For most women diagnosed with breast cancer, there’s plenty of good news to report. Steady declines in the death rate for this type of cancer have furthered overall progress in cancer mortality in the United States. Notably, about nine in 10 women with breast cancer survive for at least five years after diagnosis.

But breast cancer can also be tenacious. For 6% of patients diagnosed with the disease, the cancer has already spread to distant parts of the body when it is found. Of that group, only 32% survive to the five-year mark. This statistic makes breast cancer the second deadliest (after lung cancer) for women in this country. Breast cancer can also sometimes recur in distant parts of the body many years after an apparent cure.

“Most people think, ‘It’s breast cancer, and it’s so common; just get treatment and you’re done,’” said Sandy Cassanelli, a Yale patient who has lived with metastatic breast cancer since 2015. “But Stage I could come back 10 years later, and once it spreads, you’re in treatment forever. People don’t realize how deadly breast cancer is and how much research is really needed.”

While significant advances have been made in breast cancer treatment, Eric P. Winer, MD, director of the Yale Cancer Center (YCC), president and physician-in-chief of Smilow Cancer Hospital, and Alfred Gilman Professor of Medicine and Pharmacology, envisions an even brighter future. “I really hope we get to the point where the vast majority of women with breast cancer can say that even if they have to live with it on an ongoing basis, it’s unlikely to ever take their life because we’ll have enough treatments to keep it at bay. And the majority of people who are diagnosed with anything other than the most advanced disease will actually be able to be effectively cured. We are so close!”

To accomplish this, Winer is leveraging his more than 30-year career as a breast cancer researcher and clinician, which included leading a breast cancer program at Dana-Farber Cancer Institute for over two decades, to help build on the significant strengths of the YCC Breast Cancer Center and advance it to become a world-class program.

In the meantime, a great deal remains to be understood. From bench scientists to pathologists to trial doctors to epidemiologists, Yale breast cancer researchers are sharing research tactics and findings, listening to patients, and working toward a future in which breast cancer is no longer a killer. Here are a few of the many questions being studied—and a look at the promising work under way.

Who is at increased risk of breast cancer?

It was over a decade ago that the actress Angelina Jolie announced that she had undergone a preventive double mastectomy after learning she had a mutation in the BRCA1 gene that put her at high risk of breast cancer. Genetic sequencing of genes like BRCA1 or BRCA2 often uncovers mutations known to increase the risk of breast cancer in women and men, as well as ovarian cancer and—to a lesser extent—such other malignancies as prostate and pancreatic cancer, as well as melanoma.

Thousands of mutations have been identified in genes associated with breast cancer. These include not only BRCA1 and BRCA2, but others such as PALB2 and ATM. These mutations can inform surgical decision making, cancer risk-reduction strategies, targeted breast cancer treatment (particularly for patients with BRCA1 or BRCA2 mutations), and hereditary cancer testing in families, explained Veda N. Giri, MD, director of the Cancer Genetics and Prevention Program and professor of internal medicine (medical oncology).

However, genetic testing can also report many variants of uncertain significance (VUSs). These are genetic variants where it is currently unclear, based on available evidence, whether they are disease-associated or benign. VUSs do not currently inform the management of breast cancer risk or treatment and can be confusing for patients who receive these results, said Giri. Furthermore, VUSs are reported at higher rates in minority populations whose genetic data are limited—which points to the need to engage more diverse populations in genetic studies.

“We often don’t know if these variants are pathogenic or benign, and that’s frustrating,” said Ryan Jensen, PhD, an associate professor of therapeutic radiology and pathology, who studies DNA repair and genome instability. “They’re a problem for precision medicine.”

Jensen is working to characterize those variants one by one, introducing them into human cell lines and then testing how they react to cancer drugs like cisplatin and PARP inhibitors. The goal is to develop a lab test that can give patients useful information about their particular mutations.

“I’ve studied BRCA2 for the past 20 years, but if someone tells me [they have] a specific amino acid missense mutation, I usually have no idea what that’s going to do to the protein functionally,” said Jensen. Nor could any existing software predict it, he added. “I would have to take that variant into the lab and put it into cells and then see what it does. That’s the only way to do it for unique variants lacking genetic linkage studies."

Do patients get the most effective therapies?

Highly efficacious cancer drugs typically work in some malignancies but not others, and determining which cancers will respond is not always straightforward. For example, deciding which patients with metastatic breast cancer are eligible for trastuzumab deruxtecan requires an assay that quantifies the HER2 protein. This antibody-drug conjugate, which links a cytotoxin to an antigen-specific antibody, is FDA-indicated for patients with positive or low levels of HER2, but not for those in whom it is zero.

Yet the traditional immunohistochemical assay is not sensitive enough for every individual, according to research by David Rimm, MD, PhD, Anthony N. Brady Professor of Pathology and Professor of Medicine (Medical Oncology), and director of Yale Pathology Tissues Services.

“A lot of the ‘zeros’ may actually have signals that are missed because of this faulty testing,” said Maryam Lustberg, MD, MPH, director of the Center for Breast Cancer and an associate professor of internal medicine (medical oncology), who is collaborating with Rimm. “Not accurately characterizing breast tumors may deprive potentially eligible patients from receiving this important therapy.”

An alternative test using different technology might detect additional patients who stand to benefit. With Rimm and Patricia LoRusso, DO, Amy and Joseph Perella Professor of Medicine (Medical Oncology) and associate cancer center director for experimental therapeutics, and others, Lustberg is planning to conduct a clinical trial of the drug in patients deemed HER2-zero by the traditional test.

“It’s an important study that builds on the emerging thought that maybe a lot more patients actually benefit from these more targeted HER2-antibody-drug conjugates than we thought before,” Lustberg said.

Why do good drugs stop working?

In recent decades, the group of powerful drugs called PARP inhibitors has revolutionized the treatment of certain cancers. These drugs target malignant cells while leaving healthy cells untouched. Susceptible tumors are those in which a mutation has damaged a DNA repair pathway called homologous recombination—a mutation in BRCA1 or BRCA2 is commonly involved. The BRCA proteins are involved in DNA repair in many tissues, which is why these tumors can occur not only in the breast but also in other organs, including the ovaries, pancreas, and prostate.

“A germline mutation in [one copy of a] BRCA [gene] is what gives you the high cancer risk. In the tumor, you’ve also lost the functional-copy allele, so the tumor is essentially BRCA-null—there’s no functioning BRCA protein. That’s why the tumor cells are so sensitive to PARP inhibitors,” Jensen explained.

As a cancer continues to evolve, additional “reversion” mutations in BRCA2 can result in the protein being expressed once again, restoring the homologous recombination repair pathway, even if imperfectly. Then the tumor may no longer be sensitive to PARP inhibitors. These resistance pathways are particularly important in advanced breast cancer when ongoing effective therapies are needed to control the disease.

“We are continuing to search for better therapies that can be translated from the bench to the clinic,” Lustberg said. “When a patient is told that the cancer has progressed on a drug which is no longer helping, that is difficult news to hear. To be able to understand resistance pathways and develop either better drugs or better interventions that address the underlying biology of the cancer is absolutely key to improving our existing therapies.”

Yet, Jensen said, we still lack a clear understanding of the roles of the BRCA proteins in homology-directed DNA repair, how tumorigenesis is initiated in the absence of BRCA1 or BRCA2, and why PARP inhibitors can specifically target BRCA-deficient tumors.

“The more we learn about DNA repair pathways, the more we’re going to understand how resistance develops in these tumors,” Jensen said. “If we can understand how PARP inhibitors work, maybe that’ll help us come up with ways to prevent that resistance in the first place by targeting other mutagenic repair pathways that are causing those secondary reversion mutations.”

What can bench scientists and clinicians learn from one another?

Plenty—and cancer center leaders like Qin Yan, PhD, see to it that everyone gets opportunities to interact regularly, including in two monthly meetings focusing on either basic and translational research or clinical research. Yan, co-director of Translational Research at the Center for Breast Cancer and a professor of pathology, recalls how one such conversation steered him, earlier in his career, as he was designing a study of metastasis before he had gained much experience with breast cancer.

Yan had planned to compare primary breast tumor tissue with metastatic tissue from lymph nodes. But his colleague David Rimm explained that lymph node metastases are in many respects very similar to the primary tumor, while those occurring at other body sites are different.

“Because I wanted to identify drivers of distal metastasis, which is the major cause of breast cancer-related death, comparing primary with lymph node metastases would not have given us much information,” Yan explained.

Rimm not only advised him to study distal metastases instead but also helped arrange access to these rare and hard-to-obtain samples. Ultimately, Rimm, Yan, and their collaborators identified an important protein called CECR2 that is upregulated in distal metastases.

Surgeons also play a pivotal role in translational research. “Surgeons are members of the cancer team resecting these cancers, with hands-on access to tissue in the operating room,” said Rachel Greenup, MD, MPH, co-director of the Center for Breast Cancer and associate professor of surgery (oncology, breast). “This tissue can then be shared downstream with the biobanking lab and can be critical for basic and translational researchers.”

Having that kind of access to tissue samples is crucial, according to biochemist Megan King, PhD, an associate director of basic science at the cancer center, who studies how PARP inhibitors induce the death of cancer cells.

“The ultimate experiment is always happening in patients—genetic diseases or failed therapy are the data. You need basic scientists to engage with that data to say, ‘What hypotheses can I pull out of these patient data? What are the open questions that have clinical implications?’” King said.

Rather than doing, say, a CRISPR screen with cells in a plastic dish, King added, “I serve everyone better by actually trying to use clinical samples to make those discoveries. It’s a better experiment at the end of the day, and it’s much more likely to be relevant for what’s happening in a patient.”

Winer sums up the value of translational research succinctly. “These days, there’s no clinical research without translational research—you take what you learn clinically to the lab to understand how it works and where it doesn’t work … and in the reverse direction, translational research figures out how to bring lab findings to the clinic.”

Jensen, whose lab is “just down the hall” from the cancer center, enjoys interacting with colleagues who run clinical trials.

“It’s so much fun to see Pat [LoRusso] in the hallway, bring her to the lab and show her what we’re doing, running proteins on the gel, explain how we’re trying to figure out if these variants are significant or not,” he said. “She sees these patients all the time, and the patients have to make these serious, life-impacting decisions. It’s very satisfying from my side to be able to hopefully make a difference in some patients’ lives.”

How can we ensure that patients can participate in research?

Breast cancer death rates have long been higher in non-Hispanic Black women, one of many appalling disparities in American cancer care.

“There are huge disparities in outcomes based on race, ethnicity, financial status, education, sexual orientation, and gender identification,” said Tracy Battaglia, MD, MPH, associate director of YCC’s newly established cancer care equity research.

“If you’re a 20-year-old Black woman living in the United States,” she said, “you have twice the chance of dying from breast cancer before you’re 50 compared to the 20-year-old white woman sitting next to you. Cancer inequities are pervasive and may even get worse if we are not intentional about ensuring that new discoveries are representative of all patients and reach all patients equally. This requires a community-engaged approach where we address root causes of inequity, such as social determinants of health, as well as biologic differences.”

The evidence suggests that clinical trial participation is associated with better outcomes, yet such participation is out of reach for many people. The data have demonstrated that these barriers can be disproportionately greater for people in minoritized subgroups.

“They want to go on a trial, they want the treatment, but staying on it is overwhelming, and sometimes they can’t,” LoRusso said. “‘Who’s going to babysit for my kids when I’m on the trial and I have to spend all day in a clinic? How am I going to get back and forth? Who’s going to pick my kids up at school? Who’s going to take care of my mother—I’m her caregiver and she’s living with me. How do I pay my rent if I have to take days off work to be on these trials?’ These are real-life issues that many of these patients are facing that interfere with their ability to participate in clinical research.”

So LoRusso and others are helping to spearhead what LoRusso calls a “logistical overhaul” to make early-phase trials available closer to home for the patients by bringing the early-phase trials program to Smilow Cancer Center’s community sites.

“With our new YCC director, Dr. Winer, there’s an increased commitment to the needs of patients who are underrepresented or face barriers because of social and structural determinants of health,” said LoRusso.

Cassanelli recalls driving to New Haven for a trial three days in a row from her home in Glastonbury. “It’s a lot physically and mentally, but also financially. And what if you’re a mom?” she said. “If you can go to a satellite office in your backyard, it’s a game-changer.”

Traveling to participate in a clinical trial is just one aspect of the overall financial hardship of a cancer diagnosis. “There are obviously major disparities based on women’s socioeconomic status at the time of a breast cancer diagnosis,” said Greenup, who is also a health services researcher. “But even women who are well insured and well resourced are at risk of having cancer treatment impact their job and financial security.”

LoRusso added, “Providing broader access to trial participation is not only fair and just, but also improves our understanding of how the drug works for a variety of people—and may even accelerate FDA approval. If you can minimize the timelines because you’re maximizing recruitment and retention, you can theoretically get an effective and safe drug to market that much sooner.”

Can other cancers benefit from these lessons?

Given the shared mechanisms underlying so many cancers, what we learn about breast cancer treatments—and failures—can be applied to other cancers. PARP inhibitors, a cornerstone of breast cancer treatment, were initially approved to treat ovarian cancer and are now being used for prostate and other cancers. A similar process is under way for the antibody-drug conjugate sacituzumab, whose FDA approvals have expanded from breast to bladder cancer. Research into drug resistance will also apply to many tumor types.

And many researchers have developed expertise that’s broadly applicable, King pointed out.

“One of the reasons why we basic scientists are great partners for translational and clinical scientists is that we’re disease-agnostic,” King said. “I study genome integrity. It turns out that breast and ovarian cancer are the cancers you get when you have a deficiency in [the DNA repair mechanism] homologous recombination. So these are cancers where we know that genomic integrity is particularly important, and that’s a good home for our work. But we’re realizing BRCA mutations are also tied to prostate and pancreatic cancers.

“In fact, much of what we’ve learned about breast cancer and ovarian cancer is relevant to a subset of those other cancers—the mechanisms play out in different places—and so as researchers we’re very flexible. We can actually help people who are interested in multiple diseases,” King added. “In an institution where you have collaborations, I can go into five different rooms and be five different people because I work on something really fundamental.”

What does the future hold?

Yale has big ambitions for breast cancer research and treatment. It is one of four types of malignancy that the cancer center plans to emphasize in the coming five years, in addition to prostate, liver, and lung cancer. Plans are under way to become a Specialized Programs of Research Excellence (SPORE) site—a National Cancer Institute initiative to translate basic science into clinical practice quickly, said Winer, who previously served for a decade as the principal investigator of a SPORE site in breast cancer. There are also plans to secure a broad-based National Institutes of Health Program Project P01 grant to fund further research into DNA damage and repair.

In the meantime, many more studies are in the works. One Yale group is investigating whether giving an antihyperglycemic drug can improve the effectiveness of chemotherapy, based on promising Yale findings showing targets within the oncometabolic pathways. Another study is exploring the use of blood tests to monitor whether patients are taking a drug correctly and to watch for recurrent disease. Researchers are examining how to safely reduce aggressive therapies in slow-growing cancers. They are looking to better understand patients’ experiences with symptoms and financial burdens during active disease. And they are studying the life changes survivors face following a cure, including anxiety about recurrence.

Amid so many efforts to comprehend the origins, treatment, and social context of breast cancer, what does the future hold? “We have real potential in breast cancer treatment at Yale to provide truly unsurpassed care,” said Winer. “We already do great research, and we can play a leading role there. We’ve got the right team in place. I think we can do something special.”