Lisa Richters

Prevalence of deleterious germline variants in risk genes including BRCA1/2 in consecutive ovarian cancer patients (AGO-TR-1)

Background Identification of families at risk for ovarian cancer offers the opportunity to consider prophylactic surgery thus reducing ovarian cancer mortality. So far, identification of potentially affected families in Germany was solely performed via family history and numbers of affected family members with breast or ovarian cancer. However, neither the prevalence of deleterious variants in BRCA1/2 in ovarian cancer in Germany nor the reliability of family history as trigger for genetic counselling has ever been evaluated. Methods Prospective counseling and germline testing of consecutive patients with primary diagnosis or with platinum-sensitive relapse of an invasive epithelial ovarian cancer. Testing included 25 candidate and established risk genes. Among these 25 genes, 16 genes (ATM, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, NBN, PMS2, PTEN, PALB2, RAD51C, RAD51D, STK11, TP53) were defined as established cancer risk genes. A positive family history was defined as at least one relative with breast cancer or ovarian cancer or breast cancer in personal history. Results In total, we analyzed 523 patients: 281 patients with primary diagnosis of ovarian cancer and 242 patients with relapsed disease. Median age at primary diagnosis was 58 years (range 16–93) and 406 patients (77.6%) had a high-grade serous ovarian cancer. In total, 27.9% of the patients showed at least one deleterious variant in all 25 investigated genes and 26.4% in the defined 16 risk genes. Deleterious variants were most prevalent in the BRCA1 (15.5%), BRCA2 (5.5%), RAD51C (2.5%) and PALB2 (1.1%) genes. The prevalence of deleterious variants did not differ significantly between patients at primary diagnosis and relapse. The prevalence of deleterious variants in BRCA1/2 (and in all 16 risk genes) in patients <60 years was 30.2% (33.2%) versus 10.6% (18.9%) in patients ≥60 years. Family history was positive in 43% of all patients. Patients with a positive family history had a prevalence of deleterious variants of 31.6% (36.0%) versus 11.4% (17.6%) and histologic subtype of high grade serous ovarian cancer versus other showed a prevalence of deleterious variants of 23.2% (29.1%) and 10.2% (14.8%), respectively. Testing only for BRCA1/2 would miss in our series more than 5% of the patients with a deleterious variant in established risk genes. Conclusions 26.4% of all patients harbor at least one deleterious variant in established risk genes. The threshold of 10% mutation rate which is accepted for reimbursement by health care providers in Germany was observed in all subgroups analyzed and neither age at primary diagnosis nor histo-type or family history sufficiently enough could identify a subgroup not eligible for genetic counselling and testing. Genetic testing should therefore be offered to every patient with invasive epithelial ovarian cancer and limiting testing to BRCA1/2 seems to be not sufficient.

Individuals with FANCM biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display chromosome fragility

PurposeMonoallelic germ-line mutations in the BRCA1/FANCS, BRCA2/FANCD1 and PALB2/FANCN genes confer high risk of breast cancer. Biallelic mutations in these genes cause Fanconi anemia (FA), characterized by malformations, bone marrow failure, chromosome fragility, and cancer predisposition (BRCA2/FANCD1 and PALB2/FANCN), or an FA-like disease presenting a phenotype similar to FA but without bone marrow failure (BRCA1/FANCS). FANCM monoallelic mutations have been reported as moderate risk factors for breast cancer, but there are no reports of any clinical phenotype observed in carriers of biallelic mutations.MethodsBreast cancer probands were subjected to mutation analysis by sequencing gene panels or testing DNA damage response genes.ResultsFive cases homozygous for FANCM loss-of-function mutations were identified. They show a heterogeneous phenotype including cancer predisposition, toxicity to chemotherapy, early menopause, and possibly chromosome fragility. Phenotype severity might correlate with mutation position in the gene.ConclusionOur data indicate that biallelic FANCM mutations do not cause classical FA, providing proof that FANCM is not a canonical FA gene. Moreover, our observations support previous findings suggesting that FANCM is a breast cancer-predisposing gene. Mutation testing of FANCM might be considered for individuals with the above-described clinical features.

Intraoperative Boost Radiotherapy during Targeted Oncoplastic Breast Surgery: Overview and Single Center Experiences

Breast-conserving surgery followed by whole-breast irradiation is the standard local therapy for early breast cancer. The international discussion of reduced importance of wider tumor-free resection margins than “tumor not touching ink” leads to the development of five principles in targeted oncoplastic breast surgery. IORT improves local recurrence risk and diminishes toxicity since there is less irradiation of healthy tissue. Intraoperative radiotherapy (IORT) can be delivered in two settings: an IORT boost followed by a conventional regimen of external beam radiotherapy or a single IORT dose. The data from TARGIT-A and ELIOT reinforce the conviction that intraoperative radiotherapy during breast-conserving surgery is a reliable alternative to conventional postoperative fractionated irradiation, but only in a carefully selected population at low risk of local recurrence. We describe our experiences with IORT boost (50 kV energy X-rays; 20 Gy) in combination with targeted oncoplastic breast surgery in a routine clinical setting. Our experiences demonstrate the applicability and reliability of combining IORT boost with targeted oncoplastic breast surgery in breast-conserving therapy of early breast cancer.

BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer

BackgroundGermline mutations in the BRIP1 gene have been described as conferring a moderate risk for ovarian cancer (OC), while the role of BRIP1 in breast cancer (BC) pathogenesis remains controversial.MethodsTo assess the role of deleterious BRIP1 germline mutations in BC/OC predisposition, 6341 well-characterized index patients with BC, 706 index patients with OC, and 2189 geographically matched female controls were screened for loss-of-function (LoF) mutations and potentially damaging missense variants. All index patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germline testing and tested negative for pathogenic BRCA1/2 variants.ResultsBRIP1 LoF mutations confer a high OC risk in familial index patients (odds ratio (OR) = 20.97, 95% confidence interval (CI) = 12.02–36.57, P < 0.0001) and in the subgroup of index patients with late-onset OC (OR = 29.91, 95% CI = 14.99–59.66, P < 0.0001). No significant association of BRIP1 LoF mutations with familial BC was observed (OR = 1.81 95% CI = 1.00–3.30, P = 0.0623). In the subgroup of familial BC index patients without a family history of OC there was also no apparent association (OR = 1.42, 95% CI = 0.70–2.90, P = 0.3030). In 1027 familial BC index patients with a family history of OC, the BRIP1 mutation prevalence was significantly higher than that observed in controls (OR = 3.59, 95% CI = 1.43–9.01; P = 0.0168). Based on the negative association between BRIP1 LoF mutations and familial BC in the absence of an OC family history, we conclude that the elevated mutation prevalence in the latter cohort was driven by the occurrence of OC in these families. Compared with controls, predicted damaging rare missense variants were significantly more prevalent in OC (P = 0.0014) but not in BC (P = 0.0693) patients.ConclusionsTo avoid ambiguous results, studies aimed at assessing the impact of candidate predisposition gene mutations on BC risk might differentiate between BC index patients with an OC family history and those without. In familial cases, we suggest that BRIP1 is a high-risk gene for late-onset OC but not a BC predisposition gene, though minor effects cannot be excluded.

COMBATing Breast Cancer Conference 2013-Chances for Cure

therapy. To obtain valuable data, international cooperation is needed. This excellent lecture was followed by comprehensive overviews over the German research landscape regarding translational research in gyneco-oncology and senology. The award winners of the AGO TraFo meeting in May 2013 were given time to present their latest findings during an oral presentation (Anna-Lena Krause (Heidelberg), best lecture; Melanie Kurschner (Hamburg), best poster). The pre-symposium then finished with a poster presentation; the 3 best contributions were rewarded with prizes during the evening’s festivities (1st prize Carolin Hulsewig (Munster), 2nd prize Florian Bitterer (Regensburg) and 3rd prize Benjamin Ley (Halle)).

COMBATing Breast Cancer Conference 2012 - Deciphering Breast Cancer

The meeting started with an update on recent developments since the last COMBATing in 2011. Anton Scharl (Amberg) predicted a paradigm shift from adjuvant to neoadjuvant chemotherapy as the standard concept in certain subtypes (triple negative, HER2 positive) of primary breast cancer thereby improving surgical outcome and allowing an early evaluation of therapy effectiveness. Furthermore, the question of the necessity of chemotherapy in nodal positive breast cancer, the role of Everolimus in bone health and the interaction of the tumor with its microenvironment were discussed. Breast cancer treatment has experienced several changes during the past decades due to discovery of specific prognostic and predictive biomarkers. Therefore, the next session focused on the evidence-based use of biomarkers in the clinic. Hans Kreipe (Hannover) gave an overview over traditional biomarkers, such as hormone receptors and the role of the proliferation marker Ki-67 in chemotherapy response and prognosis after neoadjuvant therapy. Unfortunately, the exact cut-off value for Ki-67 has not yet been validated and thus still has to be evaluated in ongoing studies like the WSG-ADAPTtrial. In addition, the medical and scientific benefit of the new molecular tests (e.g. Onkotype DX, Endopredict) and their role in DCIS were discussed. Novel discoveries for the therapy of hereditary breast cancer were presented by Rita Schmutzler (Cologne). 2012 was a very successful year for the German Consortium of Hereditary Breast and Ovarian Cancer with the detection of new potential high risk genes, which are currently under evaluation. The 5th COMBATing (Conference On Molecular Basics And Therapeutic implications in breast cancer) meeting was held in Munich, November 23-24, 2012. Breast cancer is a heterogeneous disease on the molecular, histopathological, and clinical level. For this reason, this year’s conference was dedicated to a better understanding of the diversity of breast cancer. Chaired by Nadia Harbeck (Munich), Achim Rody (Lübeck), and Michael Gnant (Vienna), COMBATing 2012 attracted over 260 physicians and medical scientists including national and international pioneers in breast cancer research. In two days, recent controversial aspects of translational breast cancer research and treatment were discussed, from the evaluation of traditional histopathological classifications, to clinical trials to the role of the molecular subtypes.

COMBATing Breast Cancer Conference 2011 – Stories of Success and Failure

On November 18–19, 2011 the 4th COMBATing (Conference On Molecular basics And Therapeutic Implications In Breast Cancer) meeting took place, for the first time in Munich. This years meeting had the motto ‘Stories of Success and Failure’ The congress, chaired by Nadia Harbeck (Cologne), Manfred Kaufmann (Frankfurt/M.), and Achim Rody (Homburg/Saar), was an outstanding success. For the more than 250 participants, predominantly young physicians and medical scientists, this conference offered a unique platform for the interdisciplinary exchange and translational networking in breast cancer research. An impressive number of invited national and international speakers gave an overview of recent scientific discoveries in breast cancer research. In 30 lectures they presented the newest developments in basic, translational and clinical research focusing on targeted therapy, predictive markers, subtypes, and tumorous stroma, evaluating their future clinical relevance.