Translational Genomics: Practical Applications of the Genomic Revolution in Breast Cancer

Abstract

The genomic revolution has fundamentally changed our perception of breast cancer. It is now apparent from DNA-based massively parallel sequencing data that at the genomic level, every breast cancer is unique and shaped by the mutational processes to which it was exposed during its lifetime. More than 90 breast cancer driver genes have been identified as recurrently mutated, and many occur at low frequency across the breast cancer population. Certain cancer genes are associated with traditionally defined histologic subtypes, but genomic intertumoral heterogeneity exists even between cancers that appear the same under the microscope. Most breast cancers contain subclonal populations, many of which harbor driver alterations, and subclonal structure is typically remodeled over time, across metastasis and as a consequence of treatment interventions. Genomics is deepening our understanding of breast cancer biology, contributing to an accelerated phase of targeted drug development and providing insights into resistance mechanisms. Genomics is also providing tools necessary to deliver personalized cancer medicine, but a number of challenges must still be addressed.

Immunotherapy for Breast Cancer: What Are We Missing?

“…Successfully developing immunotherapy in breast cancer will be best achieved as part of a collaborative effort with investigators addressing other critical areas of this disease (7–10). A chief challenge for advancing immunotherapy for patients with advanced breast cancer is to move beyond PD-1/PD-L1 blockade alone and empiric combination of other agents with PD-1/PD-L1.…”

Breast Cancer Disparities at Home and Abroad: A Review of the Challenges and Opportunities for System-Level Change

“…(4,5) As discussed elsewhere in this issue by Desmedt and colleagues, considerable genomic variability exists among HR+/HER2− cancers, as well as other clinical subtypes, with regard to both pre-treatment mutational status and acquired mutations associated with treatment resistance. (6) With the plethora of recent sequencing data, it is argued that sequencing further primary breast tumors is unlikely to discover new, common mutational signatures. (7) However, we posit that further characterization of racial differences in within-subtype biology, made possible by sequencing of tumors from large minority-enriched cohorts such as the Carolina Breast Cancer Study, may yield novel information regarding the biologic underpinnings of racial disparities.…”

Unmet Needs in Clinical Research in Breast Cancer: Where Do We Need to Go?

“…They highlight five major issues hampering our ability to harness the cancer genome to improve patient outcomes and elucidate not only the gaps, but potential steps to move forward. (16) In our view, the greatest obstacles for this work leading to improvements for patients with breast cancer include: a) the limited proportion of breast tumors found to have “actionable” mutations as currently defined, b) the need for integrative DNA- and RNA-based approaches, c) mixed results in terms of patient outcomes of molecularly-targeted approaches to date, d) within-patient tumor heterogeneity and challenges of obtaining optimal tumor testing at any given time, and e) the infrastructure and resource constraints that hamper our ability to implement such testing broadly to reach all patients. (17, 18)…”

“…For example, the top-ranked priority was identifying patients at risk of late relapse using genomics, and testing novel endocrine therapy to prevent such late relapse in hormone receptor-positive early breast cancer. Transcriptomic assays show promise in this realm (31, 32), which may be further aided by identifying relevant driver mutations in the primary as described in Focus article #2(16), although it should be noted that mature datasets with a high proportion of banked primary tissue that are large enough to address late relapse are rare, complicating design of trials to address this question. Next in priority was immunotherapy, the subject of Focus #3.…”

“…A currently accruing ALLIANCE study, ALTERNATE (NCT01953588), will test the clinical utility of an immunohistochemistry-based prognostic score, the PEPI score (33). At this time, testing for clinical utility of mutational analyses of the type described in Focus articles #1 and #2 (1, 16) is premature, even though several other highly rated “unmet needs” involved genomic applications that may be informed by these sorts of mutational analyses, including optimizing treatment choices for hormone receptor-positive breast cancer, decision-making regarding need for radiation therapy, and identifying targetable aberrations in triple negative disease. As noted, RNA-based assays have begun to be studied in several of these realms, including guiding metastatic treatment in hormone receptor-positive disease (34), determining need for dual HER2-targeting and less aggressive regimens (10, 11), and tailoring radiation therapy to those at higher risk of locoregional failure.…”