One Size Does Not Fit All: Breast Cancer in Young Women

In this issue of Clinical Cancer Research, Waks and colleagues performed exome sequencing of tumor and germline samples derived from 92 women with breast cancer diagnosed at ≤35 years of age (Young Women's Study) compared with older women (≥45 years old) from The Cancer Genome Atlas (TCGA), according to intrinsic subtype (1). In luminal A tumors, the authors found that somatic PIK3CA alterations were more prevalent in breast tumors from older women, whereas somatic GATA3 and ARID1A alterations were more common in tumors from younger women. The occurrence of young-onset cancers is a typical clinical red flag for the likelihood of an underlying hereditary predisposition to cancer. Accordingly, it was found that 23.9% of the young women with breast cancer carried germline pathogenic variants in cancer-related genes, with greater than half having germline BRCA1/2 variants. Importantly, a subset of the cancer-related variants was missed even at germline clinical testing, underscoring the importance of revisiting testing individuals with high suspicion of germline predisposition, as new genes associated with cancer are uncovered and more precise detection methodologies are standardized over time (2).

History has shown that important clinical and scientific lessons can be learned from rare clinical phenotypes (3). By focusing on a smaller subset of young women with breast cancer, the authors were presumably challenged by sample size. However, sample size limitations can often be overcome by study design and/or homogeneity of phenotypes. Indeed, the current authors’ study design proved to be effective in identifying notable differences in breast cancer biology based on age group. Importantly, they identified such somatic genomic differences in the luminal A subgroup, despite the fact that it was not the highest powered group in the Young Women's Study. The authors’ data are in line with recent work demonstrating that cancers occurring at younger ages have distinct tumor biology and response to therapy (4, 5). Extending these data further, it will be important to investigate whether such intrinsic biologic factors are different between patients with young breast cancer with and without known cancer predisposition gene alterations. Undoubtedly, these studies will necessitate national and even international efforts to assemble a powered sample size, ideally representative of women from all ancestries.

At the bench, the authors’ data pave the way for functional studies to characterize the tumor biology of breast cancers developing in young versus older women. Whereas significant progress has been made to stratify breast cancers by intrinsic clinical and molecular characteristics, it is evident that identical subtypes can behave differently depending on the age of onset; rather, it may be that these fundamental differences may drive age of onset of identical subtypes. Additional investigation of genomic differences and associated pathways could identify biological differences governing cancer initiation and progression in these contexts. Accordingly, the authors’ identification of fewer PIK3CA alterations and enrichment of GATA3 and ARID1A alterations in luminal A tumors from young women would suggest that gene regulatory mechanisms may be the Achilles’ heel of such young-onset cancers. These data are predicted to inform preclinical in vitro and in vivo studies investigating how the identified genes and pathways influence breast carcinogenesis and therapeutic strategies. Notably, as the authors noted, only a subset of young women with breast cancer have underlying germline alterations that could explain their early-onset breast cancer phenotype, whereas the majority remain with unidentified etiologies. From a discovery perspective, this highlights a major gap in our understanding of early-onset cancer initiation and our limited capacity to comprehensively interrogate all possible mechanisms. Certainly, these data also underscore the complexity and heterogeneity of cancer, even within a highly uniform sample of women with respect to age and intrinsic subtype.

More directly, this work has important clinical implications. Whereas large prospective clinical trials suggest differential chemotherapy benefit and outcomes between younger and older women with hormone receptor–positive breast cancer, it remains elusive whether such differences may be accounted for by true biological differences intrinsic to the tumors, versus endocrine effects based on age. The identified genomic differences in this study may indeed form the basis for distinct therapeutic targets in patients with young breast cancer, pushing the envelope further in the realm of precision oncology (Fig. 1). Expectedly, the fact that a subset of patients with young breast cancer was found to harbor known cancer predisposing genes would suggest that individuals with hereditary predisposition to cancer should follow more individualized therapeutic and management protocols based on tumor-intrinsic molecular signatures. Undoubtedly, in the context of such hereditary breast cancers, it becomes more critical to identify such individuals as early as possible, prior to cancer development, a strategy of current cancer genetic risk management programs. Thus, identifying why breast cancer develops at such a young age will be important not only for improving treatment options for young women with breast cancer, but also for prevention.

The data presented by Waks and colleagues (1) represent important progress in understanding breast cancer characteristics in young women, and calls for more precise stratification of patients according to risk, age, tumor characteristics including the somatic genomic profile, and response to therapy. Although the authors had longitudinal follow-up data, with a median of 9.2 years, another future direction may be to identify whether young women with breast cancer are also at a higher risk of second malignant neoplasms during their lifetimes, mimicking those with germline mutations, even in the absence of such. Importantly, integrating multimodal data from the tumor microenvironment and environmental exposures will be vital to get at possible mechanisms of cancer initiation. At the other extreme end of the spectrum, it would be informative to study older women with known breast cancer susceptibility genes and no cancer diagnosed into old age. This rare subset of women is equally invaluable to identify genomic modifiers that are protective against cancer. The work by Waks and colleagues reinforces the value of rare subsets of patients in the effective implementation of precision oncology.

No disclosures were reported.

L. Yehia is an Ambrose Monell Foundation Cancer Genomic Medicine Fellow at the Cleveland Clinic Genomic Medicine Institute. C. Eng is the Sondra J. and Stephen R. Hardis Chair of Cancer Genomic Medicine at the Cleveland Clinic and an American Cancer Society Clinical Research Professor.