BRCA1/2 Mutations: Missed Opportunities
By Robert L. Coleman, MD, Professor, University of Texas, M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman reports no financial relationship to this field of study.
Synopsis: Patients referred and cared for with the diagnosis of ovarian cancer often had an accurate family history documented in the medical record but were infrequently referred for genetics counseling despite having substantial risk (20%-25% probability) of carrying a mutation in BRCA1 or BRCA2. Over time, the proportion significantly increased; however, at study closure, less than half had been referred.
Source: Meyer LA, et al. Evaluating women with ovarian cancer for BRCA1 and BRCA2 mutations: Missed opportunities. Obstet Gynecol 2010;115:945-952.
The primary objective of this retrospective study was to estimate the incidence of genetic counseling referral for ovarian cancer patients who were at high risk for carrying a mutation in BRCA1 or BRCA2. To do this, Meyer and colleagues evaluated all patients presenting at a comprehensive cancer center with the diagnosis of known or suspected ovarian cancer over a 9-year period. Patients meeting criteria for substantial risk (defined as a 20%-25% chance of carrying a BRCA mutation) were identified and the medical records reviewed for genetics counseling referral. In all, 3765 patients were seen over the study duration. On average, about 24% of the cohort met the criteria. The percent did not vary over the study duration. However, the percentage of these patients who were referred for genetic counseling significantly increased from just 12% in year 1 to 49% at year 9. The median time to referral was > 3 years for the study population, but lessened each year of the study. Patients with a new diagnosis of ovarian cancer and non-African-American women were more likely to be referred. Overall, 86% of women referred and recommended for testing had it performed; approximately half of the patients were BRCA1 or BRCA2 mutations carriers. Although family history was accurately detailed in the medical record, a substantial number of patients went unreferred for genetics counseling. Improvements in referral practices accompanied greater faculty awareness, intake questionnaires reflecting ACOG guidelines, and the development of an in-clinic referral service.
Sophocles is credited with saying, "Look and you will find it what is unsought will go undetected." It is of little debate that developing a keen clinical index of suspicion is one of the vital stepping stones to achieving expert clinical aptitude. Unfortunately, it appears the converse is not always true. While the axiom is clear and somewhat obvious, it appears the message is applicable to the practice of identifying at-risk individuals for BRCA mutation. In light of the potential for direct patient intervention, as well as the continued impact on at-risk family members, the stakes for identifying these individuals has never been higher. The manuscript highlights several pertinent and practical issues, which deserve further discussion and consideration.
Underutilized genetics counseling services for family members. It has been extensively documented that both positive and negative results of genetics testing for an inherited malignancy have an emotional, financial, physical, and psychological impact for family members.1,2 While it is easy to appreciate the impact a positive result could have on a young asymptomatic woman or man, particularly as they contemplate potential prophylactic interventional strategies, it can be equally devastating to a family member who tests negative or who carries an uninformative, or previous undocumented mutation. These issues are among the many domains expert genetic counseling brings to a blood test, which can be ordered in their absence. Fortunately, more and more centers are employing staff with expertise and time to discuss and explore these concerns. However, without referral, many of these interventions never take place.
As highlighted in the paper by Meyer et al, a prospective strike was necessary to improve referral patterns at this major tertiary care cancer center. This first involved reviewing already established clinical guidelines (see Table, below) and adding these questions to the intake form as patients presented to the center.3 The second was having a team in the clinic, available for both outpatient and inpatient referral. The long-term impact was a substantial increase in referral, but the rate of positive testing (nearly 50%) suggests many continue to slip through. A striking observation in the study was that although there was a high degree of agreement between physician-documented and patient-reported family history at initial presentation, the median time until referral to genetic counseling for women at high risk of mutation was > 3 years. The authors suggest these findings may result from the lack of a perceived benefit or clinical urgency by the patient due to lack of knowledge of these data.
Table. Risk factors associated with substantial risk (20%-25%)
for carrying a deleterious mutation in BRCA1 or BRCA2
Clearly, as outlined below, this issue is changing and likely will bring to the forefront new therapeutic options. Still, it is recommended that affected individuals meeting criteria as potential mutation carriers be tested as a more focused, cheaper, and informative test can be offered to other family members.4
New therapeutic opportunities for affected patients (and tumors?). In the September 2009 issue of OB/GYN Clinical Alert, I summarized a provocative study in BRCA mutations carriers treated with olaparib, which inhibits the DNA repair enzyme, poly ADP-ribose polymerase or PARP. The trial, published as a phase I trial in the New England Journal of Medicine, demonstrated tumor efficacy in patients with platinum-refractory, -resistant, and -sensitive recurrent ovarian cancer with a very favorable toxicity profile.5 Since this report, a phase II study has also been presented, confirming the favorable therapeutic index and a greater understanding has been made into the mechanisms of PARP inhibitor resistance, such as the appearance of reversion mutations, which restore normal BRCA protein function.6,7 Nevertheless, the identification of heightened specific tumor cell vulnerability to a compound with otherwise little innate impact in the presence of a normal DNA reparative pathways (so called "synthetic lethality") has fostered robust clinical development. Indeed, despite the relatively small cache of potential candidates for PARP inhibitors, at least six pharmaceutical companies have launched clinical programs in breast and ovarian cancer patients to formally evaluate these compounds for FDA registration.
Epigenetic alterations expand indications of novel therapeutics. An interesting development over the last 3 years has been the recognition that BRCA dysfunction can occur in tumor while the patient, themselves, have normal germline BRCA gene function. Preclinical models of this situation would suggest the PARP inhibitors would be of clinical value.8,9 BRCA genes function, among other mechanisms, to repair double-strand DNA damage through a process called homologous recombination. Epigenetic changes, such as promoter methylation, appear to be present in about 15%-20% of high-grade serous ovarian cancers from patients without germline mutation. In this manner, tumor-associated BRCA dysfunction is likely to be represented by a spectrum of protein dysfunction. Currently, the critical level of dysfunction for which tumors become vulnerable to PARP inhibitors has yet to be elucidated. Challenging the situation further has been the need for fresh tumor tissue to do traditional quantifying measures of protein expression. Since tissue from ovarian cancer patients is not freely available or attainable without some risk, this presents a clinical problem. Methods are currently being optimized, which may overcome this limitation, but, ultimately, the representation of archival material to current tumor status will remain a concern.
Another therapeutic approach attempting to leverage this pathway is pharmacologically to induce BRCA dysfunction. Several agents, such as the DNA-alkylators, are suspected to be able to induce homologous recombination deficits, which may augment the tumoricidal impact of PARP inhibitors. However, this hypothesis has yet to be directly confirmed in the clinic. Nevertheless, a randomized phase II trial of the nucleoside analogue, gemcitabine, and DNA-alkylating agent, cisplatin, in combination with a PARP inhibitor, BSI-201, demonstrated highly significant clinical efficacy over the non-PARP inhibitor chemotherapy arm in unselected patients with triple-negative (Her2/neu-negative, ER-negative, PR-negative) breast cancer.10 While this cohort of generally chemo-insensitive women is associated with BRCA1 deficiency, the trial demonstrates the potential of treating unselected patients who may benefit from this approach.
A corollary to BRCA story may be relevant in another familial syndrome, the Lynch Syndrome. This disease, characterized by young age of colorectal (non-polyposis) cancer and also associated with other cancers including uterine cancer (nearly the same prevalence), small bowel cancer, and upper urinary tract cancer, is caused from an inherited mutation in one of several DNA mismatch repair genes. A recent report suggests the concept of synthetic lethality is present when tumor cells deficient in one of these genes is treated with agents targeting DNA polymerases (POL-beta and POL-gamma).11 Inhibitors of these genes already exist, such as vitamin K3 and zidovudine-TP. While it remains to be seen if this strategy will translate to the clinic, it is clear that correctly identifying individuals and family members who harbor a risk for carrying a genetic mutation is a necessary first step.
The prospect for personalized cancer therapeutics in genetic mutation carriers has never been higher and the developing knowledge of cancer biology continues to pave this path. However, the fruits of this labor may be under-realized if we fail to identify these patients. The paper by Meyer et al serves to remind us to be on our clinical guard, utilizing and revising our resources to optimize care for these patients.
- Hughes C, et al. All in the family: Evaluation of the process and content of sisters' communication about BRCA1 and BRCA2 genetic test results. Am J Medical Genet 2002;107:143-150.
- Lerman C, et al. The influence of psychological distress on use of genetic testing for cancer risk. J Consult Clin Psychol 1997;65:414-420.
- ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome. Obstet Gynecol 2009;113:957-966.
- Guillem JG, et al. ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes. J Clin Oncol 2006;24:4642-4660.
- Fong PC, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009;361:123-134.
- Edwards SL, et al. Resistance to therapy caused by intragenic deletion in BRCA2. Nature 2008;451:1111-1115.
- Sakai W, et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature 2008;451:1116-1120.
- Farmer H, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005;434:917-921.
- Bryant HE, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005;434:913-917.
- Pal SK, Mortimer J. Triple-negative breast cancer. Maturitas 2009;63:269-274.
- Martin SA, et al. DNA polymerases as potential therapeutic targets for cancers deficient in the DNA mismatch repair proteins MSH2 or MLH1. Cancer Cell2010;17:235-248.