Breast Cancer Program: Actualizing Translational Advances to Address Unmet Needs

MARCH 4, 2019

Targeted drugs, improved screening, and an increasing understanding of breast cancer biology helped lower mortality rates in the past few decades; the American Cancer Society reports a 39% overall decline in breast cancer mortality from 1989 through 2015.However, this progress is not uniform across populations, subtypes, or stages of breast cancer. Molecular subtypes, such as triple-negative breast cancer (TNBC), lacking detectable expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2), have proven particularly intractable. Improvements are lacking or lagging in certain understudied subpopulations. For instance, in young women (< 40 years old) with breast cancer, the aggressive biology is underscored by other factors, including the impact of diagnosis and treatment on quality of life (QoL) and fertility preservation. Add to this list minimal survival gains in metastatic breast cancer in recent years, owed in part to tumor heterogeneity. This list of challenges is but a primer on critical knowledge and practice gaps in breast cancer.

These areas of greatest unmet needs are the focus of the Breast Cancer Program (BCP) at DF/HCC, Eric P. Winer, MD, (DFCI) notes. Winer, along with co-leaders Leif W. Ellisen, MD, PhD (MGH), Stuart J. Schnitt, MD (BWH), Rulla M. Tamimi, ScD (BWH), and Jean J. Zhou, PhD (DFCI), lead the Program.  Speaking to the wide range of expertise of Program members, including expertise beyond laboratory and clinical research, Winer said, “We are a really broad-based research program; for instance, we are looking at exercise and diet as interventions for reducing the risk of breast cancer recurrence. We have ongoing work in the health services arena, including for example the work conducted by Ann Partridge’s group in young women with breast cancer.”

Unique aspects of breast cancer in young women

Women younger than 40 with breast cancer represent 7%-10% of new invasive breast cancer cases in the US, however, they account for over 40% of all cancers in young women. Young women are a particularly vulnerable and an understudied population, often presenting with more aggressive disease, with devastating impact on their psychosocial, emotional, and medical well-being. These unique issues have been the research focus of Ann H. Partridge, MD, MPH (DFCI), who was recently awarded the 2018 AACR Outstanding Investigator Award for Breast Cancer Research in recognition of her seminal work.

Dr. Partridge, as principal investigator, established and now directs the Young Women's Breast Cancer Study (YWS), in collaboration with Tamimi as lead epidemiologist. The YWS — a multi-institutional cohort of 1300 women aged 40 and younger at diagnosis, enrolling at MGH, BIDMC, DFCI, and other collaborative and satellite sites in the United States and Canada — seeks to evaluate short and long-term disease and treatment issues, including tumor biology, its relationship to patient outcomes, and psychosocial concerns. “There are key differences in women who are diagnosed at a younger versus an older age, both in terms of the biology (more likely to harbor hereditary predisposition to breast cancer development), the services (less likely to be screened), and access to the care (not Medicare-eligible). “Emotionally, young women are more likely to experience stress and lack adjustments for handling their diagnosis and treatment,” Partridge explained. “Collectively, these factors collude to impinge on their clinical outcomes.” To help address the disparities in the care and clinical outcomes of young women with breast cancer, Partridge and her colleagues are expanding the young women’s breast cancer program to other institutions within and beyond DF/HCC.

Detangling tumor heterogeneity

Heterogeneity of breast cancer, both inter- and intra-tumoral, contributes to a diverse tumor ecosystem. Tumor heterogeneity presents diagnostic, prognostic, and therapeutic challenges, and is a major driving force in recurrence of breast cancer. With the utilization of newer technologies, such as single-cell RNA sequencing, Program members are uncovering the extent, profile, and consequence of breast tumor heterogeneity.

In a seminal study, Kornelia Polyak, MD, PhD (DFCI) collaborated with DF/HCC Cancer Data Science Program leaderFranziska Michor (DFCI) to uncover the role of an epigenetic modulator, the lysine demethylase KDM5, in driving higher transcriptomic heterogeneity and associated endocrine resistance and poor prognosis in ER-positive breast tumors.2 The Polyak lab previously identified KDM5B, encoding a histone H3 lysine 4 demethylase, as an oncogene that is commonly overexpressed and amplified in luminal ER-positive breast tumors.3 Polyak and Michor, together with program members Peter Sicinski (DFCI), Myles Brown (DFCI) and Nikhil Wagle (DFCI), found that deletion of KDM5A/B or inhibition of KDM5 activity increases sensitivity to antiestrogens, and that higher KDM5B expression is associated with higher transcriptomic heterogeneity.2 Using innovative approaches, including single-cell RNA sequencing, cellular barcoding, and mathematical modeling, they demonstrated two distinct mechanisms of resistance - endocrine resistance originated via selection of pre-existing genetically distinct cells, while resistance to KDM5 inhibitors was acquired.

One of the first studies to utilize single-cell analytical methods in TNBC, which was conducted by Ellisen and Michor with collaborators Michelle Specht (MGH) and Brad Bernstein (MGH, Cancer Genetics Program), highlighted the role of non-uniformity of gene expression programs that are driven by genotypic changes in intra-tumoral heterogeneity, a striking hallmark of TNBC.4 The study identified subpopulations of cancer cells within the bulk tumor. One subpopulation was associated with a treatment/metastases-associated signature, characterized by activation of glycosphingolipid metabolism and associated innate immune responses, predictive of long-term patient outcomes.

Breast immuno-oncology is heating up: Turning “cold” tumors “hot”

Immuno-oncology has shifted the treatment paradigm in many difficult-to-treat cancers such as metastatic melanoma, and researchers are now devising creative strategies to utilize immune approaches in breast cancer treatment. Recent work from Program members is helping propel breast immune-oncology forward by turning “cold” tumors “hot”.  This involves flagging the “cold” breast tumors with immune response-augmenting therapies, in combination with immune checkpoint inhibitors (ICIs) that target checkpoint regulators, including cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed cell death protein (PD)/PD-ligand (PD-L).

Tumor infiltration by CD8+ cytotoxic T cells is an indicator of favorable prognosis in several cancers, including breast cancer, and “among the molecular subtypes of breast cancer, TNBC has the greatest infiltration of immune cells, indicating the potential for utilizing immunotherapy,” said Elizabeth A. Mittendorf, MD, PhD (BWH), “While immunotherapy as monotherapy is not particularly clinically efficient, there is a lot of interest in combining immunotherapy with other therapies.” Dr. Mittendorf anticipates that nearly all breast cancer subtypes would require immunotherapy in combination with other sensitizing treatments, given the low response rate (Sara M. Tolaney, MD, MPH (DFCI), Nancy U. Lin, PhD (DFCI), Adrianne G. Waks, MD (BWH), and Ian E. Krop, MD, PhD (DFCI). As proof of the utility of combination therapies including ICIs, she pointed to a recent study showing that a combination of the PDL-1-directed antibody atezolizumab with the chemotherapeutic agent nab-paclitaxel extended progression-free survival in patients with metastatic TNBC,5 which she anticipates will result in regulatory approval of this combination in this setting. 

The first randomized trial for metastatic ER-positive breast cancer with chemotherapy (eribulin mesylate) with or without immunotherapy (pembrolizumab), led by Tolaney, recently completed accrual (NCT03051659). Tolaney said that "there are no data for this in the ER-positive field, so this [trial] will provide unique information.” Another notable trial is the AVIATOR study, led by Krop, evaluates the combination of HER2-targeted trastuzumab and chemotherapy agent vinorelbine, with or without the immunotherapy agents avelumab and/or utomilumab. Program members are also leading four trials addressing the utility of immunotherapy in TNBC - NCT03316586 and  NCT03414684 (Tolaney), and NCT03483012 (Lin).

The conduit between basic and translational science and clinical trials and practice is apparent throughout the Program. Dr. Mittendorf pointed to the intersection of studies led by Geoffrey Shapiro, MD, PhD (DFCI), Gerburg Wulf, MD, PhD (BIDMC), and Jennifer Guerriero, PhD (DFCI), on activation of the innate immune system with conventional chemotherapy agents, including poly ADP ribose polymerase (PARP) inhibitors. “PARP inhibitors were thought to impact immune response by increasing the mutational load via deficiencies in DNA damage repair, but this new work suggests that PARP inhibitors upregulate the STING pathway (Shapiro and Wulf) and affects macrophages within the tumor microenvironment (Guerriero),” said Mittendorf. “We are extrapolating these observations, to test whether these effects also hold true in samples from PARP inhibitor-treated breast cancer patients.”

Immune escape during breast tumor progression was the focus of recent work led by Polyak, with contributions from Michor, Judy Garber (DFCI) and Gordon Freeman (DFCI; Cancer Immunology Program). Using a sophisticated analysis of the leukocyte composition in normal breast tissues, ductal carcinoma in situ, and invasive ductal carcinomas (IDC), the study revealed coevolution of immune and tumor cells in the tumor microenvironment during breast cancer progression.6 “Concomitant with increased leukocyte infiltration, we observed a decrease in activated cytotoxic granzyme B+ CD8+ T cells. There is an upregulation of immune checkpoint proteins such as PD-L1/CTLA-4, so it seems that there is an active immune suppression concomitant with cancer progression,” Polyak said. Dr. Polyak and her colleagues are recapitulating these findings in animal models of breast cancer to test whether combinations of ICIs with other agents can arrest or even revert tumor progression.

Reading between the lines: Identifying genetic drivers of breast cancer

Genetic mutations are characteristic features of all tumors; however, only a subset of these mutations are “drivers” of tumorigenesis. Pivotal studies from researchers at DF/HCC institutions, including Ellisen and Gad Getz, PhD (MGH), a computational biologist and co-leader of the Cancer Genetics Program, identified two novel classes of genetic drivers in breast cancer.7,8 Using deep sequencing of primary breast tumors and developing computational methods for identifying markedly-mutated promoters, Getz and his colleagues showed that regulatory promoter regions harbor recurrent mutations, with functional consequences and at frequencies comparable to that of coding regions.7 In the second study, Ellisen, with MGH collaborators John Iafrate (Cancer Genetics Program), Dennis Sgroi, Paul Goss and Dianne Finkelstein (Cancer Data Sciences Program) identified intergenic fusions involving driver genes, including the ERα-encoding ESR1, in a significant subset of patients with advanced hormone receptor-positive breast cancer.8

Seamless integration from risk prediction to surgical oncology

A recurring theme in the Breast Cancer Program is not only capturing the entire continuum of issues in breast cancer – from interventions for primary and recurrence prevention, all the way to innovative surgical methods, cutting-edge therapies, and care delivery strategies – but that the Program is intensely and purposefully collaborative.

To delineate the mechanisms related to risk of breast cancer, for instance, Tamimi and Polyak are collaborating, “with the ultimate goal of identifying opportunities for prevention.” Tamimi said, “Based on experimental studies in [Polyak’s] group, we are able to take the markers that were identified and extend them into tissue samples from the Nurses’ Health Studies to test whether expression of the same markers in tissue samples is predictive of risk of developing breast cancer later on in life.” The collaboration resulted in identification of proliferative markers in benign breast lesions that were associated with subsequent risk of developing breast cancer.9,10 Examples of such crosstalk between laboratory science, clinical research, and epidemiology abound in the Program.

“DF/HCC is a great example of collaborative research, where not only are we working with our clinical colleagues and providing multidisciplinary optimal care for our patients with radiation, surgical, and medical oncologists working together, [but] we are also working closely and reciprocally with colleagues in the lab to converge on critical questions to accelerate discovery and delivery of cutting-edge patient care,” Ellisen said.

Winer emphasized the breadth of investigations in the BCP, adding, “The highlight of the program is that we have a SPORE grant, which complements the activities and questions tackled in the core program.” The Breast Cancer SPORE (Specialized Program of Research Excellence) grant, awarded by the National Cancer Institute and led by Winer, is undertaking four new projects. The first project deals with assessing CDK4/6 inhibitor resistance and it is led by Winer and Peter Sicinski, MD, PhD (DFCI)Dr. Winer and Sicinski's project builds on studies by DF/HCC members which show that selective CDK4/6 inhibitors not only induce cancer cell cycle arrest, but they also sensitize tumors to HER2-targeted agents, delaying tumor recurrence,11 and promoting anti-tumor immunity.12 The other three projects are immune approaches to the treatment of HER2-positive breast cancer, led by Krop and Thomas Roberts, PhD (DFCI); brain metastases, led by Lin and Jean Zhao, PhD (DFCI); and immune aspects of TNBC, led by Polyak and Shapiro.

With over 120 members representing all seven DF/HCC institutions, the Breast Cancer Program is geared up for taking roads less travelled and correcting critical deficits in breast cancer research and patient care.

–  Written by Krithika Subramanian, PhD

References

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