Elsevier

European Journal of Cancer

Volume 69, December 2016, Pages 127-134
European Journal of Cancer

Current Perspective
Current perspectives on recommendations for BRCA genetic testing in ovarian cancer patients

https://doi.org/10.1016/j.ejca.2016.10.006Get rights and content

Highlights

  • Offer BRCA genetic testing to all invasive epithelial OC patients (excluding borderline and mucinous cancers).

  • Testing should be irrespective of age.

  • Ideally offer testing at diagnosis, although patients can be referred at any stage.

  • Retrospective testing should be offered to patients in long-term follow-up.

  • Tumour testing should be considered in non-germline-mutated patients.

Abstract

Traditionally, BRCA genetic testing has been undertaken to identify patients and family members at future risk of developing cancer and patients have been referred for testing based on family history. However, the now recognised risk of ovarian cancer (OC) patients, even those with no known family history, harbouring a mutation in BRCA1/2, together with the first poly adenosine diphosphate ribose polymerase inhibitor (PARPi; olaparib [Lynparza]) being licenced for the treatment of BRCA-mutated OC, has led to reconsideration of referral criteria for OC patients. Provided here is a review of the existing data and guidelines in the European Union, relating to recommendations, as well as considerations, for the referral of OC patients for BRCA genetic testing. Based on this review of newly updated guidance and up-to-date evidence, the following is recommended: all patients with invasive epithelial OC (excluding borderline or mucinous), including those with fallopian tube and peritoneal cancers, should be considered as candidates for referral for BRCA genetic testing, irrespective of age; genetic testing should ideally be offered at diagnosis, although patients can be referred at any stage; retrospective testing should be offered to patients in long-term follow-up because of the implications for family members and individual future breast cancer risk; and germline BRCA testing of a blood/saliva sample should initially be conducted and, if negative, tumour tissue should be tested (to identify non-germline [somatic] BRCA PARPi therapy candidates).

Introduction

Ovarian cancer (OC) is the fifth most common cancer in European women; estimated 65,500 cases and 42,700 deaths annually [1]. Germline mutations in BRCA1 and BRCA2 (tumour suppressor genes) incur an increased risk of breast cancer (BC) and/or OC and, to a lesser extent, other cancers [2], [3]. The general population's lifetime risk of developing OC is 1.5% [4], compared with 40–60% and 11–30% for women with BRCA1 and BRCA2 germline mutations, respectively [5]. Approximately 6–25% of OC patients have a BRCA1/BRCA2 germline mutation [4], and a further 5–11% have a somatic mutation [5], [6].

Identification of BRCA-mutated OC patients is important to identify those at further cancer risk, at-risk family members and for individual treatment decisions, as germline/somatic BRCA-mutated OCs are associated with improved response to platinum-based chemotherapy (OC standard-of-care) and long-term prognosis than non-BRCA-associated OCs [2], [7]. Furthermore, in 2015, the first poly adenosine diphosphate ribose polymerase inhibitor (PARPi; olaparib [Lynparza]) was licenced in Europe for BRCA-mutated (germline/somatic) high-grade serous OC treatment [8]. Thus, BRCA genetic analysis is now also important to identify PARPi therapy candidates.

Despite up to 25% of OCs harbouring a BRCA1/2 germline mutation [4], >40% of mutation carriers have no known family history of BC/OC [4], [10]. Traditionally, BRCA genetic testing referral was based on family history, thus likely to miss many OC BRCA carriers. In light of the now recognised high incidence of BRCA mutations in OCs, recently updated guidelines have extended testing beyond those with a family history. For example, the European Society of Medical Oncology BRCA testing guidelines, 2011 update, recommend testing based on family history and estimated mutation risk [11], whereas international guidelines by the National Comprehensive Cancer Network [12], 2015 update, recommend BRCA testing in all invasive OC patients and the Society of Gynaecological Oncology guidelines [13], 2014 update, recommend testing all patients with epithelial ovarian, tubal and peritoneal cancers (Table 1). OC BRCA testing guidelines have recently been updated in many European countries, representing a shift away from family-history-based testing towards OC histology-based recommendations, reflecting the need to identify patients for treatment decisions and patient's lack of accurate family history. The published/open-access guidelines available for BRCA testing in OC patients are summarised in Table 1 [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25]. The referral criteria differ between these published guidelines due, mostly, to guideline publication timing and understanding of OC patients' mutation risk at that time, along with considered local practicalities of excluding/including minority patient groups with a low mutational risk. Furthermore, many institutions have established practices not stipulated in their national guidelines; for example, the Royal Marsden Hospital (United Kingdom) and the Leuven Cancer institute (Belgium, EU) test all ovarian (fallopian tube and primary peritoneal), non-mucinous cancer patients for germline BRCA mutations. The aim of this manuscript is to review the existing data/guidelines and provide an updated opinion on recommendations and considerations for the referral of OC patients for BRCA genetic testing.

Section snippets

Referral criteria for BRCA testing in OC patients

In unselected population studies, BRCA mutations are most frequently associated with high-grade serous OC (17%) and to a lesser extent with low-grade serous carcinoma [26]; 1–13% of other homologies also harbour BRCA mutations (Table 2; [8], [26], [27], [28], [29], [30]). Based on this evidence, and in line with recently updated guidance, it is recommended that OC patients with invasive epithelial OC (excluding borderline and mucinous), including fallopian tube and peritoneal cancers,

BRCA genetic testing recommendations

Ideally, to eliminate follow-up loss and for treatment implications previously stated, patients should be offered genetic testing at diagnosis, as this information is helpful for patient management. However, if this does not occur, patients can be referred at any stage during the patient pathway; Fig. 1 is a proposed algorithm, devised during a consensus meeting held in Europe with European experts.

BRCA analysis differs from other genetic tests for cancer treatment decisions, e.g. RAS or

Conclusions

Worldwide studies have highlighted that BRCA mutations among OC patients are more frequent than previously thought. This together with the licensing of the first PARPi therapy for BRCA-associated OC (with further drugs in this class likely to be licensed soon) has led to a change in the rationale for BRCA testing criteria. Referral criteria, previously based on family cancer history and designed to identify those at risk of future cancers, are being changed to identify those who may benefit

Funding

Support for the development of this manuscript was provided by AstraZeneca.

Conflict of interest statement

Christi van Asperen has received honoraria for advisory board participation from AstraZeneca and received a research grant from AstraZeneca.

Susana Banerjee's institution has received honoraria for her role at Astrazeneca sponsored advisory boards and lectures (no personal financial remuneration).

Nicoletta Colombo has received honoraria from AstraZeneca for attending industry sponsored advisory boards.

Anne-Marie Gerdes has received honoraria for advisory board participation and a travel grant

Acknowledgements

Medical writing support for the preparation of this manuscript was provided by Dr Debra Scates from integrated medhealth communications (imc), supported by AstraZeneca.

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