Birgid Markiefka

Guidance Statement On BRCA1/2 Tumor Testing in Ovarian Cancer Patients

The approval, in 2015, of the first poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi; olaparib, Lynparza) for platinum-sensitive relapsed high-grade ovarian cancer with either germline or somatic BRCA1/2 deleterious mutations is changing the way that BRCA1/2 testing services are offered to patients with ovarian cancer. Ovarian cancer patients are now being referred for BRCA1/2 genetic testing for treatment decisions, in addition to familial risk estimation, and irrespective of a family history of breast or ovarian cancer. Furthermore, testing of tumor samples to identify the estimated 3%-9% of patients with somatic BRCA1/2 mutations who, in addition to germline carriers, could benefit from PARPi therapy is also now being considered. This new testing paradigm poses some challenges, in particular the technical and analytical difficulties of analyzing chemically challenged DNA derived from formalin-fixed, paraffin-embedded specimens. The current manuscript reviews some of these challenges and technical recommendations to consider when undertaking BRCA1/2 testing in tumor tissue samples to detect both germline and somatic BRCA1/2 mutations. Also provided are considerations for incorporating genetic analysis of ovarian tumor samples into the patient pathway and ethical requirements.

Genotype/Phenotype Correlations in Patients with Hereditary Breast Cancer

Of all breast cancer cases, 5-10% can be attributed to germline mutations, and the high-susceptibility genes BRCA1 and BRCA2 account for about 25-28% of these cases. For the remainder, several genes of moderate and low penetrance have been discovered. Histopathologic characteristics have been studied in small cohorts, but for most of the known non-BRCA1/2-associated hereditary breast cancers, the histologic and immunohistochemical phenotypes are not yet identified. Particularly BRCA1 tumors are associated with a distinct morphology and immunohistochemical characteristics that differ from sporadic breast cancer of age-matched controls. The recognition of features characteristic of these mutations can be helpful to identify patients likely to carry a germline mutation and to assess which gene should be screened for first, in families with a high occurrence of breast and ovarian cancer.

Squamous Cell Carcinoma of the Pancreas in a Patient with Germline BRCA2 Mutation-Response to Neoadjuvant Radiochemotherapy.

Primary squamous cell carcinoma of the pancreas is a rare malignant neoplasia, accounting for approximately 0.5–2% of all malignant pancreatic tumors. These lesions are characterized by poor prognosis. Here we report on a case of a 57-year-old female patient with known BRCA2 germline mutation presenting with primary squamous cell carcinoma of the pancreas as the only malignancy. The tumor was locally advanced at the first presentation but responded almost completely to neoadjuvant radio-chemotherapy. Our case highlights the facts (i) that pancreatic carcinomas belong to the tumor spectrum of patients with the BRCA2-associated hereditary breast and ovarian cancer syndrome (HBOC) and (ii) that tumors of the pancreas can represent the first or even the only manifestation of HBOC. Furthermore, this case of a nonkeratinizing squamous cell carcinoma indicates that HBOC-associated carcinomas of the pancreas might be characterized by a broader morphological spectrum than was previously thought. Since BRCA mutations cause deficiency of DNA double-strand breakage repair in tumors, neoadjuvant treatment regimens might become a reasonable option in HBOC-associated pancreatic carcinomas. To our knowledge, this is the first reported case of a primary pancreatic squamous cell carcinoma in a patient with this particular genetic background of BRCA2-associated HBOC.

Non-small cell neuroendocrine carcinoma of the ovary in a BRCA2-germline mutation carrier: A case report and brief review of the literature

Non-small cell neuroendocrine carcinomas (NSCNEC) account for 2% of gynecological cancer cases and are associated with a poor prognosis due to delayed diagnosis and aggressive tumor behavior. BRCA2-associated ovarian carcinomas predominantly possess a high-grade serous phenotype, which respond to platinum and targeted therapy with PARP inhibitors. Presented here is the case of an adult patient with NSCNEC of the ovaries associated with a deleterious BRCA2 germline mutation. The pathogenic mutation was also confirmed on the somatic level, while the wild-type allele had a high variant fraction, suggesting loss of heterozygosity. To the best of our knowledge, this is the first report of an adult BRCA2 germline mutation carrier with the rare NSCNEC of the ovary phenotype. Therefore, ovarian cancer patients with histological subtypes other than high-grade serous carcinomas should be tested for BRCA1/2 mutations, as they may benefit from targeted therapy with poly (ADP-ribose) polymerase inhibitors.

Vacuum-assisted breast biopsies (VAB) carried out on an open 1.0 T MR imager: Influence of patient and target characteristics on the procedural and clinical results

PURPOSE The study was conducted in order to assess the clinical impact of MRI-guided vacuum-assisted breast biopsies carried out using an open 1.0T open MRI-system. MATERIAL AND METHODS The clinical, imaging, interventional and histological data of all 132 patients with a first MRI-guided vacuum-assisted breast biopsy carried out between 07/2005 and 03/2012at the Radiological Department were extracted from the clinical files. The clinical outcome of patients with benign histological findings was assessed based on the clinical files and queries of the local gynecologists in charge. In the 103 interventional image data sets available target localization and target size were evaluated by two board-certified senior radiologists. Clinical data, lesion characteristics and interventional results were evaluated statistically using subgroup analyses. RESULTS 131 of 132 MRI-guided breast biopsies (99.2%) were carried out successfully. The median interventional duration was 30min (25%-percentile 25min, 75%-percentile 35min, maximum 75min). Minor complications occurred in 12 interventions of the 131 (9.2%). The histological work-up of the biopsy specimen showed benign results in 98 of 131 interventions (74.8%), lesions with uncertain biological potential in 5 biopsies (3.8%) and malignant findings in 28 biopsies (21.4%). There were 2 false negative histological findings. Neither the patient age nor the medical history nor the anticipated risk of developing breast cancer had an impact on the success rates and the complication rates. In the 103 interventions with available image data sets the maximum target lesion diameters were 1-5mm in 16 lesions (15.5%), 6-10mm in 41 lesions (39.8%) and 11-15mm in 29 lesions (28.2%). There was a positive correlation between the maximum diameters and the rate of malignancy of the target lesions (p=0.020) as well as a trend towards longer interventional procedure durations in smaller target lesions (p=0.183). CONCLUSION MRI-guided vacuum-assisted breast biopsy for suspicious breast lesions is a clinically safe and feasible method even in small target lesions when using an open high-field MRI-system.

BCY 2 - Second Breast Cancer in Young Women Conference 4th-5th November 2014 Dublin, Ireland

and the importance of improvement of psychosocial and medical care of those patients mainly focusing on the US perspective. She also focused on the unique aspects of young women with BC. They often present an advanced disease because of delays of diagnosis (‘you are too young to have breast cancer’) and a more aggressive tumor biology (e.g. ER negative, high grade, LVI disease, HER2-positive). Genetics, fertility and sexuality concerns as well as body image and the premenopausal situation play an important role in these patients, they need to be understood and supported. Diagnostic tools were presented in the session by M. SklairLevy (IL), who discussed new technologies of breast imaging such as tomosynthesis (a modification of digital mammography to create 3-dimensional data), contrast-enhanced spectral mammography (CESM), automated breast volume scanner and also nuclear breast imaging (positron emission mammography, FDG) which are intended to be implemented in the individual diagnosis of young breast cancer patients. The session on hereditary and familial breast cancer was well discussed. E. Levy-Lahad (IL) presented data about the right time for genetic testing and discussed issues about rapid genetic testing before initiating any treatment and traditional BRCA-testing in the young patient. As genetic testing has a yield of about 25% in the young patient, it affects treatment decisions and has therefore therapeutic impact. The goal of genetic testing might in any case be a treatment-focused genetic testing (TFGT), after diagnosis but before surgery. In her talk about local therapy considerations in BRCA1/2 mutation carriers, Ella Evron (IL) showed the markedly increased risk of BRCA carriers of contralateral BC and presented the design of an initiated Israeli multicenter study on the prophylactic contralateral irradiation after breast conserving therapy as a potential option of prevention in high-risk patients and to reduce the rate of bilateral mastectomy. New systemic therapies in hereditary BC were discussed by Judy Garber who presented recent data with a neoadjuvant regimen of platinum in TNBC (pathologic complete remission (pCR) 61%, Breast Cancer Res Treat 2014;147:401–405) as also shown by GEPARSIXTO (higher pCR rates after neoadjuvant anthracycline/taxane in TNBC). PARPP inhibitors such as olaparib (Olympia) or niraparib (BRAWO) for 1 year after neo-/adjuvant therapy are currently tested in several protocols as also in combination with platinum (carboplatin/gemcitabine/iniparib) in the PrECOG 0105 scheme. Breast cancer (BC) in women under 40 years of age is a complex disease which strikes in a phase of life when young women are at the peak of their reproductive years and when family planning, professional career, and partnership have a lot of importance. Furthermore, as young women are more likely to have a risk of a higher grade and stage of the disease, tumor biology at the time of diagnosis and genetic factors play an important role, medical treatment and consultation has to be well adapted to the needs of this population. So far, little is known about the etiology of breast cancer in young women and more research is needed to establish an optimal management of these patients. The Breast Cancer in Young Women Conference was initiated in 2012 by high-ranking breast cancer specialists from Europe, Israel, and the US to create a platform about novel research results, future research concepts and to give the opportunity of networking and discussion in this so far poorly researched field. Additionally, the first international consensus guidelines for breast cancer in young women were developed by international BC specialists, being finally published in June 2014 (Breast 2014;23:209–220). Initially planned to take place in Tel Aviv, Israel, BCY 2 was changed this year to take place again in Dublin, Ireland because of the political conflicts in the Middle East. The BCY 2 conference was supported and organized by the European School of Oncology (ESO) (www.eso.net). In 9 sessions and 25 talks in total, all ‘hot topics’ around the treatment and diagnosis of young BC patients were covered. International speakers gave an overview of recent results of breast cancer research, newest developments in the treatment of young breast cancer patients and an outlook on the results to be presented in San Antonio in December 2014. During the conference, the 205 participants from 35 different countries heard talks that touched upon tumor biology and pathology, genetics, diagnostics, surgery, systemic therapy, radiotherapy, fertility preservation, and supportive offers. After the presentation by Bella Kaufmann from the Israel Cancer Association (IL), one of the chairs of the conference, BCY 2 was opened by a field report of a young BC patient. With a very personal report, Nicola Elmer (IE) illustrated this intensive and difficult phase of her life around the BC diagnosis and all her problems during and after systemic therapy, so that a perfect introduction to the conference was given. Ann Partridge (US) continued in another keynote lecture to refer about the growing population of young BC patients, and its relevance for public health