In a recent publication, Dr Moulder and colleagues examined the clinical effects of multigene profiling among patients with metastatic breast cancer (MBC).7 In that study, researchers used hotspot mutation testing, a method that looks for common mutations that occur at specific “hotspots,” or areas of the genome where mutations tend to concentrate. They found that patients with TNBC had the highest incidence of hotspot mutations in the TP53 gene and the lowest incidence in PIK3CA. TP53 mutation was associated with shorter relapse-free and overall survival, while PIK3CA mutation was associated with better clinical outcomes. Dr Moulder and colleagues contended that the results countenance that clinical hotspot testing “identifies potentially actionable mutations” for MBC.

Ingrid Mayer, MD, MSci, chair of the breast cancer research program at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, spoke about adjuvant and neo-adjuvant systemic therapy for TNBC. Dr Mayer’s research is focused on identifying targetable pathways in breast cancer, resistance to endocrine therapy and chemotherapy, and biomarker prediction of treatment response in breast cancer.

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Dr Mayer is the principal investigator of an ongoing phase 3 clinical trial (ClinicalTrials.gov Identifier: NCT02445391) investigating how well cisplatin or carboplatin works compared to capecitabine in treating patients with TNBC following neoadjuvant chemotherapy. The trial’s primary outcome measure will be invasive disease-free survival (IDFS) up to 86 months, and secondary outcomes including overall survival (OS), toxicity, and relapse-free survival (RFS).

In a 2016 article in Nature Reviews: Clinical Oncology, Dr Mayer and colleagues discussed the challenges and opportunities in treating TNBC.9 The major challenge to treatment, they wrote, is the lack of targeted therapies coupled with the poor prognosis of patients with TNBC. These factors have, however, encouraged a major effort to find actionable molecular targets for the disease. The review discussed massive parallel sequencing (MPS), sometimes also called next-generation sequencing, which includes a number of high-throughput approaches to DNA sequencing. MPS has revealed the heterogeneity of TNBC and allowed researchers to identify a number of potentially actionable targets.

The challenge is to determine whether mutations associated with TNBC are molecular “drivers,” and if they play a role in oncogenesis and metastasis of the disease. The review also discussed the discovery of a subgroup of TNBC that show “a high degree of tumor-infiltrating lymphocytes that also correlates with a lower risk of disease relapse and a higher likelihood of benefit from chemotherapy.” Studies of immune-checkpoint inhibitors in advanced-stage TNBC have been promising, which may indicate a benefit from immunotherapy for patients with the disease.

References

  1. Rugo HS, Perou CM, Moulder SL, Mayer IA. Triple negative breast cancer. 39th San Antonio Breast Cancer Symposium; December 2016; San Antonio, TX.
  2. Pfefferle AD, Agrawal YN, Koboldt DC, et al. Genomic profiling of murine mammary tumors identifies potential personalized drug targets for p53-deficient mammary cancers. Dis Model Mech. 2016;9(7):749-57. doi: 10.1242/dmm.025239
  3. Parker JS, Perou CM. Tumor heterogeneity: Focus on the leaves, the trees, or the forest? Cancer Cell. 2015;28(2):149-50. doi: 10.1016/j.ccell.2015.07.011
  4. Yates LR, Gerstung M, Knappskog S, et al. Subclonal diversification of primary breast cancer revealed by multiregion sequencing. Nat Med. 2015;21(7):751-9. doi: 10.1038/nm.3886
  5. Robertson-Tessi M, Anderson, AR. Big Bang and context-driven collapse. Nat Genet. 2015;47(3):196-7. doi: 10.1038/ng.3231
  6. Wendler, R. Sights set on first targeted therapy for triple-negative breast cancer. MD Anderson Cancer Center website. https://www.mdanderson.org/publications/conquest/conquest-spring-2016/therapy-for-triple-negative-breast-cancer.html. Updated 2016. Accessed November 24, 2016.
  7. Basho RK, Gagliato DM, Ueno NT, et al. Clinical outcomes based on multigene profiling in metastatic breast cancer patients. Oncotarget. 2016 Oct 28. doi: 10.18632/oncotarget.12987 [Epub ahead of print]
  8. Rogozin IB, Pavlov YI. Theoretical analysis of mutation hotspots and their DNA sequence context specificity. Mutat Res. 2003;544(1):65-85.
  9. Bianchini G, Balko JM, Mayer IA, Sanders ME, Gianni L. Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease. Nat Rev Clin Oncol. 2016;13(11):674-90. doi: 10.1038/nrclinonc.2016.66

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Breast Cancer Conference Coverage SABCS 2016