Multigene Testing for All Patients with Breast Cancer Could Identify Many More Mutation Carriers

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 279,100 new cases of invasive breast cancer will be diagnosed in 2020 and about 42,690 individuals will die of the disease. DNA can be damaged due to errors during its replication or as a result of environmental exposure to ultraviolet radiation from the sun or other toxins. The tumor suppressor genes such as BRCA1 (Breast Cancer 1) and BRCA2 help repair damaged DNA and thus play an important role in maintaining cellular genetic integrity, failing which these genetic aberrations can result in malignancies. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. These mutations can be inherited from either of the parents in an Autosomal Dominant pattern and a child has a 50% chance of inheriting this mutation, and the deleterious effects of the mutations are seen even when an individual’s second copy of the gene is normal.
It is estimated that BRCA1/2 gene mutations occur in approximately 1 in 400 women in the general population and account for 20-25% of hereditary breast cancers, about 5-10% of all breast cancers and 15% of ovarian cancers. Mutations in the BRCA1/2 genes increase breast cancer risk 45-65% by age 70 years. The risk of ovarian, fallopian tube, or peritoneal cancer, increases to 39% for BRCA1 mutations, and 10-17% for BRCA2 mutations. PALB2 (Partner And Localizer of BRCA2) gene provides instructions to make a protein that works along with the BRCA2 protein, to repair damaged DNA. PALB2 mutation is rare in sporadic breast cancer, and is considered a high-penetrance breast cancer predisposing gene associated with 14% risk of developing breast cancer by age 50 and a 35% risk of developing breast cancer by age 70. Women with a PALB2 mutation face an increased risk of triple negative breast cancer and higher risk of death from breast cancer. PALB2 gene mutations have also been implicated in ovarian, pancreatic and other malignancies.
Current guidelines recommend genetic testing in women with breast cancer who fulfill recognized or established family history or clinical criteria. However, patients with breast cancer and genetic pathogenic variants do not always have a positive family history, and these criteria miss approximately 50% of pathogenic variant carriers. Further, genetic testing based on family history or clinical criteria depends on the awareness and understanding both by the health care providers and patients, and appropriate referrals to genetic counselors. Because of limited awareness and restricted access to genetic testing and counseling services, only 20-30% of eligible patients undergo genetic testing, and 97% of estimated carriers in the general population remain unidentified, thereby missing substantial opportunities for primary prevention. 
Knowledge of a patient’s genetic pathogenic variant status has important therapeutic and prognostic implications. Identifying unaffected relatives carrying pathogenic variants enables early diagnosis and cancer prevention by offering risk management options such as enhanced MRI imaging and mammography screening, risk-reducing surgeries such as prophylactic mastectomy, salpingo-oopherectomy and chemoprevention with Selective Estrogen Receptor Modulators.
The authors in this study estimated the downstream health effects, costs and cost-effectiveness of multigene testing for all patients with breast cancer, compared with current practice of BRCA testing based on clinical criteria or family history alone. In this modeling study, data was incorporated from four large breast cancer clinical trials and/or research cohorts in the United States, United Kingdom, and Australia. This analysis included 11,836 women with invasive breast cancer, regardless of the family history, and compared lifetime costs and effects of high-risk BRCA1/BRCA2/PALB2 (multigene) testing of all unselected patients with breast cancer (Strategy A) with BRCA1/BRCA2 testing based on family history or clinical criteria (Strategy B), in UK and US populations, from January 1, 2018, through June 8, 2019.
Affected patients with BRCA/PALB2 mutations could undertake contralateral preventive mastectomy and BRCA carriers could choose Risk-Reducing Salpingo-Oophorectomy (RRSO). If patients had a BRCA1/BRCA2/PALB2 pathogenic variant, their first-degree relatives undergo testing for the familial pathogenic variant. If the first-degree relative had a BRCA1/BRCA2/PALB2 pathogenic variant, second-degree relatives undergo testing. Unaffected relative carriers could undergo MRI or mammography screening, chemoprevention, or risk-reducing mastectomy for breast cancer risk and RRSO for ovarian cancer risk. This analysis incorporated lifetime risks and long-term consequences to provide a lifetime horizon. Incidence of ovarian cancer, breast cancer, excess deaths due to heart disease, and the overall population effects were estimated.
Multigene testing was restricted to BRCA1/BRCA2/PALB2, to comply with the ACCE framework for genetic testing, which was advocated for clinical applicability of genetic testing. The ACCE framework includes Analytic validity which is technical test performance, Clinical validity which is the ability of a genetic test to identify or predict accurately and reliably the clinically defined disorder or phenotype of interest, Clinical utility which is evidence that a genetic test improves clinical outcomes measurably and that it adds value for patient management decision making compared with current management without genetic testing, and ELSI which are the complex Ethical, Legal, and Social Implications associated with genetic tests.
This study showed that unselected BRCA1/BRCA2/PALB2 testing for all patients at breast cancer diagnosis was extremely cost-effective compared with BRCA1/BRCA2 testing based on clinical criteria or family history for both UK and US health systems, with incremental cost-effectiveness ratios of £10,464 or £7,216 and $65,661 or $61,618 per Quality-Adjusted Life-Year, respectively. Quality-Adjusted Life-Year (QALY) is a measurement of health outcomes in economic evaluations recommended by NICE (National Institute of Health and Clinical Excellence). This is well below UK and US cost-effectiveness thresholds. The authors estimated that one year’s unselected panel genetic testing could prevent 1142 cases of breast cancer, 959 cases of ovarian cancer, and 633 deaths related to breast or ovarian cancer in the UK. In the US, one year’s unselected panel genetic testing could prevent 5478 cases of breast cancer, 4255 cases of ovarian cancer, and 2406 deaths related to breast or ovarian cancer. 
It was concluded from this analysis that unselected, high-risk multigene testing for all women with breast cancer is extremely cost-effective, compared with testing based on family history or clinical criteria, and could identify many more mutation carriers who can benefit from precision prevention. The authors added that these findings support changing current policy to expand genetic testing to all women with breast cancer. A Cost-effectiveness Analysis of Multigene Testing for All Patients with Breast Cancer. Sun L, Brentnall A, Patel S, et al. JAMA Oncol. 2019;5:1718-1730