Two oncologic surgeons squared off at the 32nd Miami Breast Cancer Conference to debate whether breast cancer genetic susceptibility panel testing is ready for routine use in the clinic. J. Michael Dixon, MD, Professor of Surgery and Consultant Surgeon at the Edinburgh Breast Unit in the United Kingdom, argued against testing, and Pat Whitworth, MD, Director of the Nashville Breast Center in Tennessee, countered.
Panels Don’t Meet WHO Standard
There are now 14 next-generation sequencing tests that include BRCA1 and BRCA2, but according to Dr. Dixon, “Just because you can test for susceptibility using these panels doesn’t mean you should…. Gene panels cannot be recommended at present in an evidence-driven health-care system.”
The World Health Organization (WHO) has published criteria to be met for any genetic test to be considered valuable: the disease is an important health problem, the risk in mutation carriers is high in the general population (not just in a high-risk group), mutations for the disease can be accurately identified, and effective interventions exist.
Among the breast cancer susceptibility genes, only BRCA1/2 meets these criteria, although many other genes are included in gene panels—and they are generally not common in breast cancer patients, Dr. Dixon indicated. CHEK2, ATM, BRIP1, PALB2, and RAD51 (among others) demonstrate low penetrance, unclear clinical applicability, and/or weak associations with cancer risk.
“For most genes in the panel, we have limited data on cancer risk and penetrance and no consensus on the management if mutations are found,” he said.
Variants of Unknown Significance
Variants of unknown significance constitute another problem. In a recent study, investigators sequenced 22 cancer susceptibility genes in 278 BRCA1/2-negative women; they found that 31 (11%) had at least one deleterious or likely deleterious variant (guidelines were available for only 2.5%), and 19% of all patients had at least one variant of unknown significance.1 Another 2014 study identified an average of 2.1 variants of unknown significance per breast cancer patient tested.2
Dr. Dixon pointed out that women often undergo risk-reducing surgical procedures on the basis of findings of variants of unknown significance, although about half of these findings are eventually reclassified, often as benign. “This information usually arrives too late to inform these decisions,” he said.
Kurian et al documented 16 pathogenic variants in a variety of genes other than BRCA1/2—aberrations for which management guidelines are lacking,2 he added. “We need much more information about which mutations are deleterious, what their associated risks are, and how we should manage these women,” he commented.
He noted that the National Comprehensive Cancer Network (NCCN) recently stated that testing must be focused on identifying a mutation known to be clinically actionable,3 a requirement that is not met by most genes in the panel, he said.
This leaves physicians at a loss as to how to counsel patients, given the uncertain value of these findings. They are not aided by the current clinical and counseling framework, which was developed to support single-gene testing and is not adequate for dealing with next-generation sequencing and panel testing.
“Gene panels are like a black hole,” Dr. Dixon concluded. “The problems are deep, and there is no clear light as to how to interpret many of the results. Undoubtedly, gene testing should be performed—but panels with limited genes are the best bet just now.”
Too Late to Turn Back
Dr. Whitworth took the opposite point of view, arguing, “Physicians need to be educated and ready…. We’ve come too far, the tests are available, and we need to use them properly on behalf of our patients.”
“Right now, we are doing a terrible job with BRCA testing. We are not testing those who need it, we are not delivering care where it is needed, and our system is inadequate,” he maintained.
An estimated 220,000 American women are BRCA carriers, yet most carriers have not been identified and informed prior to a breast cancer
diagnosis, he said, meaning that most carriers will only be identified after developing cancer.4
He believes the challenge of inadequate delivery of care where it is needed, and the expansion of testing for other breast cancer susceptibility genes, can best be met through physician education. Although genetic counselors are important, they are not a substitute, he said.
“Referring our patients to genetic counselors is not solving the problem. Counselors cannot possibly handle what’s coming. There are approximately 3,000 genetics counselors nationwide, and just less than one-third are focused on cancer, according to the National Society of Genetics Counselors,” he suggested.
Countering the Objections
An asymptomatic person worried about an inherited cancer risk could undergo sequencing for cancer-related genes or could have whole-genome sequencing, which may reveal other preventable or treatable conditions. These screening approaches have raised some objections, he acknowledged.
Some of these objections are that the current state of knowledge is incomplete “therefore, we don’t know what to do with the results”; that guidelines are lacking, “therefore, experts urge caution outside of clinical trials”; that screening will increase patients’ distress and lead to more unnecessary mastectomies; and that mistakes will ensue because recommendations are based on limited information.
Dr. Whitworth responded, “Yes, we are working with incomplete knowledge, but we do know what to do with the results. Yes, we lack guidelines, but although guidelines are helpful, they are for followers, not leaders. Distress will not increase; in fact, distress and mastectomies will decrease if we do a good job educating doctors. As for making recommendations based on limited information, we do this every day. We just must proceed with caution.”
According to Dr. Whitworth, panel testing is “logical,” as there are many known pathogenic mutations beyond BRCA. Early studies using a 25-gene panel have indicated that 50% more pathogenic mutations are identified in patients, compared with single-gene testing. Testing for them gives relevant information while avoiding the additional expense and distress of the “diagnostic odyssey” that prevails when BRCA1/2 results are negative.
“Patients know there are other mutations beyond BRCA, and they want this information,” he said. Ultimately, he maintained, testing for known familial mutations will result in more appropriate use of resources (screening, surveillance, intervention) and a reduction in fear, distress, and unnecessary surgeries.
He added that management can be guided by family history, which is a key modifier of risk in the case of moderate penetrance mutations. For example, PALB2 carries a 33% breast cancer risk in the absence of a family history and a 58% breast cancer risk when a family history is present. The risks associated with CHEK2 are 20% and 45%, respectively.5-7 None of these findings justifies mastectomy, but special surveillance (ie, with MRI) is warranted.
Revisiting Variants of Unknown Significance
Acknowledging that variants of unknown significance are problematic, Dr. Whitworth believes that these issues will be sorted out once broader testing is achieved and with the aid of “well-designed research” and education of physicians. Meanwhile, he suggested “keeping a clinical point of view” in managing variants of unknown significance and not falling prey to one’s own scientific curiosity.
The patient should understand that variants of unknown significance do not explain one’s family history and mean nothing with regard to patient care; that the vast majority of variants of unknown significance are benign and only occasionally reclassified as pathogenic; that action based on finding a variant of unknown significance is not appropriate; and that care will be designed according to standard family history and risk.
He indicated that panel testing has become a standard of care at leading institutions; predicted population-based testing is coming soon; and projected that in 10 to 20 years, whole-genome or whole-exome sequencing will guide management. “We will need to navigate there safely, wisely, and economically,” he added. ■
Disclosure: Drs. Dixon and Whitworth reported no potential conflicts of interest.
References
1. Maxwell KN, Wubbenhorst B, D’Andrea K, et al: Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. Genet Med. December 11, 2014 (early release online).
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 32:2001-2009, 2014.
3. Domchek SM: Evolution of genetic testing for inherited susceptibility to breast cancer. J Clin Oncol 33:295-296, 2015.
4. Drohan B, Roche CA, Cusack JC Jr, et al: Hereditary breast and ovarian cancer and other hereditary syndromes: Using technology to identify carriers. Ann Surg Oncol 19:1732-1737, 2012.
5. Antoniou AC, Casadei S, Heikkinen T, et al: Breast-cancer risk in families with mutations in PALB2. N Engl J Med 371:497-506, 2014.
6. Goldgar DE, Healey S, Dowty JG, et al: Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Res 13(4):R73, 2011.
7. Cybulski C, Wokołorczyk Dd, Jakubowska A, et al: Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer. J Clin Oncol 29:3747-3752, 2011.
