Clinical and Translational Oncology (2020) 22:193–200 https://doi.org/10.1007/s12094-019-02262-0 CLINICAL GUIDES IN ONCOLOGY SEOM clinical guidelines in hereditary breast and ovarian cancer (2019) S. González‑Santiago1 · T. Ramón y Cajal2 · E. Aguirre3 · J. E. Alés‑Martínez4 · R. Andrés5 · J. Balmaña6 · B. Graña7 · A. Herrero8 · G. Llort9 · A. González‑del‑Alba10 on behalf of the SEOM Hereditary Cancer Working GroupIA1 Received: 5 December 2019 / Accepted: 5 December 2019 / Published online: 30 December 2019 © The Author(s) 2019 Abstract Mutations in BRCA1 and BRCA2 high penetrance genes account for most hereditary breast and ovarian cancer, although other new high-moderate penetrance genes included in multigene panels have increased the genetic diagnosis of hereditary breast and ovarian cancer families by 50%. Multigene cancer panels provide new challenges related to increased frequency of variants of uncertain significance, new gene-specific cancer risk assessments, and clinical recommendations for carriers of mutations of new genes. Although clinical criteria for genetic testing continue to be largely based on personal and family history with around a 10% detection rate, broader criteria are being applied with a lower threshold for detecting mutations when there are therapeutic implications for patients with breast or ovarian cancer. In this regard, new models of genetic counselling and testing are being implemented following the registration of PARP inhibitors for individuals who display BRCA mutations. Massive sequencing techniques in tumor tissue is also driving a paradigm shift in genetic testing and potential identification of germline mutations. In this paper, we review the current clinical criteria for genetic testing, as well as surveillance recommendations in healthy carriers, risk reduction surgical options, and new treatment strategies in breast cancer gene-mutated carriers. Keywords Hereditary breast · Ovarian cancer · SEOM guidelines 1 * S. González‑Santiago Medical Oncology Department, Hospital Universitario santigsanti@gmail.com San Pedro de Alcántara, Cáceres, Av. Pablo Naranjo, s/n, 10003 Cáceres, Spain T. Ramón y Cajal 2 tramon@santpau.cat Medical Oncology Department, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain E. Aguirre 3 elenaaguirreortega@yahoo.es Medical Oncology Department, Hospital Quirónsalud, Zaragoza, Zaragoza, Spain J. E. Alés‑Martínez 4 jeales@saludcastillayleon.es Medical Oncology Department, Hospital Nuestra Señora de Sonsoles, Ávila, Ávila, Spain R. Andrés 5 andresraquelc@gmail.com Medical Oncology Department, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain J. Balmaña 6 jbalmana@vhio.net Medical Oncology Department, Hospital Universitario Vall D’Hebron, Barcelona, Spain B. Graña 7 begona.grana.suarez@gmail.com Medical Oncology Department, Complexo Hospitalario Universitario (CHUAC), A Coruña, A Coruña, Spain A. Herrero 8 herreroa@yahoo.es Medical Oncology Department, Hospital Universitario Miguel Servet, Zaragoza, Spain G. Llort 9 llortgemma@gmail.com Medical Oncology Department, Corporació Sanitària Parc Taulì, Sabadell, Barcelona, Spain A. González‑del‑Alba 10 aranzazu.gonzalezalba@salud.madrid.org Medical Oncology Department, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain 13 Vol.:(0123456789) 194 Clinical and Translational Oncology (2020) 22:193–200 Hereditary breast and ovarian cancer ovarian cancer, such as TP53, PALB2, PTEN, CHEK2, syndrome (HBOC): Introduction ATM, NF1, NBN, CDH1, STK11, RAD50, RAD51C, RAD51D, or BRIP1, among others [3]. Hereditary breast and ovarian cancer (HBOC) is a syn- All this progress has not come about without generating drome that involves increased predisposition primarily to new challenges as well, such as the large number of variants breast cancer (BC), and/or to ovarian cancer (OC). of uncertain significance (VUS) detected and the lack of Most breast and ovarian cancers are sporadic, while information on the degree and spectrum of risks associated hereditary predisposition accounts for 10–15% of the with these new genes. cases, principally with respect to germline mutations in Moreover, the introduction of PARP inhibitors in cancer high penetrance BRCA1/2 genes. Cumulative BC risk for therapy can lead to a major change in the framework for BRCA1 and BRCA2 mutation carriers at 70 years of age genetic testing in oncology patients. is about 57%, respectively, while cumulative OC risk is approximately 40% for BRCA1 and 18% for BRCA2 muta- tion carriers [1]. Clinical criteria for germline testing in HOBC BRCA1/2 genes were discovered in the 1990s and are risk assessment involved in homologous recombination repair pathway. HBOC families associated with BRCA1 or BRCA2 ger- We strongly recommend genetic risk evaluation and genetic mline mutations present an autosomal dominant hereditary counselling (before and after germline testing) for patients pattern, with early age of cancer onset, bilaterality, and who are at high.risk of harboring a pathogenic mutation male breast cancer. in one of the breast/ovarian cancer predisposition genes. Initial studies by the Breast Cancer Linkage Consortium Genetic counselling is a process that guarantees a discus- have also pointed toward an association between BRCA1 sion about the benefits and limitations of genetic testing, and BRCA2 mutations and prostate and pancreatic adeno- including information about cancer risk, recommendations carcinomas, among others. Subsequent research has fur- for early detection and prophylactic interventions, as well ther confirmed these associations [2]. as advice regarding reproductive options, and support for The past 5 years has witnessed substantial advances in psychological well-being. the field of cancer genetics. The development of next‐gen- At least nine different European guidelines containing eration sequencing (NGS) has enhanced the ability to test recommendations for BRCA1/2 testing have been published for many genes concurrently and significantly lowered the in the last 4 years [4]. These criteria are associated with a cost of genetic testing. We have gained greater insights probability of ≥ 10% mutation detection. Clinical criteria for into hereditary cancer, with the identification of additional genetic testing differ from one set of guidelines to the next, genes found to confer significant risk for either breast or but all of them are based on clinical risk factors such as age, hormone receptor status, ancestry with founder mutations, Table 1  Selection criteria for germline testing Regardless of family history: Women with synchronous or metachronous breast and ovarian cancer Breast cancer ≤ 40 years Bilateral breast cancer (the first diagnosed ≤ 50 years) Triple-negative breast cancer ≤ 60 years High-grade epithelial non-mucinous ovarian cancer (or fallopian tube or primary peritoneal cancer) Ancestry with founder mutations BRCA somatic mutation detected in any tumor type with a allele frequency > 30% (if it is known) Metastatic HER2-negative breast cancer patients eligible to consider PARP inhibitor therapy 2 or more first degree relatives with any combination of the following high-risk features: Bilateral breast cancer + another breast cancer < 60 years Breast cancer < 50 years and prostate or pancreatic cancer < 60 years Male breast cancer Breast and ovarian cancer Two cases of breast cancer diagnosed before age 50 years 3 or more direct relatives with breast cancer (at least one premenopausal) and/or ovarian cancer and/or, pancreatic cancer or high Gleason (≥ 7) prostate cancer 13 Clinical and Translational Oncology (2020) 22:193–200 195 and personal and family history of cancer (Table 1). The cancer patients and testing is recommended for treatment application of these criteria to select patients has two major decision-making (IIIA). limitations: Clinical guidelines are being developed to provide recom- mendations to prompt germline testing after a pathogenic (a) Most of these guidelines are based predominantly on variant has been identified in tumor sequencing [10, 11]. the probability of carrying pathogenic mutations in Despite the challenges and limitations of assessing variant BRCA1 or BRCA2. Thus, the sensitivity of these cri- allele frequency (VAF) in the tumor, a VAF > 30% is within teria to identify pathogenic mutations in different high the range to raise suspicions of a germline origin. Based on or moderate-risk genes is limited. this and the algorithms used in earlier guidelines, triggering (b) Recent research supports BRCA testing in a broader of germline analysis for BRCA1, BRCA2, PALB2, BRIP1, range of individuals, if not in every breast cancer RAD51C, and RAD51D is recommended following identi- patient. This recommendation is based on the findings fication of a pathogenic variant with > 30% VAF in any of of studies that conclude that the traditional approach these genes in any tumor at any age. (IIA). The ATM and may miss up to 50% of mutation carriers [5, 6]. CHEK2 genes remain controversial, as they might be present in some germline panels although there is no broad agree- ment regarding their clinical validity and subsequent sur- New criteria for germline testing, regardless of family veillance recommendations. Multidisciplinary genetic tumor history, are arising thanks to improvements in massive tumor boards should be charged with managing interpretation of sequencing techniques, as well as in predicting response to variants and referral for germline testing (IIIB). new therapeutic agents. Following detection of a somatic mutation in a cancer predisposition gene with high allele frequency, it is advisable to rule out a germline mutation Cancer screening in carriers of mutated considering possible implications in genetic counselling. HBOC‑involved genes Use of PARP inhibitors for germline BRCA1/2 mutated HER2-negative metastatic breast cancer patients obviously The current standard of care for patients with moderate-risk implies previous germline testing. germline mutations is based on expert recommendations. We should not extrapolate the same guidelines for the high- risk genes. Genetic testing methodologies in HBOC There is currently no international consensus regarding the optimal risk threshold for recommending MRI surveil- HBOC linked to pathogenic variants in high and moderate lance. Some experts recommend initiating mammographic penetrance cancer genes constitutes 5 and 15% of the bur- surveillance at the age when the estimated 5-year risk den of breast and ovarian cancer, respectively. BRCA1 and approaches 1%, and add breast MRI at the age when the risk BRCA2 are the most common mutated susceptibility genes reaches 2.5% [12]. However, the most practical approach in both tumors, followed by PALB2 (in BC) and genes with is to begin with mammography and MRI at the same age pathogenic variants that confer moderate penetrance cancer (Table 2). risk, such as ATM/CHEK2 (in BC) and BRIP1, RAD51C, Studies on the association of BRCA1/2 mutations with RAD51D, MLH1, MSH2, and MSH6 (in OvC) [7]. Clinical colorectal cancer have yielded controversial results. A validity for BRCA1/2 and PALB2 (BC/OvC), and BRIP1, recent meta-analysis concluded that colorectal cancer risk RAD51C, RAD51D, MLH1, MSH2, MSH6 (OvC) has been is increased in BRCA1 (OR 1.49), but not in BRCA2 [13]. established with subsequent surveillance and preventive Because BRCA1/2 mutation carriers have an increased clinical options. Therefore, HBOC germline panels includ- risk of prostate cancer before 65 years of age, and BRCA2 ing these genes are recommended (Evidence II, Recommen- carriers are diagnosed earlier and are associated with a dation A) (II, A) [8]. worse prognosis, it is reasonable to consider prostate can- Reported mutations consist chiefly of small deletions/ cer screening at the age of 40 and to consider screening insertions, nonsense mutations, and splice variants result- annually. ing in truncated proteins. In addition, large rearrangement Mutations in BRCA2, PALB2, and ATM have been asso- alterations may also be found in < 10%. Therefore, genetic ciated with increased familial risk of pancreatic cancer testing for these genes should include sequence analysis and (PC), but the associated absolute risks are not robust. ATM, deletion/duplication analysis (IIA) [9]. BRCA2, and PALB2 mutation carriers with a first- or second- Tumor genomic profiling is becoming an integral part of degree relative with PC are candidates for clinical trials of care in the setting of metastatic cancer. A somatic mutation PC screening strategies. Issues such as age when screening of BRCA1/2 is a biomarker for PARPi treatment in ovarian should be initiated, which is the best imaging technique, 13 196 Table 2  Cancer screening in mutation carriers Gen Breast cancer screening Ovarian cancer screening Other cancer screening 13 BRCA1/BRCA2 Women 6-monthly, transvaginal ultrasound and Ca.125 may be Annual screening with PSA for prostate cancer from the Annual breast MRI with contrast from the age of considered from the age of 30 until the age of RRSO age of 40 years, Recommended in BRCA2, and offer in 30–70 years (II,A)a,b or for those who have not elected RRSO (III,C) BRCA1 (II,B) Annual mammography from the age of 30 to 75 years Consider pancreatic cancer surveillance with EUS and (II,A)c,d MRI in carriers with a first-degree-relative with pan- Men creatic cancer from the age of 50 or 10 years before the No evidence of clinical benefit of breast screening (III, youngest diagnosis in the family (II,C) C). Consider mammography in the case of gyneco- Consider skin and eye examination for melanoma screen- mastia ing according personal/familiar risk factors (III,C) PALB2 Annual breast MRI with contrast from the age of Moderate evidence of increased OC risk. Insufficient Discuss pancreatic cancer surveillance with EUS and 25 years (III,A)e evidence for recommend RRSO or screening (III,C) MRI in carriers with a first-degree-relative with pan- Annual mammography from the age of 35 years creatic cancer from the age of 50 or 10 years before the (III,A)e youngest diagnosis in the family (II,C) ATM Consider annual breast MRI with contrast from the age Potential increase in OC risk. Insufficient evidence for Consider offer pancreatic cancer surveillance with EUS of 40 years according personal/familiar risk factors recommend RRSO or screening (III,C) and MRI in carriers with a first-degree-relative with (III,A)e pancreatic cancer from the age of 50 or 10 years before Annual mammography from the age of 40 years the youngest diagnosis in the family (II,C) (III,A)e CHEK2 Consider annual breast MRI with contrast from the age No evidence of increased risk Consider colonoscopy from the age of 40 years, and of 40 years (III,A)e repeat every 5 years (II,B) Annual mammography from the age of 40 years (III,A)e RAD51C Unknown o insufficient evidence for BC risk Recom- No evidence of clinical benefit. Consider offer annual mend BC screening based only on family history transvaginal ultrasound and Ca.125 from the age of 40 until the age of RRSO or for those who have not elected RRSO (III,C) RAD51D Unknown o insufficient evidence for BC risk Recom- No evidence of clinical benefit. Consider offer annual mend BC screening based only on family history transvaginal ultrasound and Ca.125 from the age of 40 until the age of RRSO or for those who have not elected RRSO (III,C) BRIP1 No increased BC risk No evidence of clinical benefit. Consider offer annual Recommend BC screening based only on family history transvaginal ultrasound and Ca.125 from the age of 40 until the age of RRSO or for those who have not elected RRSO (III,C) (II, A): (Evidence Level II, Recommendation Grade A) BC breast cancer, OV ovarian cancer, RRSO bilateral risk reduction salpingo-oophorectomy, EUS endoscopic ultrasound, MRI magnetic resonance imaging a Or early if family history of breast cancer before 30 years b When MRI is unavailable, we recommend screening with mammography and breast ultrasound (II,B) c Discuss delaying until 40 years for BRCA1 if annual MRI screening d Even beyond, according to comorbidity e Individualised if family history Clinical and Translational Oncology (2020) 22:193–200 Clinical and Translational Oncology (2020) 22:193–200 197 interval, or optimum duration of follow-up have yet to be for women who carry a BRCA1mutation and do not wish to determined. The benefits and limitations of PC screening have more children (IA), aged 35–40 years; whereas the same should be discussed with the carriers. PC screening in high- recommendation is made for BRCA2 mutation carriers with risk individuals is associated with a higher detection and ages of 40–45. This age difference is established because higher resectability rates and longer survival, but more mul- BRCA1 mutated carriers tend to develop OC at younger ages. ticenter and prospective studies are needed to evaluate the Individual circumstances and familial patterns of occurrence benefits of PC screening [14]. must be taken into consideration (IIA). Several studies have Unlike BRCA1/2 mutations, in the presence of a very demonstrated a 50% reduction in BC risk when an RRSO is strong BC family history, moderate-risk mutations in performed in premenopausal women. However, it is possible CHEK2 or ATM account for only a portion of the familial that this benefit may have been overestimated. RRSO for breast risk. A woman from these families with a negative predic- cancer reduction should be recommended only to women tive result of moderate-risk mutation probably remains at under the age of 50 (IIC). Short-term and low-dose hormone some degree of elevated cancer risk and will likely require therapy in oophorectomized BRCA mutation carriers without increased breast cancer surveillance. a personal history of breast cancer might be considered (IIB). RRSO in carriers of moderately penetrant pathogenic genes should be contemplated on a case-by-case basis. For Risk‑reducing surgery and chemoprevention BRIP1 carriers, RRSO is recommended from 45 to 50 years of age. The same recommendations have been proposed for Prophylactic mastectomy RAD51C/D carriers, unless family history suggests an earlier risk of developing ovarian cancer. Cumulative life endometrial Prospective studies suggest that bilateral risk reduction and ovarian cancer risk for Lynch syndrome carriers is 60% mastectomy (BRRM) decreases the occurrence of breast and 24%, respectively. Therefore, RRSO is also an option to cancer in women with a moderate-high risk by 90% with- be considered (IIIC). out a decrease in all-cause mortality [15]. One cohort study suggests that a survival benefit of BRRM may be limited Pharmacological prevention (chemoprevention) to BRCA1, but does not extend to BRCA2 carriers [16]. In female BRCA​ mutation carriers without a prior history of Preventive treatments are an option for female BRCA​-mutated cancer, BRRM entails a considerable decrease in BC risk carriers who do not want to undergo BRRM, at least initially. (IIB). Prophylactic contralateral mastectomy in patients In the subgroup of women with BRCA2 mutations assigned with BC and BRCA1/2 mutation significantly decreases the to tamoxifen in the NSABP-P1 study, there was a 62% breast incidence of contralateral BC (IIB). BRRM options include cancer risk reduction compared to placebo, but not in BRCA1 skin-sparing mastectomy or a nipple–areola sparing mastec- mutated carriers, although definitive conclusions cannot be tomy (NASM). There are no studies comparing these sur- drawn due to the small sample size [19]. Thus, tamoxifen in geries; nevertheless, NASM is deemed safe and effective in primary prevention could be considered (IIIC). In second- reducing BC risk (II, C). ary prevention, several non-randomized observational stud- Cumulative life breast cancer risk for PTEN (Cowden’s ies found a reduction in the risk of contralateral breast can- syndrome), CDH1, PALB2, CHEK2, ATM, and Li–Fraumeni cer by45–60% in BRCA1/2 mutation carriers with a previous mutation carriers are 85.2%, 39–52%, 35%, 28–37%, 33%, diagnosis of breast cancer and adjuvant treatment with tamox- and 5%, respectively. There are no specific data regarding ifen (IIA) [20]. Use of AI for risk Query prevention in BRCA​ the benefit of BRRM in these populations, although it seems -mutated carriers is investigated in the ongoing randomized reasonable to discuss this procedure on an individual basis, phase 3 clinical trial LIBER. based on family history, comorbidities, and life expectancy Oral contraceptives in BRCA1/2 mutation carriers can (IIIC) [17]. reduce the risk of OC by 50%, with the benefit being greater with longer duration of treatment. Their use is not contraindi- Bilateral risk reduction salpingo‑oophorectomy cated, although there is a possibility of an increased risk of BC. (RRSO) A meta-analysis of 10 studies demonstrated a risk reduction of OC, fallopian tube cancer, and primary peritoneal cancer of ~ 80% in women with BRCA 1/2 mutation after salpingo- oophorectomy (RRSO). A 1–4.3% residual risk of primary peritoneal carcinoma has been reported. RRSO confers a 77% reduction in all-cause mortality [18]. RRSO is recommended 13 198 Clinical and Translational Oncology (2020) 22:193–200 Treatment strategies in cancer patients treatment after platinum-based chemotherapy in OC have with BRCA​mutations been demonstrated to significantly improve PFS. Patients positive for homologous recombination deficiency (HRD) Surgery and mainly, BRCA​-mutated carriers, obtained the greatest benefit. BRCA​ genetic testing in patients with early stage BC can Olaparib and talazoparib are indicated as monotherapy affect their locoregional treatment because mutation carri- for the treatment of BRCA​-mutated carriers who have HER2- ers have a higher risk of contralateral BC than non-carrier negative, locally advanced or metastatic breast cancer after BC patients. Therefore, patients with a history of unilateral progression to endocrine therapy and/or chemotherapy. breast cancer may benefit from bilateral mastectomy [21] Currently, olaparib has also shown a clinically meaning- (IIIA). ful benefit in radiological PFS in men with BRCA1, BRCA2, or ATM mutations in metastatic castration-resistant prostate cancer, and in PFS as maintenance therapy in pancreatic can- Platinum‑based chemotherapy cer following platinum-based chemotherapy regimen. None- theless, indications for each agent will continue to evolve in Triple-negative BC platinum-based neoadjuvant chemother- keeping with upcoming and ongoing clinical trials. apy significantly increased pathological complete response (pCR); nevertheless, in the 96 BRCA​-mutated patients included in two randomized controlled trials, the addition of Management of women with familial risk carboplatin was not associated with significantly increased and no germline mutation pCR rates [22]. The effect of these compounds on long-term outcomes is unknown (IB). In the metastatic setting, car- For those women with a positive family history of BC and boplatin has shown a statistically clinical benefit compared no mutation in a high/moderate penetrance gene, BC risk to docetaxel among BRCA​mutation carriers [23]. Platinum can be estimated by predictive models, such as BOADICEA salts might be considered in the neoadjuvant setting (IC), or Tyrer–Cuzyck. In women with a cumulative lifetime BC and in the metastatic setting among BRCA​-mutated patients risk of 25–30%, both annual mammography and breast MRI with BC (IA). should be offered (IIB) beginning at the age when their Retrospective studies have shown improved prognosis, 10-year BC risk reaches 5% (IIIC) [25, 26]. higher response rates to platinum-containing regimens, and Bilateral mastectomy should be put forth as a risk-reduc- longer treatment-free intervals between relapses in patients ing option in women at high risk based on predictive models with BRCA1- and BRCA2- (BRCA1/2)-mutated ovarian can- and managed by a multidisciplinary team (IIIC). Neither cer (OC) compared to wild-type BRCA1/2. gynecological screening nor risk-reducing surgery is recom- mended unless there is a positive family history of OC, in which case medical management should be individualized PARP inhibitors by a multidisciplinary team. Tamoxifen, anastrozole, exemestane, and raloxifene Poly ADP–ribose polymerase (PARP) inhibitors are a class might be offered for BC chemoprevention for a maximum of targeted agents capable of inducing synthetic lethality of 5 years to women at high and moderate-risk for BC (I, in mutated BRCA1/2 tumor cells and have been proven to A) [27]. improve progression-free survival (PFS) in phase III clinical Family history should be updated to refine risk assess- trials in several types of BRCA​-related cancer such as ovary, ment, surveillance protocol, and consideration of additional breast, pancreas, and prostate. testing to rule out the possibility of phenocopy. In high-grade epithelial ovarian, fallopian tube, or pri- mary peritoneal cancer, olaparib is indicated as monother- apy in the maintenance treatment of FIGO stages III and IV Other hereditary breast and/or ovarian BRCA​-mutated (germline and/or somatic) cancer patients cancer syndromes who are in response (complete or partial) following comple- tion of first-line platinum-based chemotherapy [24]. Ruca- Multi-gene testing is necessary when more than one gene parib is also indicated in the same type of person who has could account for a personal and/or family cancer history. been treated with two or more previous lines of platinum- For example, although ovarian cancer is mainly associated based chemotherapy and who are unable to tolerate further with BRCA1/2 and other homologous recombination repair platinum-based chemotherapy. Large phase III trials have pathway genes, it can also be associated with variants in recently reported that niraparib and veliparib as maintenance mismatch repair genes (MLH1, MSH2, PMS2, MSH6, or 13 Clinical and Translational Oncology (2020) 22:193–200 199 EPCAM). Genes linked to hereditary breast cancer also Astellas, EUSA pharma, Ipsen, EISAI, and Astra–Zeneca, outside the include TP53, PTEN, STK11, and CDH1, among others. submitted work. It should be noted that germline mutations in these lat- Ethical approval The current study has been conducted in accordance ter genes are often associated with a syndromic phenotype with the ethical standards laid down in the 1964 Declaration of Hel- that determines diagnosis and guides genetic testing. sinki and its later amendments. Carriers of a mismatch repair gene mutation (MLH1, Informed consent As Clinical guideline, patient informed consent does MSH2, EPCAM, PMS2, or MSH6) are at increased risk not apply. for endometrial and ovarian cancers (up to 60% and 24%, respectively); however, association with increased risk for Open Access This article is licensed under a Creative Commons Attri- breast cancer is controversial. bution 4.0 International License, which permits use, sharing, adapta- Li–Fraumeni syndrome is the consequence of germline tion, distribution and reproduction in any medium or format, as long TP53 pathogenic variants involved only in about 1% of as you give appropriate credit to the original author(s) and the source, hereditary breast cancer cases. Carriers show a cumulative provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are lifetime cancer incidence of nearly 100% and a cumulative included in the article’s Creative Commons licence, unless indicated incidence rate for breast cancer by 70 years of age of at otherwise in a credit line to the material. If material is not included in least 50% [28]. the article’s Creative Commons licence and your intended use is not The myriad of disorders resulting from germline muta- permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a tions in PTEN are referred to as the PTEN hamartoma copy of this licence, visit http://creat​iveco​mmons​.org/licen​ses/by/4.0/. tumor syndrome (PHTS). The lifetime risk for breast cancer for women diagnosed with Cowden syndrome has been estimated at 25% to 50%, with an average age of 38–50 years at diagnosis [29]. References Germline STK11 pathogenic variants cause the 1. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 pen- Peutz–Jeghers syndrome (PJS), an autosomal dominant etrance. J Clin Oncol. 2007;25:1329–33. disorder characterized by gastrointestinal polyps, mucocu- 2. Mersch J, Jackson MA, Park M, Nebgen D, Peterson SK, Single- taneous pigmentation, and elevated risk for gastrointes- tary C, et al. Cancers associated with BRCA1 and BRCA2 muta- tinal cancers, as well as breast or non-epithelial ovarian tions other than breast and ovarian. Cancer. 2015;121(2):269–75. 3. Hoang LN, Gilks BC. Hereditary breast and ovarian cancer syn- cancers. Breast cancer risk in women with PJS is 45% at drome: moving beyond BRCA1 and BRCA2. Adv Anat Pathol. 70 years of age [30]. 2018;25(2):85–95. Mutations in germline CDH1 are associated with 4. Tung NM, Garber JE. BRCA1/2 testing: therapeutic implications hereditary diffuse gastric cancer and lobular breast can- for breast cancer management. Br J Cancer. 2018;119:141–52. 5. Beitsch PD, Whitworth PW, Hughes K, Patel R, Rosen B, Com- cer, reporting a cumulative lifetime risk for breast cancer pagnoni G, et al. Underdiagnosis of hereditary breast cancer: are of up to 50% [31]. genetic testing guidelines a tool or an obstacle? J Clin Oncol. 2019;37:453–60. 6. O’Leary E, Iacoboni D, Holle J, Michalski ST, Esplin ED, Yang S, et al. Expanded gene panel use for women with breast cancer: Compliance with ethical standards identification and intervention beyond breast cancer risk. Ann Surg Oncol. 2017;24:3060–6. Conflict of interest SGS reports honoraria for speaking from Amgen, 7. Domchek SM, Robson ME. Update on genetic testing in gyneco- Eisai, Novartis, Roche, Pfizer, and Astra–Zeneca; Advisory role for logic cancer. J Clin Oncol JCO. 2019;19:363. https ​ : //doi. Amgen, Novartis, Roche, Celgene, Astra–Zeneca, and Pfizer, and org/10.1200/jco.19.00363​. travel expenses from Pfizer, MSD, and Roche outside the submitted 8. Feliubadaló L, López-Fernández A, Pineda M, Díez O, Del work. TRC reports travel expenses from Pfizer and Astellas. EA re- Valle J, Gutiérrez-Enríquez S, et al. Opportunistic testing of ports honoraria for speaking from Roche, Novartis, Pfizer, Astra–Ze- BRCA1, BRCA2 and mismatch repair genes improves the yield neca, Eisai, and MSD; Advisory role for MSD and Pfizer, and travel of phenotype driven hereditary cancer gene panels. Int J Cancer. expenses from MSD, Roche, and Pfizer. JEAM reports honoraria for 2019;145(10):2682–91. speaking from MSD, Roche, Pfizer; Advisory role for Roche, Pfizer, 9. Judkins T, Rosenthal E, Arnell C, Burbidge LA, Geary W, Bar- BMS, Tesaro, and travel expenses from MSD, Roche, and BMS. RA rus T, et al. Clinical significance of large rearrangements inBR- has nothing to disclose. JB reports advisory role for Astra–Zeneca and CA1andBRCA2. Cancer. 2012;118(21):5210–6. Pfizer, honoraria for speaking from Bristol–Myers Squibb, Cor2ED, 10. Mandelker D, Donoghue M, Talukdar S, Bandlamudi C, Srini- and Medscape, and grants for research from Astra–Zeneca, Phar- vasan P, Vivek M, et al. Germline-focussed analysis of tumour- mamar, Pfizer, and Tesaro. BG has nothing to disclose. AH reports only sequencing: recommendations from the ESMO Preci- honoraria for speaking from Roche, Tesaro, MSD, Clovis, and Astra– sion Medicine Working Group. Ann Oncol. 2019. https​://doi. Zeneca and travel expenses from Roche outside the submitted work. org/10.1093/annon​c/mdz13​6. GLL has nothing to disclose. AGdA reports Advisory Board, consul- 11. Leonardis K, Hogan L, Cannistra SA, Rangachari D, Tung N. tancy, and speaker honoraria/travel support from Pierre Fabre, Roche, When should tumor genomic profiling prompt consideration of Bristol–Myers Squibb, MSD, Pfizer, Novartis, Bayer, Janssen, Sanofi, germline testing? J Oncol Pract. 2019;15(9):465–73. 13 200 Clinical and Translational Oncology (2020) 22:193–200 12. Tung N, Domchek SM, Stadler Z, Nathanson KL, Couch F, Garber triple-negative breast cancer: a systematic review and meta-anal- JE, et al. Counselling framework for moderate-penetrance cancer- ysis. Ann Oncol. 2018;29:1497–508. susceptibility mutations. Nat Rev Clin Oncol. 2016;13(9):581–8. 23. Tutt A, Tovey H, Chon U, Cheang M, et al. A randomised phase 13. Oh M, McBride A, Yun S, Bhattacharjee S, Slack M, Martin JR, III trial of carboplatin compared with docetaxel in BRCA1/2 et al. BRCA1 and BRCA2 gene mutations and colorectal cancer mutated and pre-specified triple negative breast cancer “BRCA- risk: systematic review and meta-analysis. J Natl Cancer Inst. ness” subgroups: the TNT Trial. Nat Med. 2018;24(5):628–37. 2018;110(11):1178–89. 24. Moore K, Colombo N, Scambia G, Kim BG, Oaknin A, 14. Canto MI, Kerdsirichairat T, Yeo CJ, Hruban RH, Shin EJ, Friedlander M, et al. Maintenance olaparib in patients with Almario JA, et al. Surgical outcomes after pancreatic resection of newly diagnosed advanced ovarian cancer. N Engl J Med. screening-detected lesions in individuals at high risk for devel- 2018;379:2495–505. oping pancreatic cancer. J Gastrointest Surg. 2019. https​://doi. 25. Evans DG, Graham J, O’Connell S, Arnold S, Fitzsimmons D. org/10.1007/s1160​5-019-04230​-z. Familial breast cancer: summary of updated NICE guidance. BMJ. 15. Li X, You R, Wang X, Liu C, Xu Z, Zhou J, et al. Effective- 2013;25(346):3829. https​://doi.org/10.1136/bmj.f3829​. ness of prophylactic surgeries in BRCA1 or BRCA2 mutation 26. Saadatmand S, Geuzinge HA, Rutgers EJT, Mann RM, van carriers: a meta-analysis and systematic review. Clin Cancer Res. Zuidewijn DB, Zonderland HM, et al. MRI versus mammography 2016;22:3971–81. for breast cancer screening in women with familial risk (FaM- 16. Heemskerk-Gerritsen B, Jager A, Koppert LB, Obdeijn AI, Collée RIsc): a multicentre, randomised, controlled trial. Lancet Oncol. M, Meijers-Heijboer HEJ, et al. Survival after bilateral risk- 2019;2045(19):1–12. reducing mastectomy in healthy BRCA1 and BRCA2 mutation 27. Visvanathan K, Fabian CJ, Bantug E, Brewster AM, Davidson NE, carriers. Breast Cancer Res Treat. 2019;177:723–33. https​://doi. DeCensi A, et al. Use of endocrine therapy for breast cancer risk org/10.1007/s1054​9-019-05345​-2. reduction: ASCO clinical practice guideline update. J Clin Oncol. 17. National Comprehensive Cancer Network (NCCN). NCCN Clini- 2019. https​://doi.org/10.1200/JCO.19.01472​. cal practice guidelines in oncology. Genetic/familial high-risk 28. Mai PL, Best AF, Peters JA, DeCastro RM, Khincha PP, Loud JT, assessment: breast and ovarian. Version 3. 2019. https​://www. et al. Risks of first and subsequent cancers among TP53 mutation nccn.org/profe​ssion​als/physi​cian_gls/pdf/genet​ics_scree​ning.pdf carriers in the National Cancer Institute Li- Fraumeni syndrome 18. Xiao YL, Wang K, Liu Q, Li J, Zhang X, Li HY. Risk reduction cohort. Cancer. 2016;122:3673–81. and survival benefit of risk-reducing salpingo-oophorectomy in 29. Tan MH, Mester JL, Ngeow J, Rybicki LA, Orloff MS, Eng C. hereditary breast cancer: meta-analysis and systematic review. Lifetime cancer risks in individuals with germline PTEN muta- Clin Breast Cancer. 2019;19(1):e48–e65. tions. Clin Cancer Res. 2012;18:400–7. 19. King M, Wieand S, Hale K, Lee M, Walsh T, Owens K, et al. 30. Hearle N, Schumacher V, Menko FH, Olschwang S, Boardman Tamoxifen and breast cancer incidence among women with inher- LA, Gille JJ, et al. Frequency and spectrum of cancers in the ited mutations in brca1 and brca2: national surgical adjuvant Peutz-Jeghers syndrome. Clin Cancer Res. 2006;12:3209–15. breast and bowel project (NSABP-P1) breast cancer prevention 31. Pharoah PD, Guilford P, Caldas C. Incidence of gastric cancer trial. JAMA. 2001;286(18):2251–6. and breast cancer in CDH1 (E-cadherin) mutation carriers from 20. Phillips KA, Milne RL, Rookus MA, Daly MB, Antoniou AC, hereditary diffuse gastric cancer families. Gastroenterology. Peock S, et al. Tamoxifen and risk of contralateral breast can- 2001;121:1348–53. cer for BRCA1 and BRCA2 mutation carriers. J Clin Oncol. 2013;31:3091–9. Publisher’s Note Springer Nature remains neutral with regard to 21. Heemskerk-Gerritsen BA, Rookus MA, Aalfs CM, Ausems MG, jurisdictional claims in published maps and institutional affiliations. Collée JM, Jansen L, et al. Improved overall survival after con- tralateral risk-reducing mastectomy in BRCA1/2 mutation carriers with a history of unilateral breast cancer: a prospective analysis. Int J Cancer. 2015;136(3):668–77. 22. Poggio F, Bruzzone M, Ceppi M, Pondé NF, La Valle G, Del Mastro L, et al. Platinum-based neoadjuvant chemotherapy in 13