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One of the “hot button” topics right now in the cancer therapeutics industry is precision medicine. This is a practice whereby a tumor’s genetics, immune landscape, and biomarkers are compiled and evaluated holistically in order to more accurately make treatment decisions. Breast cancer especially has benefited from the targeted therapies that have been built from precision approaches. Trastuzumab, for example, is a monoclonal antibody treatment that is targeted to the HER2 growth receptor protein often over-expressed in HER2-positive breast cancers [link]. Patients that have evidence of high HER2 expression are eligible for treatment and have been positively responding since the drug’s release [link].
However, not all precision medicine approaches focus solely on the genetics of the tumor. Germline mutations, a gene change in a body’s egg or sperm that becomes incorporated into the DNA of every cell in the offspring, also play a role in cancer treatment approaches. Breast cancer was the first cancer type to introduce extensive germline testing into preventative screening to determine the susceptibility of developing the disease [1,2]. Two of the most common mutations that drive breast cancer development occur in the BRCA1 or BRCA2 genes. Both genes produce proteins that help repair damaged DNA . When BRCA1 or BRCA2 are mutated, DNA damage may not be repaired, leading to the opportunity for sustained subsequent mutations that promote cancer development. This is why BRCA1 and BRCA2 are studied in relation to breast cancer risk.
As germline testing became commonly incorporated into precision medicine, therapeutic decision-making became more complicated. No longer was a decision singularly based on the genetics of the tumor, but now the genetics of the individual must also be considered. A 2020 study sought to investigate this relationship, asking if the increasing use of germline genetic testing is associated with the degree of treatment of women diagnosed with breast cancer . For this population-based cohort study, data were collected from women aged 20 years or older who were diagnosed with stages 0 to III breast cancer between 2014 and 2016 and underwent genetic testing within 3 months after diagnosis.
The study hypothesized that the association of genetic test results with treatment would be consistent with treatment guidelines. Current guidelines for women carrying disease-related mutations suggest preventative surgical removal of both breasts’ tissue to be the primary treatment, radiotherapy only with certain mutations, and very rarely chemotherapy . If the study’s hypothesis were supported, results would show increased surgery for patients carrying BRCA1/2 mutations and no difference in rates of radio- or chemotherapy.
To understand the large dataset, researchers identified two categories of genetic backgrounds: (1) women with BRCA1/2 mutation and (2) those who didn’t carry relevant breast cancer mutations. Researchers found that BRCA1/2 mutation-carrying patients received mildly higher rates of chemotherapy, much higher rates of surgery, and lower rates of radiotherapy, compared to mutation-negative patients. The difference in rates of surgery supports the authors’ hypothesis, but the differential application of radio- or chemotherapy according to germline mutation status was not expected. These decisions were likely a combination of healthcare provider recommendations and patient wishes, indicating that there is a need to better understand treatment decisions and how germline testing results impact these decisions.
This study was the first of its kind and clearly demonstrates the need for further investigation into the effects of mutation and germline genetic status in oncology practices. Current searches for trends in cancer precision medicine focus almost entirely on the increase in biomarker availability , the incorporation of AI and big data , and novel approaches to finding targets . Other than the one discussed in this article, there are no recent publications that are highlighting the misalignment of treatment and germline mutations. As researchers and oncologists push to understand more about the behavior of cancers to various treatments, it is imperative, as this study shows, that nuanced conversations about germline mutations be factored into the decision-making process.
Edited by Gabrielle Dardis
Primary article: https://doi.org:10.1001/jamaoncol.2019.6400
Media: UM Health lab, How Hereditary Genetic Testing Results Impact Breast Cancer Treatment [link]
- National Comprehensive Cancer Network. Guidelines for genetic/familial high-risk assessment: breast and ovarian. Version 2.2019-July 30, 2018. https://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf.
- American Society of Breast Surgeons. Consensus guideline on genetic testing for hereditary breast cancer. https://www.breastsurgeons.org/docs/statements/Consensus-Guideline-on-Genetic-Testing-for-Hereditary-Breast-Cancer.pdf.
- National Cancer Institute. BRCA Gene Mutations: Cancer Risk and Genetic Testing. https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet.
- Kurian, A. W. et al. Association of Germline Genetic Testing Results With Locoregional and Systemic Therapy in Patients With Breast Cancer. JAMA Oncology 6, e196400 (2020).
- Ray, S. K. & Mukherjee, S. Starring role of Biomarkers and Anticancer Agents as a Major Driver in Precision Medicine of Cancer Therapy. Curr Mol Med (2021) doi:10.2174/1566524022666211221152947.
- Velmovitsky, P. E., Bevilacqua, T., Alencar, P., Cowan, D. & Morita, P. P. Convergence of Precision Medicine and Public Health Into Precision Public Health: Toward a Big Data Perspective. Front Public Health 9, 561873 (2021).
- Shirvanirad, S. et al. The Microbiome in Precision Medicine: A New Approach to Cancer Treatment. Journal of Mazandaran University of Medical Sciences 30, 21–37 (2021).