cancer because the disease didn’t have receptors that could be targeted with therapies, so providers could only use chemotherapy. However, the large global focus on the disease has led to more effective therapies, such as pembrolizumab, one of the PD-1 immunotherapy antibodies. Initially, pembrolizumab was approved in combination with chemotherapy to treat advanced triple-negative breast cancer and was approved two years ago to treat high-risk localized triple-negative breast cancer.
“We’ve seen a lot of new therapies approved for metastatic triple-negative breast cancer, and we’re starting to see these drugs move into the high-risk, early-stage setting.”
The program is working on finding effective treatments for triple-negative breast cancer. Telli notes that many of the program’s ct-DNA clinical trials are in triple-negative breast cancer patients. She points to the work of Stanford breast surgeon Candice Thompson, MD, and medical oncologist Fauzia Riaz, MD, on using ct-DNA to de-escalate treatment in patients who have high-risk tumors, like triple-negative breast cancer, by seeing if their ct-DNA is negative or positive after surgery and then using that to assign chemotherapy.
“It’s clear from this work that Black women are benefiting less from therapeutic advances, so they’re trying to probe these issues more deeply to see if it’s related to a geographic variation of care, access to treatments, living in a rural or urban zip code, and looking at socioeconomic status at the geographic level.”
SCI fellow Julia Ransohoff, MD, used tumor samples from the Breast Cancer Family Registry, run by SCI member Esther John, PhD, that oversampled patients from underrepresented minority groups to check for tumor-infiltrating lymphocytes (TILs), immune cells found in and around a tumor that indicate a favorable prognosis if present. Ransohoff found that there was no difference in the baseline level of TILs by race or ethnicity. However, the long-term survival data showed that the presence of TILs only conferred a benefit if the patient was white or Asian, and there was no benefit if the patient was Black or Hispanic.
“There’s a big question as to why. Are these TILs different in their activation status from what we’re seeing in white and Asian women? If they are functionally different, then what’s driving that?”
Finally, a group in neurosurgery led by SCI member Melanie Hayden Gephart, MD, is focused on breast cancer-related brain metastasis. They’ve identified LAT1, an overexpressed transporter in these tumors. They’re currently enrolling patients with triple-negative and other aggressive breast cancer subtypes in a clinical trial of a novel drug that mimics a LAT1 substrate. This allows the drug to pass through the blood-brain barrier and selectively target rapidly dividing cancer cells.
Developing a community presence to improve health inequities
Trevil says that effective community efforts to reduce the disparity should focus on increasing awareness, dispelling myths that mammograms cause harmful effects, and improving education and awareness about clinical trials.
“It’s a lot more impactful to create and disseminate culturally relevant materials about breast cancer so that Black women in the community can see resources and tools that they can connect to and that are relatable.”
She says the SCI is focused on building its foundation for a stronger community presence. To identify community partners, the SCI Community Advisory Board (CAB) members are crucial to connecting the SCI with community-based organizations that can be potential partners. Community partners identify lay health navigators to reach people in the community. As an example of the SCI’s community efforts, SCI member Lisa Goldman Rosas, PhD, uses lay health navigators to educate Black women about opportunities to participate in clinical trials and help them navigate the process through the group Black Ladies Advocating for Cancer Care (BLACC).
There is a collaboration with Stanford Healthcare regarding community events by supporting community partners and their breast cancer programs and initiatives. The SCI also goes out in the community, including the annual SCI Breast Cancer and African American (BCAA) conference, to connect Bay Area Black women with culturally relevant resources and information.
Diversity in clinical trials is another essential area to improve treatment for Black women, and increasing representation is a focus area for the SCI. Trevil says that Black women aren’t offered the opportunity to participate in clinical trials as much and that participation could lead to more effective treatments for breast cancer in Black women. To reach more patients in the communities we serve and expand access to clinical trials, the SCI has set up a satellite campus in the South Bay and will be adding oncologists to its East Bay satellite campus next year. Trevil says that the SCI is working closely and connecting with network sites in the East Bay, participating in community events when the opportunity arises, building a community presence, and increasing visibility.
Telli explains that the campuses will make accessing clinical trials easier for patients since the trials will be present in the neighborhood where patients receive care.
“We have a responsibility to serve the 6.5 million people across the nine counties in the diverse communities we serve. In step with all this research, we’re paying attention to how to make it relevant and accessible for patients.”
October 2023 by Katie Shumake