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Genetic testing for all breast cancer patients: Is this becoming a reality?

The evolution of genetic testing for breast cancer patients is outlined, including the ASBrS consensus guidelines and the potential implications of germline genetic mutation detection on surgical management.

Anna Weiss, MD, FACS, Henry M. Kuerer, MD, PhD, FACS, Judy C. Boughey, MD, FACS

January 1, 2020


  • Describes the evolution of genetic testing for breast cancer patients
  • Identifies the five major points of the ASBrS consensus guidelines
  • Summarizes the implications of germline genetic mutation detection and implications on surgical management

Editor’s note: This article was developed and written as part of a series of feature stories by members of the American College of Surgeons Clinical Research Program to inform Bulletin readers about issues that affect cancer surgeons and patients.

The American Society of Breast Surgeons (ASBrS) released consensus guidelines February 10, 2019, regarding testing for hereditary breast cancer syndromes.1 The major takeaway from these guidelines is that germline genetic testing should be available to every breast cancer patient; however, the consensus statement also discusses many of the challenges related to germline genetic testing, presents an unbiased review of the literature, and suggests appropriate management strategies. This article summarizes background information pertaining to expanded genetic testing, presents the five major points contained in the ASBrS guidelines, highlights the importance of germline genetic mutation detection, and discusses the implications this practice change will have for surgical management.


Approximately 10 to 15 percent of breast cancers are attributable to an inherited genetic mutation.2 According to the National Comprehensive Cancer Network (NCCN) guidelines, clinicians should consider genetic testing for breast cancer patients who are 50 years old or younger, have triple-negative breast cancer at an age younger than 60 years old, are male with breast cancer, have bilateral or a second primary breast cancer, or also have had ovarian cancer.3 For individuals without this personal history, additional family history criteria must be met: At least one relative with breast cancer diagnosed at 50 years old or younger; one relative with ovarian cancer; and more than two relatives with breast cancer, prostate cancer (Gleason score ≥7 or metastatic disease), or pancreatic cancer. However, these guidelines are cumbersome for providers and may lead to lapses in identifying patients who can be considered for genetic testing.4 In fact, only one in five patients who meets these guidelines is referred for genetic testing. A cross-sectional look at the National Health Interview Survey Cancer Control Supplement in 2005, 2010, and 2015 estimated that at least 1.2 million patients never underwent genetic testing.2

Many groups internationally have recognized the problem of not testing a significant proportion of patients with genetic mutations in breast cancer predisposition genes and have started to provide evidence for broadening their nations’ genetic testing guidelines to simplify the process and capture more genetic mutation carriers. A group in Norway tested all breast cancer patients for BRCA1/2 mutations and found that 3 percent of the 1,371 patients tested had a BRCA1 or BRCA2 mutation and that existing guidelines were insufficient to identify all BRCA1/2 mutation carriers.5 A group in the U.K. conducted a study that used broadened and simplified guidelines. The researchers tested patients with breast cancer who were younger than 45 years old, had two primary breast cancers before the age of 60, had triple-negative breast cancer at any age, had ovarian cancer at any age, were men of any age, or any breast cancer patient in whom genetic testing would affect their cancer management. They found that 117 of 1,184 people tested had BRCA mutations, which represented 50 percent more mutations detected than would have been found if they had used their prior guidelines.6

These studies, though, only tested for BRCA1/2 mutations; the percentage of genetic mutation carriers identified would likely have been higher had panel testing been performed. Yang and colleagues retrospectively examined deidentified data from 4,196 Medicare patients undergoing genetic testing. Rates of germline genetic mutation were similar among patients who met NCCN criteria (10.5 percent) and patients who did not meet NCCN criteria (9 percent, p = 0.26).7 Another group in the U.S. prospectively performed broad panel testing (80 genes) for a series of consecutive breast cancer patients and discovered that 9.65 percent of 959 tested patients carried a pathogenic germline mutation. These rates were similar among patients who met the NCCN guidelines for genetic testing (9.39 percent) and those who did not (7.9 percent; p = 0.4241).4

Five points from the consensus guidelines

The ASBrS consensus guidelines include the following major take-home points:1

  • Health care professionals who are knowledgeable about genetic testing can discuss and arrange genetic testing for patients. It may be useful to refer complicated patients to certified genetic counselors.
  • Germline genetic testing should be offered to all breast cancer patients, both newly diagnosed and those with a previous personal history.
  • Patients with prior genetic testing may benefit from updated testing.
  • Genetic testing should be available to patients without cancer but who otherwise meet NCCN guidelines.
  • Variants of uncertain significance (VUS) results are not clinically actionable findings.

The importance of detecting a genetic mutation

Discovering deleterious genetic mutations in breast cancer predisposition genes can have many important implications for the breast cancer patient. These include a change in the patient’s cancer management, enhanced surveillance strategies for recurrent breast cncer, enhanced surveillance and prevention of other cancers, and cascade testing for family members.

An important reason to identify genetic mutation carriers is that different systemic therapies may be more effective in this population. There is substantial evidence that poly (ADP-ribose) polymerase inhibitors are especially effective in metastatic breast tumors with DNA-repair defects, such as those in BRCA1/2 patients,8,9 and cisplatin, an alkylating agent that disrupts DNA replication, has shown activity in BRCA1/2-mutated patients, possibly because of their impaired DNA repair mechanisms.10,11 Based on this body of work, ongoing clinical trials are examining BRCA patient-specific regimens.12 As certain treatments are found to be more effective in some patient populations than others and the field of cancer treatment moves toward personalized or precision medicine, the identification of genetic mutation carriers will be increasingly important.

Another reason to test breast cancer patients for genetic mutations is that germline genetic mutation carriers with residual breast tissue are at increased risk of a second primary breast cancer of both the ipsilateral and contralateral breast, and increased posttreatment surveillance should be recommended. This continuum of care involves mammogram/tomosynthesis and magnetic resonance imaging (MRI) every year. In contrast, average-risk women without a predisposition to genetic mutation require only bilateral mammogram annually.

Genetic testing results can have considerable implications for unaffected relatives, especially siblings and offspring—from improved risk stratification to specialized medical and surgical interventions for risk modification. For example, unaffected patients who are found to be genetic mutation carriers at increased risk of breast cancer are offered enhanced screening with annual MRI and mammogram for early detection of breast cancer to minimize morbidity and mortality. In addition to the higher rates of genetic mutation detected in the study by Grindedal and colleagues, the testing of relatives after the identification of a mutation resulted in, on average, one additional family member being identified as having a genetic mutation for each of the patients who tested positive. One early-stage breast cancer and one early-stage ovarian cancer were identified on average in these “unaffected” family members.5 The identification of genetic mutation carriers and early detection of breast cancer or risk reduction with surgery to prevent ovarian cancer can be lifesaving. Panel-based testing results also can detect mutations in genes that confer an increased risk of other malignancies, such as colorectal cancer. Earlier and more frequent colonoscopy screening can effectively prevent colorectal cancer if such a pathogenic mutation is discovered.

It is a common and reasonable concern that the increased demand for genetic testing will overcome the supply of genetic counselors.

Implementation concerns

It is a common and reasonable concern that the increased demand for genetic testing will overcome the supply of genetic counselors.13 In the Surveillance, Epidemiology, and End Results (SEER) study conducted by Kurian and colleagues, half of the patients tested for a genetic mutation never saw a genetic counselor.14 Consequently, the ASBrS recommendation encourages surgeons or other clinicians experienced and knowledgeable in genetic testing to educate patients and order genetic testing for patients.1 The ASBrS, cautions, however, that patients with complicated family histories or complex genetic mutation results would benefit from referrals to genetic counselors.

To address the genetic counselor workforce issue, expedited genetic mutation pre-counseling and testing practices are in development.15 One such model implemented a rapid testing practice, which included pre-test counseling and genetic testing performed by the cancer team and then cascade testing performed by genetic counselors.16 As at least some of the genetic testing responsibility likely will shift to surgeons; rapid genetic testing models will prove crucial in the coming years, and consideration should be given to developing such models with genetic counseling input.

Health care resource use and cost containment is another common concern regarding broadening genetic testing practices. According to the National Human Genome Research Institute, the cost of coding the human genome has dramatically declined since 2001.17 Also, the number of genetic tests on the market is increasing,18 and genetic testing is widely available to the public via direct-to-consumer saliva/cheek swabs,19 resulting in heightened competition between companies. For these reasons, it can be assumed that the trend of decreasing genetic testing costs will continue to align with pricing for other routine medical screening tests. Furthermore, several studies indicate that broad genetic testing applied to all breast cancer patients is cost-effective, with the prevention of breast and ovarian cancers in family members of affected individuals offsetting the costs of testing.20,21 A recent microsimulation modeling study published in JAMA Oncology21 examined two testing strategies among 11,836 patients in the U.S. and U.K.—testing only those with family history or clinical criteria versus testing all affected patients. This study showed that the cost of broad genetic testing would fall well below each country’s cost-effectiveness threshold and would prevent more than 2,000 breast and ovarian cancer cases and 600 deaths in the U.K. and more than 9,000 cases and 2,000 deaths in the U.S. annually. The authors concluded that broad genetic testing would be cost-effective.

Genetic mutation status significantly affects surgical decision making. Even in patients who are not affected by a pathogenic genetic mutation, the rates of CPM have been on the rise for the past two decades.

Implications for surgical practice and patient management

Genetic mutation status significantly affects surgical decision making. Even in patients who are not affected by a pathogenic genetic mutation, the rates of contralateral prophylactic mastectomy (CPM) have been on the rise for the past two decades—increasing from 2 percent in 1998 to 12.7 percent in 2012.22 Despite this more aggressive surgical treatment, bilateral mastectomy is not associated with a decreased mortality compared with breast conservation.23 Patients who have an inherited genetic mutation may be more likely to choose a mastectomy and/or CPM as their surgical procedure based on their increased risk of a second breast cancer.14 Risks of contralateral breast cancer and benefits of prophylactic surgery for BRCA germline mutation carriers are well established. Although it has not been shown to improve survival, bilateral mastectomy does reduce contralateral breast cancer risk by 95 percent among BRCA1/2 mutation carriers.24

Generally, the NCCN guidelines successfully identify many patients with BRCA mutations because the guidelines were based on clinical factors and family histories of BRCA mutation carriers; as such, the major increase in discovery of genetic mutations resulting from broad-based genetic testing will be moderate penetrance gene mutations.25,26 Unfortunately, unlike for BRCA carriers, specific estimates are not available with regard to the benefits of prophylactic surgery for carriers of mutations in other breast cancer susceptibility genes.27,28 Most of these patients are at lower risk than BRCA mutation carriers, but risk estimates are unstable because of smaller numbers, variable penetrance, and lack of long-term follow-up.

So, although we have less clear surgical guidance for these moderate penetrance genetic mutation carriers, clinicians will be identifying these patients more frequently. Hence, the ASBrS consensus guidelines made recommendations regarding prophylactic mastectomy. For the following four genes, the ASBrS recommends consideration of risk-reducing mastectomy: BRCA1, BRCA2, PTEN, and TP53. For the other germline mutations associated with increased breast cancer risk, the ASBrS recommends enhanced screening: ATM, CDH1, CHEK2, NBN, NF1, PALB2, and STK11. The authors reinforce that data are insufficient to support risk-reducing mastectomy,1 which is in line with other recommendations.25,28 Some patients may pursue risk-reducing surgery, regardless of genetic mutation status, based on their perceived risk of contralateral breast cancer, desire for symmetry with bilateral reconstruction, peace of mind, or to forgo future breast screening. Factors such as family history and age should play a particularly important role in an informed patient-provider discussion regarding moderate penetrance gene mutation carrier status, and though ultimately patients may opt for bilateral mastectomy, the ASBrS recommendations should be considered.

Surgeons critically influence the decisions women with early breast cancer make about their surgical procedures and their satisfaction with those decisions.

Surgeons critically influence the decisions women with early-stage breast cancer make about their surgical procedures and their satisfaction with those decisions. The ASBrS has advised against routine CPM in average-risk women without a genetic mutation.29,30 A recommendation against CPM in a SEER cohort of patients with early stage breast cancer led to only a 1.9 percent rate of CPM, whereas women who received care from surgeons who did not provide management recommendations had a tenfold higher (19 percent) rate of CPM.31 Furthermore, patients reported low dissatisfaction when their surgeon did not recommend against CPM but discussed it (3.9 percent), whereas dissatisfaction was substantively higher when surgeons recommended against CPM but did not discuss it (14.7 percent), highlighting the importance of informed discussion and shared decision making. In addition, women who were advised against CPM were not more likely to seek a second opinion or have a different surgeon perform the operation.32

The oncology community has expressed general concern that increased genetic testing would lead to increased rates of contralateral prophylactic mastectomy. However, evidence indicates that the increase in mutations discovered by multigene panel testing has not led to a corresponding increase in rates of CPM.33 This finding is encouraging, though the rates were already high and approximately equal for women with a deleterious mutation, a VUS, and no mutation at all, which may point to overtreatment of women with negative or VUS results. Well-designed rapid genetic counseling and panel testing practices did not increase rates of mastectomy in two prospective single-institution trials.34,35 In a series of patients with VUS identified in BRCA,35 breast cancer patients with a known VUS in BRCA before surgery opted for CPM at a similar rate as patients who did not have preoperative knowledge of their VUS (22 percent versus 35 percent, respectively; P = 0.45); overall surgical choices made by patients with a VUS closely resembled patients with no known genetic mutation in this series from the Mayo Clinic, Rochester, MN. Patients with a VUS in BRCA but without a cancer diagnosis had high rates of bilateral prophylactic mastectomy, associated with first-degree family history and clinical risk. Over time, 22 percent of the 97 patients with BRCA VUS were reclassified (95 percent benign, 5 percent deleterious), illustrating the importance of appropriate counseling regarding VUS. Another critical aspect of the ASBrS consensus guidelines is the emphasis that a VUS result is not clinically actionable.


The ASBrS recently released consensus guidelines recommending genetic testing be made available for all breast cancer patients. This represents a departure from other guidelines, such as those from the NCCN. However, the statement recognizes the challenges of this practice and makes clear recommendations for clinical quandaries like VUS results and prophylactic surgery for moderate penetrance gene mutation carriers. Broad genetic testing practices should be considered and likely will become standard care in the coming years, and the ASBrS consensus guidelines are straightforward and can serve as an important resource for surgeons.


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