Genomic Testing in Breast Cancer: Screening for Risk Assessment and Therapeutic Options

Background and History

Breast cancer is the most common cancer in women and the second most common cancer overall. It has a heterogeneous etiology ranging from genetic predisposition, lifestyle, environment, and gender, and is a major cause of death among women. There is an estimated 2+ million new cases of breast cancer every year, which accounts for ~12 percent of all new cases of cancer for women and men.1

Most cases of breast cancer are sporadic with approximately 10-15 percent associated with hereditary cancer predisposition syndromes. With these familial cases of breast cancer, individuals typically have a family history of multiple breast or ovarian cancers.

According to National Cancer Institute, there are several factors that suggest a genetic contribution to both breast and gynecologic cancer, which include:

  1. An increased incidence occurring more frequently among individuals with a family history of these cancers
  2. Multiple family members affected with these and other cancers
  3. A pattern of cancers compatible with autosomal dominant inheritance

With a genetic evaluation of breast cancer, individuals can understand their hereditary predisposition to developing cancer and adopt protective measures for relatives. It’s important to note, both males and females can inherit and transmit an autosomal dominant cancer predisposition gene. In addition, oncologists can help direct their patients’ current treatment for breast cancer, prevention of developing other cancer mutations, and provide a risk diagnosis.   

Genetics of Hereditary Breast Cancer

Seminal studies, from Dr. King et al. in 1990, identified BRCA1 as the cause of hereditary breast cancer using a labor-intensive linkage analysis in over 25,000 patients. Five years later, the BRCA2 gene was identified after investigating families with breast cancer who had no identifiable genetic variants in BRCA1. Both BRCA1 and BRCA2 genes are “caretaker” genes protecting and repairing our genome from DNA breakage.

Commercial testing for these two genes became available soon after in the mid-1990s, using traditional inefficient testing (which, at the time, was expensive). This testing was also mired by legal issues surrounding patent claims. In 2013, these patents were subsequently overturned by the Supreme Court of the United States.

Since then, testing for hereditary variants in patients with breast cancer has significantly evolved. With the discovery of additional high and moderate risk breast cancer genes combined with the advent of next-generation sequencing (NGS), testing of multiple genes can now be performed in a cost-effective and timely fashion.

Current Status of Hereditary Breast Cancer Screening

The majority of professional society guidelines recommend genetic testing for risk evaluation for individuals with family histories that are indicative of genes predisposing to breast cancer. Furthermore, recent studies have strongly suggested that individuals affected with breast cancer without a without a family history (8-10 percent of the US population6) may also harbor predisposing variants in these genes. Due to these findings, the American Society of Breast Surgeons recommends all individuals with breast cancer be screened for breast cancer risk genes irrespective of family history.

Now, multiple gene panel testing for hereditary breast cancer is the standard-of-care for affected patients with a family history of breast cancer. These gene panels typically include high-risk and high-penetrant alleles. Various published guidelines and evidence-based clinical utility assessment studies state that genes with definitive evidence of an increased risk of breast cancer include:

  • ATM
  • BARD1
  • BRCA1
  • BRCA2
  • CDH1
  • CHEK2
  • PALB2
  • PTEN
  • STK11
  • TP53

Some of these genes may be related to high-penetrant cancer predisposition syndromes, such as Cowden syndrome (PTEN) and Li-Fraumeni syndrome (TP53); which is why family history and risk for other secondary malignancies need to be considered. Multi-disciplinary teams, including genetic counselors, collaborate to advise patients of surveillance, risk reduction prevention of next cancer, and protective measures for relatives.

Baylor Genetics offers multiple options for hereditary breast cancer genetic testing:

Additionally, comprehensive gene panels are offered with expanded gene lists to include not only high-risk and high-penetrant genes but also newly described genes that have been described in literature. (BG links here).


Overall, Substantial progress has been made in the field of germline genetic testing to aid risk assessment in breast cancer. Multiple large consortiums have made significant contributions to the understanding of the risk of various cancers associated with pathogenic variants in breast cancer predisposition genes.

Today, genetic testing for patients at high-risk for breast cancer is no longer limited to BRCA1 and BRCA2 genes. With the development of NGS, multiple genes are being tested in a more efficient manner as standard-of-care for affected patients with family histories of cancer. Clinical knowledge of the pathogenicity and penetrance of genes are the most limiting factor of widespread adoption of large gene panels. However, multi-institutional consortiums like the National Institutes of Health-funded Clinical Genome Resource (ClinGen), where I am an investigator and co-chairman of ClinGen Somatic Cancer Workgroup, have contributed immensely to reviewing evidence and clinical validity of some of the genes in most cancer predisposition panels. In addition, ClinVar, a public database of human genetic variations currently has ~3,000 pathogenic variants of BRCA1 and ~ 3,700 pathogenic variants in BRCA2.

Additionally, new developments like polygenic risk scores could further add to refinement of breast cancer risk assessment. Although these tools are not yet widely adopted in clinical diagnostics, eventually they will help provide answers to important questions regarding the best approach for prevention, monitoring, and making therapeutic decisions to help individuals with breast cancer.


  1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. V3. 2019. Accessed March 23, 2019.
  2. Kurian AW, Hare EE, Mills MA, et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol. 2014; 32:2001-2009.
  3. Buys SS, Sandbach JF, Gammon A, et al. A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes. Cancer. 017;123(10):1721–1730.
  4. International Agency for Research on Cancer:
  5. National Cancer Institute: Genetics of Breast and Gynecologic Cancers (PDQ®)–Health Professional Version
  6. A compilation of many publications; Huang et al., 2018, Cell 173, 355–370

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