4.1 Genetic testing in the predictive setting
During the panel discussion, questions arose around the true definition of ‘predictive’ in the light that very often testing starts with an affected family member and relatives are tested as a second step. The panel agreed on the definition set forth in the methods section of this publication.
The experts concurred with 94% agreement that predictive genetic testing in healthy individuals with a familial background of breast cancer should not be restricted to BRCA1/2 [Q5]. A set of high-risk actionable genes with evidence of clinical impact was defined as a minimum required panel of high risk actionable genes [Q7]. This basic gene panel was set to include BRCA1, BRCA2, TP53 (particularly if the patient has an early disease onset or family history suggestive of Li-Fraumeni syndrome) and PALB2. It was, however, also agreed that different populations may require different gene sets. Gene panels discussed at the meeting included BRCA1, BRCA2, TP53, PTEN, PALB2, STK-11, ATM, CHEK2, CDH-1, MLH1, MSH2, MSH6, BRIP1 and RAD51D/C. Different panelists felt a justification for a selection of some of these genes, but there was an agreement between the experts that the previously mentioned four genes represented the absolute minimum of genes that should be tested.
Experts also agreed (83%) that, given the low cost and high-throughput that can now be achieved by NGS, analysing a number of the most common BRCA1/2 variant loci (i.e. “hotspot testing”), rather than completely sequencing the whole genes is not acceptable [Q14]. A possible exception would only be founder mutations that represent more than 99% of pathogenic variants identified in the gene of interest in a specific geographical region or setting.
Overall, the panel expressed that, in the setting of limited resources, the goal of genetic counselling and testing strategies should rather focus on providing BRCA1/2 testing to a larger number of potential carriers, than on investigating large gene panels in a smaller number of individuals.
4.2 Genetic testing in the therapeutic setting
The experts agreed (89%) that currently BRCA1/2
testing is not indicated solely on the basis of a diagnosis of breast cancer, because the prevalence of BRCA1/2
germline mutations is low in the absence of a suggestive family history, or young age at onset [Q1], although it was shown that, for example, in Norway more than 60% of identified mutation carriers did not have a suggestive family history [
- Grindedal E.M.
- Heramb C.
- Karsrud I.
- Ariansen S.L.
- Maehle L.
- Undlien D.E.
- et al.
Current guidelines for BRCA testing of breast cancer patients are insufficient to detect all mutation carriers.
]. The diagnosis of TNBC, the presence of a family history, young age at onset and the presence of a clinical setting in which the detection of a BRCA1/2
germline mutation would qualify a patient for PARPi treatment are indications for BRCA1/2
testing [Q21]. In these cases, the majority of experts (69%) recommend that testing should be offered after the histological proof of breast cancer and should not be restricted to the advanced cancer setting [Q22]. Already today, the presence of a suggestive family history and young age at onset are relative indications for expedited BRCA1/2
testing in many countries, if an early breast cancer patient considers bilateral mastectomy in case a germline mutation is detected.
This implies that with the approval of PARPi in advanced disease, genetic testing may increasingly become an integral part of the routine workup in both early and advanced breast cancer.
When asked to whom genetic testing should be offered in the metastatic setting, the majority of experts (60%) voted that BRCA1/2
testing should be offered to all patients, while 20% of experts voted that BRCA1/2
testing should be limited to patient with a familial/personal history suggestive of a BRCA1/2
mutation [Q27|. The majority of experts consequently also voted that BRCA1/2
testing should be offered to patients with human epidermal growth factor receptor 2 (HER2) positive (59%) [Q26] and HR positive (57%) [Q28] disease, even if family history is not suggestive. This recommendation was given in light of the recently published Assessment of the Efficacy and Safety of Olaparib Monotherapy Versus Physicians Choice Chemotherapy in the Treatment of Metastatic Breast Cancer Patients With Germline BRCA1/2 Mutations. (OlympiAD) [
- Robson M.
- Im S.A.
- Senkus E.
- Xu B.
- Domchek S.M.
- Masuda N.
- et al.
Olaparib for metastatic breast cancer in patients with a germline BRCA mutation.
] and A Study Evaluating Talazoparib (BMN 673), a PARP Inhibitor, in Advanced and/or Metastatic Breast Cancer Patients With BRCA Mutation (EMBRACA Study) (EMBRACA) [
- Litton J.K.
- Rugo H.S.
- Ettl J.
- Hurvitz S.A.
- Goncalves A.
- Lee K.H.
- et al.
Talazoparib in patients with advanced breast cancer and a germline BRCA mutation.
] trial results, and explicitly acknowledged the fact that the likelihood for a pathogenic variant in BRCA1
/2 in a breast cancer patient, who has no family history, is around 2% [
- Nilsson M.P.
- Torngren T.
- Henriksson K.
- Kristoffersson U.
- Kvist A.
- Silfverberg B.
- et al.
BRCAsearch: written pre-test information and BRCA1/2 germline mutation testing in unselected patients with newly diagnosed breast cancer.
]. It was, however, also discussed that clinical data addressing the efficacy of PARPi in HER2 positive metastatic breast cancer are not available. Therefore, the panelists argued that it is debatable whether countries with limited health-care resources should implement a more restrictive testing strategy. Seventy-four percent of experts were in favour of also testing additional breast cancer–associated genes [Q2], even if the efficacy of PARPi has not been clinically validated in the non-BRCA1/2
setting, and although few genes are known, in particular PALB2
- Antoniou A.C.
- Casadei S.
- Heikkinen T.
- Barrowdale D.
- Pylkas K.
- Roberts J.
- et al.
Breast-cancer risk in families with mutations in PALB2.
] and BRIP1
- Ramus S.J.
- Song H.
- Dicks E.
- Tyrer J.P.
- Rosenthal A.N.
- Intermaggio M.P.
- et al.
Germline mutations in the BRIP1, BARD1, PALB2, and NBN genes in women with ovarian cancer.
], in which a functional alteration might still have potential surgical consequences such as bilateral mastectomy or risk reducing bilateral salpingo-oophorectomy. However, the therapeutic benefit of risk-reducing surgery in mutation carriers with advanced breast cancer is questionable.
Despite the unanimous support for generalised testing, it was also cautioned that as long as the test results particularly in low or intermediate penetrance genes are not clinically actionable, the mere knowledge of ‘having a mutation’ might result in false treatment expectations in affected individuals. The experts felt that particularly pretest counselling of breast (and ovarian) cancer patients should convey the limited clinical consequences particularly in women with non-BRCA1/2 mutations. Pretest counselling should also include implications of the genetic result for relatives, particularly in case high penetrance gene mutations are detected. All experts were in favour of a structured oncological counselling pathway [Q36], which should also involve informed consent before gene testing.
4.3 Genetic testing in breast cancer tissue
The majority of experts (74%; two experts abstained) agreed that in routine clinical practice genetic testing of tumour tissue for the detection of somatic BRCA1/2
and other breast cancer–associated genes should not be part of a diagnostic algorithm in metastatic breast cancer [spontaneous question arising from discussion]. The presence of somatic gene alterations does not currently have a therapeutic consequence and does not absolve from germline testing. It should, however, be noted that the prevalence of somatic mutations in BRCA1/2
is likely to be higher than previously thought. In a recently published article including 273 Swedish breast cancer patients, the likelihood of a BRCA1/2
mutation being somatic was ∼1/3, and germline, 2/3 [
- Winter C.
- Nilsson M.P.
- Olsson E.
- George A.M.
- Chen Y.
- Kvist A.
- et al.
Targeted sequencing of BRCA1 and BRCA2 across a large unselected breast cancer cohort suggests that one-third of mutations are somatic.
]. It was therefore remarked that, while available evidence does not currently support routine BRCA1/2
or panel testing in tumour tissue, it is nevertheless important for research purposes and may have clinical consequences in the future. It will therefore be particularly important to determine the prevalence of somatic genetic variants of BRCA1/2
and other breast cancer related genes in metastatic tissue, and to further improve the quality of genetic testing in tissue biopsies.