Paul Gass

Association of molecular subtypes with breast cancer risk factors: a case-only analysis.

As breast cancer (BC) screening identifies many BCs with a good prognosis, which might be overdiagnosed and therefore overtreated, the identification of subgroups with a high risk for aggressive subtypes might be helpful. The aim of this case–case analysis was to investigate the association between epidemiological risk factors and molecular subtypes in a cohort of BC patients. Epidemiological risk factors for 2587 BC patients were obtained using a structured questionnaire and from the patients’ charts. The histopathological information (estrogen and progesterone receptor, HER2 and Ki-67) used in the analysis was retrieved from the original pathology reports. Analyses using conditional inference regression trees were carried out on these data. The strongest influence factor on the distribution of the molecular subtypes was age at first diagnosis of BC. An influence of BMI was also identified in patients aged either more than 42 years or 49.6 years or less. Older patients aged more than 49.6 years and perimenopausal women with a BMI of 32.4 kg/m2 or less were most likely to develop luminal A-like BC. Young patients aged 42 years or less and perimenopausal patients with a BMI more than 32.4 kg/m2 more often developed triple-negative BC. The study confirmed that age at diagnosis is an important factor influencing the distribution of molecular subtypes. In the perimenopausal group, it may be postulated that BMI plays a critical role in the pathogenesis of BC, defining a subgroup that is more likely to develop triple-negative BC or luminal B-like disease and another group in which there is a more postmenopausal distribution pattern.

Predicting Triple-Negative Breast Cancer Subtype Using Multiple Single Nucleotide Polymorphisms for Breast Cancer Risk and Several Variable Selection Methods

INTRODUCTION Studies of triple-negative breast cancer have recently been extending the inclusion criteria and incorporating additional molecular markers into the selection criteria, opening up scope for targeted therapies. The screening phases required for studies of this type are often prolonged, since the process of determining the molecular subtype and carrying out additional biomarker assessment is time-consuming. Parameters such as germline genotypes capable of predicting the molecular subtype before it becomes available from pathology might be helpful for treatment planning and optimizing the timing and cost of screening phases. This appears to be feasible, as rapid and low-cost genotyping methods are becoming increasingly available. The aim of this study was to identify single nucleotide polymorphisms (SNPs) for breast cancer risk capable of predicting triple negativity, in addition to clinical predictors, in breast cancer patients. METHODS This cross-sectional observational study included 1271 women with invasive breast cancer who were treated at a university hospital. A total of 76 validated breast cancer risk SNPs were successfully genotyped. Univariate associations between each SNP and triple negativity were explored using logistic regression analyses. Several variable selection and regression techniques were applied to identify a set of SNPs that together improve the prediction of triple negativity in addition to the clinical predictors of age at diagnosis and body mass index (BMI). The most accurate prediction method was determined by cross-validation. RESULTS The SNP rs10069690 (TERT, CLPTM1L) was the only significant SNP (corrected p = 0.02) after correction of p values for multiple testing in the univariate analyses. This SNP and three additional SNPs from the genes RAD51B, CCND1, and FGFR2 were selected for prediction of triple negativity. The addition of these SNPs to clinical predictors increased the cross-validated area under the curve (AUC) from 0.618 to 0.625. Age at diagnosis was the strongest predictor, stronger than any genetic characteristics. CONCLUSION Prediction of triple-negative breast cancer can be improved if SNPs associated with breast cancer risk are added to a prediction rule based on age at diagnosis and BMI. This finding could be used for prescreening purposes in complex molecular therapy studies for triple-negative breast cancer.

A Standard Mammography Unit – Standard 3D Ultrasound Probe Fusion Prototype: First Results

AIM The combination of different imaging modalities through the use of fusion devices promises significant diagnostic improvement for breast pathology. The aim of this study was to evaluate image quality and clinical feasibility of a prototype fusion device (fusion prototype) constructed from a standard tomosynthesis mammography unit and a standard 3D ultrasound probe using a new method of breast compression. MATERIALS AND METHODS Imaging was performed on 5 mastectomy specimens from patients with confirmed DCIS or invasive carcinoma (BI-RADS ™ 6). For the preclinical fusion prototype an ABVS system ultrasound probe from an Acuson S2000 was integrated into a MAMMOMAT Inspiration (both Siemens Healthcare Ltd) and, with the aid of a newly developed compression plate, digital mammogram and automated 3D ultrasound images were obtained. RESULTS The quality of digital mammogram images produced by the fusion prototype was comparable to those produced using conventional compression. The newly developed compression plate did not influence the applied x-ray dose. The method was not more labour intensive or time-consuming than conventional mammography. From the technical perspective, fusion of the two modalities was achievable. CONCLUSION In this study, using only a few mastectomy specimens, the fusion of an automated 3D ultrasound machine with a standard mammography unit delivered images of comparable quality to conventional mammography. The device allows simultaneous ultrasound - the second important imaging modality in complementary breast diagnostics - without increasing examination time or requiring additional staff.

Duty Rosters and Workloads of Obstetricians in Germany: Results of a Germany-wide Survey

BACKGROUND Compiling a daily hospital roster which complies with existing laws and tariff regulations and meets the requirements for ongoing professional training while also taking the legal regulations on the health of employees into account makes planning the duty roster a challenge. The aim of this study was to obtain a realistic picture of existing duty roster systems and of the current workloads of obstetricians in Germany. METHOD This online survey was sent to 2770 physicians training to become obstetricians or specializing in specific areas of obstetric care. The survey consisted of an anonymized 95-item questionnaire which collected data on different types of duty roster systems and the workload of obstetricians in Germany for the period from 17.02.2015 to 16.05.2015. RESULTS Out of a total of 2770 physicians who were contacted, 437 (16%) completed the questionnaire. Across all forms of care, the care provided outside normal working hours usually (75%) consisted of a combination of regular working times and on-call duty or even consisted entirely of standby duty. Level I perinatal centers were most likely 20% (n = 88) to have a shift system in place. Working a shift system was significantly more common in care facilities which had previously carried out a job analysis. The number of physicians in hospitals who are present during the night shift was higher in facilities with higher numbers of births and in facilities which offered higher levels of care. In addition to regularly working overtime and the fact that often not all the hours worked were recorded, it was notable that the systems used to compile duty rosters often did not comply with legal regulations or with collectively agreed working hours nor were they compatible with the staff planning requirements. OUTLOOK The results of this study show that the conditions of work, the working times, and the organization of working times in obstetric departments are in need of improvement. Recording the actual times worked together with an analysis of the activities performed during working times and while on standby would increase the level of transparency for employers and employees.

BRCA mutations and their influence on pathological complete response and prognosis in a clinical cohort of neoadjuvantly treated breast cancer patients

PurposeBRCA1/2 mutations influence the molecular characteristics and the effects of systemic treatment of breast cancer. This study investigates the impact of germline BRCA1/2 mutations on pathological complete response and prognosis in patients receiving neoadjuvant systemic chemotherapy.MethodsBreast cancer patients were tested for a BRCA1/2 mutation in clinical routine work and were treated with anthracycline-based or platinum-based neoadjuvant chemotherapy between 1997 and 2015. These patients were identified in the tumor registry of the Breast Center of the University of Erlangen (Germany). Logistic regression and Cox regression analyses were performed to investigate the associations between BRCA1/2 mutation status, pathological complete response, disease-free survival, and overall survival.ResultsAmong 355 patients, 59 had a mutation in BRCA1 or in BRCA2 (16.6%), 43 in BRCA1 (12.1%), and 16 in BRCA2 (4.5%). Pathological complete response defined as “ypT0; ypN0” was observed in 54.3% of BRCA1/2 mutation carriers, but only in 22.6% of non-carriers. The adjusted odds ratio was 2.48 (95% CI 1.26–4.91) for BRCA1/2 carriers versus non-carriers. Patients who achieved a pathological complete response had better disease-free survival and overall survival rates compared with those who did not achieve a pathological complete response, regardless of BRCA1/2 mutation status.ConclusionsBRCA1/2 mutation status leads to better responses to neoadjuvant chemotherapy in breast cancer. Pathological complete response is the main predictor of disease-free survival and overall survival, independently of BRCA1/2 mutation status.

Using Probability for Pathological Complete Response (pCR) as a Decision Support Marker for Neoadjuvant Chemotherapy in HER2 Negative Breast Cancer Patients – a Survey Among Physicians

Background In women with early breast cancer, a pathological complete response (pCR) after neoadjuvant chemotherapy is reported to be associated with an improvement of the survival. The aim of this survey among physicians was to investigate whether the probability of achieving pCR in patients with a hormone receptor-positive, HER2-negative disease encourages physicians to recommend neoadjuvant chemotherapy. Methods The study was conducted via an online survey that was sent to 493 physicians, who were either known as members of national guideline committees, heads of breast cancer centers, being high recruiters in clinical trials or leading a private practice. Participants were asked about a specific case that should resemble patients for whom it is unclear, whether they should be treated with chemotherapy. Results 113 (24.5%) physicians participated at the survey, out of which 96.5% had a work experience of more than 10 years and 94.7% were board certified in their specialty. A total of 84.1% would consider pCR for a decision concerning neoadjuvant chemotherapy. With regard to the pCR probability, 2.7 and 10.6% of the participants demanded at least a pCR rate of 5 and 10%, respectively, while 25.7% were satisfied with 20% probability, and another 25.7% with a pCR rate of 30%. Conclusions The vast majority of the long-term experienced physicians would embrace the implementation of a further method such as the prediction of pCR probability in clinical routine to support decision making regarding the necessity of neoadjuvant chemotherapy. The cut-off of around 30% pCR probability seems to be a realizable rate to distinguish patient groups.

Efficacy of neoadjuvant pertuzumab in addition to chemotherapy and trastuzumab in routine clinical treatment of patients with primary breast cancer: a multicentric analysis

PurposeNeoadjuvant combination treatment with chemotherapy (CTX), trastuzumab (TZM), and pertuzumab (PTZ) has been shown to result in higher pathological complete response rates (pCR) in comparison with treatment with chemotherapy and trastuzumab (CTX/TZM). This analysis was aimed at real-world validation of these results from prospective randomized trials.MethodsIn a retrospective analysis conducted in the PRAEGNANT network, patients were eligible for inclusion if they had either received neoadjuvant therapy with CTX/TZM or chemotherapy, trastuzumab, and pertuzumab (CTX/TZM/PTZ) and subsequently underwent surgery for their primary breast cancer. The effect of the two neoadjuvant regimens on pCR in addition to commonly applicable predictors of pCR was analyzed in 300 patients from three study sites, using logistic regression analyses with treatment arm, age, clinical tumor stage, grading, and hormone receptor status as predictors.ResultspCR with complete disappearance of all tumor cells was seen in 30.2% (n = 58) of patients treated with CTX/TZM and in 52.8% (n = 57) of those treated with CTX/TZM/PTZ. CTX/TZM/PTZ was positively associated with pCR (adjusted odds ratio 2.44; 95% CI 1.49–4.02). Mastectomy rates were not influenced by the therapy.ConclusionsThe results of clinical trials were confirmed in this dataset of patients who were treated outside of clinical trials in everyday routine work. pCR rates can be improved by 20% with pertuzumab in routine clinical use.

The effect of participation in neoadjuvant clinical trials on outcomes in patients with early breast cancer

BackgroundClinical trials can offer novel and more advanced and/or novel treatments to cancer patients in advance of them being approved and available for all patients. While several studies have examined the effect of clinical trial participation on prognosis, there has been no clear conclusion from these studies. Therefore, we chose to test the influence of trial participation on pathological complete response (pCR) and mastectomy rates after neoadjuvant chemotherapy.MethodsIn this retrospective study, all patients treated with neoadjuvant chemotherapy from 2001 to 2014 were selected. A total of 1038 patients with complete treatment, patient, and tumor characteristics were included. A total of 260 of those were treated in clinical trials. We examined whether study participation status in addition to commonly known predictors for pCR improves prediction of pCR. Similar analyses were conducted for the mastectomy rate outcome measure. Finally, survival analyses were also conducted as part of an exploratory analysis.ResultsStudy participation was an independent predictor of pCR in addition to commonly known predictors. Adjusted odds ratio (OR) for trial participants versus non-participants was 1.53 (95% CI 1.03–2.28). Additionally, study participation improved the prediction of mastectomy risk. The adjusted OR for trial participants versus non-participants was 0.62 (95% CI 0.42–0.90). Subgroup-specific differences concerning the impact of study participation could not be shown for either pCR or mastectomy rate. Survival comparisons could not be conducted due to large differences in follow-up data in patients participating in clinical trials versus those who did not participate; however, pCR was a predictor of prognosis in both groups.ConclusionPatients taking part in neoadjuvant chemotherapy clinical trials have a higher pCR rate and a lower mastectomy risk than patients not participating in clinical trials for their cancer care. This finding is a supporting factor for trial participation in neoadjuvant chemotherapy trials.

Association between mammographic density and pregnancies relative to age and BMI: a breast cancer case-only analysis

PurposePercentage mammographic density (PMD) is a major risk factor for breast cancer (BC). It is strongly associated with body mass index (BMI) and age, which are themselves risk factors for breast cancer. This analysis investigated the association between the number of full-term pregnancies and PMD in different subgroups relative to age and BMI.MethodsPatients were identified in the breast cancer database of the University Breast Center for Franconia. A total of 2410 patients were identified, for whom information on parity, age, and BMI, and a mammogram from the time of first diagnosis were available for assessing PMD. Linear regression analyses were conducted to investigate the influence on PMD of the number of full-term pregnancies (FTPs), age, BMI, and interaction terms between them.ResultsAs in previous studies, age, number of FTPs, and BMI were found to be associated with PMD in the expected direction. However, including the respective interaction terms improved the prediction of PMD even further. Specifically, the association between PMD and the number of FTPs differed in young patients under the age of 45 (mean decrease of 0.37 PMD units per pregnancy) from the association in older age groups (mean decrease between 2.29 and 2.39 PMD units). BMI did not alter the association between PMD and the number of FTPs.ConclusionsThe effect of pregnancies on mammographic density does not appear to become apparent before the age of menopause. The mechanism that drives the effect of pregnancies on mammographic density appears to be counter-regulated by other influences on mammographic density in younger patients.

Neoadjuvant Treatment of Breast Cancer - Advances and Limitations

led to a focus of neoadjuvant chemotherapy in triple negative and HER2-positive patients, with some studies only enrolling those 2 patient groups [8, 9]. Knowing that patients with some tumor types more often achieve pCR than others and that the connection between pCR and prognosis differs between subgroups, one recent focus of research is to differentiate patients who benefit from pCR from those in which a complete disappearance of the tumor does not have a larger prognostic effect. One example is the subgroup of triple negative patients with a BRCA mutation: in a clinical cohort treated neoadjuvantly with anthracyclines and taxanes a prognostic effect of pCR could only be shown in patients with a wildtype BRCA status [10]. Similarly, patients with a PIR3K mutation in their tumor often achieve a pCR after neoadjuvant chemotherapy combined with anti-HER2 therapy. However, a PI3K mutation does not seem to have influence on prognosis [11]. This shows that we still have a lot to learn concerning the connection between pCR and prognosis. It was tried to establish pCR as a surrogate marker for prognosis, which could lead to the approval of neoadjuvant therapies. However, the combined analysis of almost 12,000 patients from 12 international trials did not validate pCR as a surrogate marker for prognosis [3]. In a subgroup analysis, the correlation between pCR and prognosis was largest in HER2-positive patients [3, 12], indicating that further research on how to use response to neoadjuvant therapy for drug development might be most successful in this breast cancer subtype. In this issue of Breast Care, Kolberg and colleagues [13] present the 4-year follow-up of patients who achieved pCR after neoadjuvant treatment with a combination of docetaxel, carboplatin, and weekly TCH. Patients who have residual disease after neoadjuvant chemotherapy are a clinical problem, as they represent a subgroup with very unfavorable prognosis. Novel therapy concepts consider these patients for an additional adjuvant therapy in so-called postNeoadjuvant chemotherapy was first introduced for the treatment of larger tumors in order to reduce tumor size and possibly increase the likelihood for a breast conserving therapy; however, after decades of clinical use of neoadjuvant chemotherapy, it can be considered as a standard chemotherapy option for any patient who has an indication for neoadjuvant chemotherapy [1, 2]. In addition to a possible clinical benefit by downstaging the tumor before surgery, a great interest in neoadjuvant chemotherapy has been developed because it serves as an in vivo experiment for both patients and physicians to see whether or not the tumor responds to the given therapy. In a relevant number of patients the tumor completely disappears from breast and the axilla. It has been shown that this pathological complete response (pCR) is an excellent predictor of prognosis, especially in some molecular subgroups [3, 4]. In a pooled analysis, up to 35% of all patients with triple negative breast cancer (TNBC) achieved pCR after neoadjuvant chemotherapy, while in HER2-positive hormone receptor (HR)-negative patients up to 50% achieved pCR after chemotherapy and trastuzumab (TCH) therapy [3]. Much lower pCR rates are achieved in HRpositive, HER2-negative patients, with pCR rates as low as 8% for tumors with a grading of 1 or 2 and about 16% with a grading of 3 [3]. With regard to outcomes, the translation of pCR into a good prognosis is prominent for triple negative and HER2-positive patients; however, this is difficult to show for other subtypes, such as HR-positive patients with a grading of 1 and 2 [3]. In this issue of Breast Care, Gaß et al. [5] explore which HR-positive patients should receive adjuvant and neoadjuvant chemotherapy. The treatment of these patients is a challenge because they have a good prognosis but often do not respond to chemotherapy. Novel molecular tests might help to identify those patients who have an excellent prognosis and therefore do not need chemotherapy [6, 7]. The low response rates in HR-positive, HER2-negative patients has Published online: October 24, 2016