Correction: Long-term Follow-up and Safety of Patients after an Upfront Therapy with Letrozole for Early Breast Cancer in Routine Clinical Care - The PreFace Study.

[This corrects the article DOI: 10.1055/a-2238-3153.].

Implementation and Evaluation of a Breast Cancer Disease Model Using Real-World Claims Data in Germany from 2010 to 2020.

Breast cancer is the leading cause of cancer-related mortality among women in Germany and worldwide. This retrospective claims data analysis utilizing data from AOK Baden-Wuerttemberg, a major statutory German health insurance provider, aimed to construct and assess a real-world data breast cancer disease model. The study included 27,869 female breast cancer patients and 55,738 age-matched controls, analyzing data from 2010 to 2020. Three distinct breast cancer stages were analyzed: Stage A (early breast cancer without lymph node involvement), Stage B (early breast cancer with lymph node involvement), and Stage C (primary distant metastatic breast cancer). Tumor subtypes were estimated based on the prescription of antihormonal or HER2-targeted therapy. The study established that 77.9% of patients had HR+ breast cancer and 9.8% HER2+; HR+/HER2- was the most common subtype (70.9%). Overall survival (OS) analysis demonstrated significantly lower survival rates for stages B and C than for controls, with 5-year OS rates ranging from 79.3% for stage B to 35.4% for stage C. OS rates were further stratified by tumor subtype and stage, revealing varying prognoses. Distant recurrence-free survival (DRFS) analysis showed higher recurrence rates in stage B than in stage A, with HR-/HER2- displaying the worst DRFS. This study, the first to model breast cancer subtypes, stages, and outcomes using German claims data, provides valuable insights into real-world breast cancer epidemiology and demonstrates that this breast cancer disease model has the potential to be representative of treatment outcomes.

Long-term Follow-up and Safety of Patients after an Upfront Therapy with Letrozole for Early Breast Cancer in Routine Clinical Care - The PreFace Study.

Introduction: Adjuvant treatment of patients with early-stage breast cancer (BC) should include an aromatase inhibitor (AI). Especially patients with a high recurrence risk might benefit from an upfront therapy with an AI for a minimum of five years. Nevertheless, not much is known about the patient selection for this population in clinical practice. Therefore, this study analyzed the prognosis and patient characteristics of postmenopausal patients selected for a five-year upfront letrozole therapy. Patients and Methods: From 2009 to 2011, 3529 patients were enrolled into the adjuvant phase IV PreFace clinical trial (NCT01908556). Postmenopausal hormone receptor-positive BC patients, for whom an upfront five-year therapy with letrozole (2.5 mg/day) was indicated, were eligible. Disease-free survival (DFS), overall survival (OS) and safety in relation to patient and tumor characteristics were assessed. Results: 3297 patients started letrozole therapy. The majority of patients (n = 1639, 57%) completed the five-year treatment. 34.5% of patients continued with endocrine therapy after the mandated five-year endocrine treatment. Five-year DFS rates were 89% (95% CI: 88-90%) and five-year OS rates were 95% (95% CI: 94-96%). In subgroup analyses, DFS rates were 83%, 84% and 78% for patients with node-positive disease, G3 tumor grading, and pT3 tumors respectively. The main adverse events (any grade) were pain and hot flushes (66.8% and 18.3% of patients). Conclusions: The risk profile of postmenopausal BC patients selected for a five-year upfront letrozole therapy showed a moderate recurrence and death risk. However, in subgroups with unfavorable risk factors, prognosis warrants an improvement, which might be achieved with novel targeted therapies.

Optical Emission Spectroscopy for the Real-Time Identification of Malignant Breast Tissue.

Breast conserving resection with free margins is the gold standard treatment for early breast cancer recommended by guidelines worldwide. Therefore, reliable discrimination between normal and malignant tissue at the resection margins is essential. In this study, normal and abnormal tissue samples from breast cancer patients were characterized ex vivo by optical emission spectroscopy (OES) based on ionized atoms and molecules generated during electrosurgical treatment. The aim of the study was to determine spectroscopic features which are typical for healthy and neoplastic breast tissue allowing for future real-time tissue differentiation and margin assessment during breast cancer surgery. A total of 972 spectra generated by electrosurgical sparking on normal and abnormal tissue were used for support vector classifier (SVC) training. Specific spectroscopic features were selected for the classification of tissues in the included breast cancer patients. The average classification accuracy for all patients was 96.9%. Normal and abnormal breast tissue could be differentiated with a mean sensitivity of 94.8%, a specificity of 99.0%, a positive predictive value (PPV) of 99.1% and a negative predictive value (NPV) of 96.1%. For 66.6% patients all classifications reached 100%. Based on this convincing data, a future clinical application of OES-based tissue differentiation in breast cancer surgery seems to be feasible.

Efficacy of Lapatinib in Patients with HER2-Negative Metastatic Breast Cancer and HER2-Positive Circulating Tumor Cells-The DETECT III Clinical Trial.

BACKGROUND: The phenotypes of tumor cells change during disease progression, but invasive rebiopsies of metastatic lesions are not always feasible. Here we aimed to determine whether initially HER2-negative metastatic breast cancer (MBC) patients with HER2-positive circulating tumor cells (CTCs) benefit from a HER2-targeted therapy. METHODS: The open-label, interventional randomized phase III clinical trial (EudraCT Number 2010-024238-46, CliniclTrials.gov Identifier: NCT01619111) recruited from March 2012 until September 2019 with a follow-up duration of 19.5 months. It was a multicenter clinical trial with 94 participating German study centers. A total of 2137 patients with HER2-negative MBC were screened for HER2-positive CTCs with a final modified intention-to-treat population of 101 patients. Eligible patients were randomized to standard therapy with or without lapatinib. Primary study endpoints included CTC clearance (no CTCs at the end of treatment) and secondary endpoints were progression-free survival, overall survival (OS), and safety. RESULTS: In both treatment arms CTC clearance at first follow-up visit-although not being significantly different for both arms at any time point-was significantly associated with improved OS (42.4 vs 14.1 months; P = 0.002). Patients treated additionally with lapatinib had a significantly improved OS over patients receiving standard treatment (20.5 vs 9.1 months, P = 0.009). CONCLUSIONS: DETECT III is the first clinical study indicating that phenotyping of CTCs might have clinical utility for stratification of MBC cancer patients to HER2-targeting therapies. The OS benefit could be related to lapatinib, but further studies are required to prove this clinical observation. ClinicalTrials.gov Registration Number: NCT01619111.

Return of individual genomic research results within the PRAEGNANT multicenter registry study.

PURPOSE: The PRAEGNANT study is a registry study for metastatic breast cancer patients, focusing on biomarker detection. Recently, within this study, genetic alterations in 37 breast cancer predisposition genes were analyzed and genetic findings were detected for 396 participants. The aim of this project was to return genetic results to the physicians and to analyze actions taken (e.g., disclosure of results to patients, validation of results, clinical impact, and impact on the patient's quality of life) using a questionnaire. METHODS: 235 questionnaires were sent out to the study centers, with each questionnaire representing one patient with a genetic finding. The questionnaire consisted of twelve questions in the German language, referring to the disclosure of results, validation of test results, and their impact on treatment decisions and on the patient's quality of life. RESULTS: 135 (57.5%) questionnaires were completed. Of these, 46 (34.1%) stated that results were returned to the patients. In 80.0% (N = 36) of cases where results were returned, the patient had not been aware of the finding previously. For 27 patients (64.3%), genetic findings had not been validated beforehand. All validation procedures (N = 15) were covered by the patients' health insurance. For 11 (25.0%) patients, physicians reported that the research results influenced current or future decision-making on treatment, and for 37.8% (N = 17) the results influenced whether family members will be genetically tested. CONCLUSION: This study provides novel insights into the return of research results and into clinical and personal benefits of disclosure of genetic findings within a German registry.

Save our surgeons (SOS) - an explorative comparison of surgeons' muscular and cardiovascular demands, posture, perceived workload and discomfort during robotic vs. laparoscopic surgery.

PURPOSE: Conventional laparoscopic surgery (CLS) imposes an increased risk of work-related musculoskeletal disorders. Technical innovations, such as robotic-assisted laparoscopic surgery (RALS), may provide ergonomic benefits. We compare the surgeon`s work-related demands of CLS vs RALS for benign hysterectomies. METHODS: Five specialists (3 females, 2 males) each performed four RALS and four CLS as part of their daily clinical routine. During the surgical procedures, muscular demands were assessed by bipolar surface electromyograms of the descendent trapezius, extensor digitorum and flexor carpi radialis muscles as well as cardio-vascular demands by electrocardiography, and neck, arm and torso posture by gravimetrical position sensors. Additionally, the subjects rated their level of perceived workload (NASA TLX questionnaire with 6 dimension) and musculoskeletal discomfort (11-point Likert-scale, 0-10). RESULTS: Muscular demands of the trapezius and flexor carpi radialis muscles were lower with RALS but extensor digitorum demands increased. Cardiovascular demands were about 9 heart beats per minute (bpm) lower for RALS compared to CLS with a rather low median level for both surgical techniques (RALS = 84 bpm; CLS 90 bpm). The posture changed in RALS with an increase in neck and torso flexion, and a reduction in abduction and anteversion position of the right arm. The perceived workload was lower in the physical demands dimension but higher in the mental demands dimension during RALS. Subjective musculoskeletal discomfort was rare during both surgical techniques. CONCLUSIONS: This explorative study identified several potential ergonomic benefits related to RALS which now can be verified by studies using hypothesis testing designs. However, potential effects on muscular demands in the lower arm extensor muscles also have to be addressed in such studies.

The impact of rehabilitation sport on breast cancer-related lymphoedema and quality of life.

PURPOSE: Surgery and radiotherapy as part of breast cancer treatment can lead to lymphoedema of the upper extremities (breast cancer-related lymphoedema = BCRL) and reduce the quality of life (health-related quality of life = HRQoL). The aim of the present study was to investigate the influence of paddling in a dragon boat (PP) on HRQoL and BCRL in breast cancer survivors (BCS). METHODS: Between April and October 2017, a prospective case-control study evaluated the effects of PP compared to a control group. In the paddle group (n = 28), weekly arm circumference measurements were taken at four defined anatomic areas of the arm before and after training; in the control group (n = 70), the measurements were taken once a month. At the beginning and end of the study, questionnaires from both groups (SF 36, EORTC QLQ C30) were evaluated to understand the differences in HRQoL. RESULTS: The paddle group started with a higher HRQoL compared to the control group. Most interesting, whether the affected or unaffected arm, whether before or after training-the arm circumference decreased over time in the paddling group. A pre-existing lymphoedema was not negatively influenced by paddling. In the paddle group, the physical health was constant over the season, while the physical health of the control group decreased significantly over time. CONCLUSION: PP in a dragon boat does not lead to the development or worsening of pre-existing lymphoedema due to breast cancer therapy, and seems to have a positive effect on the quality of life.

Implementation of CDK4/6 Inhibitors and its Influence on the Treatment Landscape of Advanced Breast Cancer Patients - Data from the Real-World Registry PRAEGNANT.

Background Comprehensive data from prospective clinical trials have led to a high level of evidence establishing CDK4/6 inhibitors in combination with endocrine treatment (CDK4/6i + ET) as a standard for the treatment of HER2-negative, hormone receptor-positive (HER2- HR+) breast cancer patients in the first-line advanced therapy setting. Data on patient populations that have been treated in the real-world setting may provide an insight into changes of patient characteristics and prognosis over time. Methods The data were extracted from the prospective real-world registry PRAEGNANT (NCT02338167). Patients had to have HER2- HR+ advanced breast cancer in the first-line metastatic setting. The chosen therapies were described as well as progression-free survival (PFS) and overall survival (OS) in relation to the given therapies and time periods during which they were indicated. Results CDK4/6 inhibitors have been rapidly implemented since their introduction in November 2016. In recent years (2018 - 2022), about 70 - 80% of the patient population have been treated with CDK4/6 inhibitors, while endocrine monotherapy was given to about 10% and chemotherapy to about 15% of all patients. The prognosis was worst in patients treated with chemotherapy. Recently, mainly patients with a good prognosis are being treated with endocrine monotherapy, and patients who are treated with chemotherapy have an unfavorable prognosis. The PFS and OS of patients treated with CDK4/6i + ET have remained similar over time despite changes in patient characteristics. Conclusion A treatment with CDK4/6i + ET has rapidly become the therapy standard for patients in the first-line advanced breast cancer setting. After the implementation of CDK4/6i + ET, endocrine monotherapy is only given to patients with a very favorable prognosis, while chemotherapy is provided to patients with a rather unfavorable prognosis. These changes in patient characteristics did not seem to influence the prognosis of patients treated with CDK4/6i + ET.

Occurrence and characteristics of patients with de novo advanced breast cancer according to patient and tumor characteristics - A retrospective analysis of a real world registry.

BACKGROUND: Patients with de novo metastatic breast cancer (dnMBC) may have different clinical and pathological characteristics. In studies concerned with first-line metastatic patients, the proportion of these patients without secondary resistance mechanisms may have a large influence ont the study results. The aim of this study was to identify patient and tumor characteristics that are associated with dnMBC vs. recurrent MBC (rMBC). METHODS: This is a retrospective analysis of data prospectively collected in the PRAEGNANT metastatic breast cancer registry (NCT02338167). Firs line treated patients were eligible. Patient and tumor characteristics were compared with common disease and tumor characteristics relative to de novo metastatic status, as well as early and late recurrences after primary disease without metastases. RESULTS: Among the 947 patients identified, 355 were included with de novo metastatic disease (37.5%). Older age and HER2-positive disease were significantly associated with a higher frequency of dnMBC. Patients younger than 50, 50-69, or 70 years or older had dnMBC frequencies of 22.7%, 44.0%, and 57.6%, respectively. HER2-positive patients had dnMBC at initial presentation in 49.1% of cases, in comparison with 21.9%, 35.5%, and 37.6% in patients with triple-negative, luminal A-like and luminal B-like breast cancer, respectively. CONCLUSION: Age and breast cancer subtype are associated with the frequency of first-line MBC patients. Inclusion criteria concerning age or breast cancer subtype can influence the frequency of these patients in a selected patient population and can therefore modify the number of patients with secondary resistance to specific therapies in clinical trials.

[Burden of Affected Persons with MRKH Syndrome: Effect of an Intervention to Support Surgical Neovaginal Placement]. / Belastung von Betroffenen mit MRKH-Syndrom: Effekt einer Intervention zur Unterstützung bei Neovagina-Anlage.

The diagnosis of Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS), a rare variant of female sexual development, is usually made during puberty. The uncertainty in self-image and the impos-sibility of becoming pregnant often lead to considerable stress. Although psychosomatic support is consistently recommended in the literature, there have been only a few studies on the psychological aspects of MRKHS. The aim of the present study is to investigate the quality of life or distress of women with MRKHS undergoing neovaginal surgery and, on the other hand, to evaluate effects of the intervention for support during treatment. Methods In an explorative quasi-experimental pre-post study at a national centre for neovaginal surgery, all patients were offered a psychosomatic intervention (intervention group IG, n=23) and their sexual function (FSFI), psychological distress (PHQ-D) and health-related quality of life (SF-12) were assessed before surgery (t0) and six months after (t1). These were compared with data from a sample collected before and after the intervention period (comparison group VG, n=30). Results While the physical quality of life (SF-12) of both groups was unremarkable at both time points, there was a significant impairment in the psychological quality of life. Both groups (IG, VG) improved from t0 to t1 in their sexual function (FSFI) and showed lower depression scores (PHQ-D). The specific intervention developed was well accepted by those affected and rated as helpful. However, this subjectively perceived effectiveness of the intervention was not reflected by improvement on the quality of life scale (SF-12) and depression scale (PHQ-D). Conclusion Those affected show a clear, clinically relevant distress (SF-12), but this is not reflected in the form of psychological comorbidity (PHQ-D). This apparent discrepancy points to psychologically stable women with acute distress due to the diagnosis of variant sex de-evolution. For them, a low-threshold support service with a supportive character seems to be necessary and helpful during the surgical treatment. The reconstructive therapy for the creation of a neovagina seems to have a positive influence on the psychological quality of life. The fact that pregnancy is still not possible due to the missing uterus could be a reason for not reaching the quality of life of the average population.

Opinion paper: gynecological surgery in local anesthesia?

PURPUSE: The paracervical block (PCB) is a local anesthesia procedure that can be used to perform gynecological surgeries without the need for further anesthesia. With the PCB, surgeries can be moved from the central operating room to outpatient operating rooms, where they can be performed without the presence of an anesthesia team. METHODS: In this paper, the indications, implementation and limitations of the procedure are discussed. CONCLUSION: Especially in times of scarce staff and OR resources during the Corona pandemic, OR capacity can be expanded in this way.

How Negative Is Negative Information.

Daily, we face a plenty of negative information that can profoundly affect our perception and behavior. During devastating events such as the current COVID-19 pandemic, negative messages may hinder reasoning at individual level and social decisions in the society at large. These effects vary across genders in neurotypical populations (being more evident in women) and may be even more pronounced in individuals with neuropsychiatric disorders such as depression. Here, we examine how negative information impacts reasoning on a social perception task in females with breast cancer, a life-threatening disease. Two groups of patients and two groups of matched controls (N TO TAL = 80; median age, 50 years) accomplished a psychometrically standardized social cognition and reasoning task receiving either the standard instruction solely or additional negative information. Performance substantially dropped in patients and matched controls who received negative information compared to those who did not. Moreover, patients with negative information scored much lower not only compared with controls but also with patients without negative information. We suggest the effects of negative information are mediated by the distributed brain networks involved in affective processing and emotional memory. The findings offer novel insights on the impact of negative information on social perception and decision making during life-threatening events, fostering better understanding of its neurobiological underpinnings.

Disseminated tumour cells from the bone marrow of early breast cancer patients: Results from an international pooled analysis.

PURPOSE: Presence of disseminated tumour cells (DTCs) in the bone marrow (BM) has been described as a surrogate of residual disease in patients with early breast cancer (EBC). PADDY (Pooled Analysis of DTC Detection in Early Breast Cancer) is a large international analysis of pooled data that aimed to assess the prognostic impact of DTCs in patients with EBC. EXPERIMENTAL DESIGN: Individual patient data were collected from 11 centres. Patients with EBC and available follow-up data in whom BM sampling was performed at the time of primary diagnosis before receiving any anticancer treatment were eligible. DTCs were identified by antibody staining against epithelial cytokeratins. Multivariate Cox regression was used to compare the survival of DTC-positive versus DTC-negative patients. RESULTS: In total, 10,307 patients were included. Of these, 2814 (27.3%) were DTC-positive. DTC detection was associated with higher tumour grade, larger tumour size, nodal positivity, oestrogen receptor and progesterone receptor negativity, and HER2 positivity (all p < 0.001). Multivariate analyses showed that DTC detection was an independent prognostic marker for overall survival, disease-free survival and distant disease-free survival with hazard ratios (HR) and 95% confidence intervals (CI) of 1.23 (95% CI: 1.06-1.43, p = 0.006), 1.30 (95% CI: 1.12-1.52, p < 0.001) and 1.30 (95% CI: 1.08-1.56, p = 0.006), respectively. There was no association between locoregional relapse-free survival and DTC detection (HR 1.21; 95% CI 0.68-2.16; p = 0.512). CONCLUSIONS: DTCs in the BM represent an independent prognostic marker in patients with EBC. The heterogeneous metastasis-initiating potential of DTCs is consistent with the concept of cancer dormancy.

Prognostic effect of low-level HER2 expression in patients with clinically negative HER2 status.

PURPOSE: Assessment of HER2 overexpression using immunohistochemistry (IHC) and/or in situ hybridisation (ISH) for the detection of HER2 amplifications is standard to identify patients for established HER2-directed treatments. Patients with lower HER2 expression levels have recently also become candidates for novel therapies targeting HER2. This study aimed to assess tumour and patient characteristics and prognosis in patients with advanced breast cancer (aBC), relative to low HER2 expression levels. METHODS: PRAEGNANT is a prospective aBC registry (NCT02338167), focusing on molecular biomarkers. Patients in all therapy lines receiving any kind of treatment are eligible. This analysis includes patients with conventionally HER2-negative aBC. Clinical outcome was compared in the groups with no (IHC score 0) or with low HER2 expression (IHC 1+, or IHC 2+/ISH negative). RESULTS: Low HER2 expression levels in triple-negative aBC patients did not influence progression-free survival. Overall survival appeared poorer in patients with IHC 2+ compared with patients with no HER2 expression in the unadjusted analysis (hazard ratio 2.24, 95% confidence interval 0.1.12-4.47). However, this effect was not maintained in the adjusted analysis. In HER2-negative, hormone receptor-positive patients, low HER2 expression appeared to have no effect on prognosis, neither progression-free survival nor overall survival. CONCLUSIONS: We could not demonstrate that HER2 expression at a low level and assessed in clinical routine can differentiate patients into prognostic groups. However, the prevalence of patients with a low expression makes this population interesting for clinical trials with potentially active treatments using HER2 as a target.

Evaluation of sonographic detectability of different markers within an in vitro simulation model of the axilla.

PURPOSE: Clip-marking of axillary lymph nodes with initial biopsy-confirmed metastasis is required for targeted axillary dissection (TAD), which includes sentinel lymph node dissection (SLND) and selective localization and removal of the clipped targeted lymph node. There have been several studies which examined the feasibility of TAD in routine clinical use. In this context, the optimal clip visualisation was noted as one of the crucial limiting factors. We, therefore, evaluated the sonographic detectability of 10 different commercially available markers within an in vitro model simulating the anatomical composition of the axilla. METHODS: In this standardised model consisting of porcine fat with 30 mm thickness, the visibility of a total of ten markers was analysed in all 3 planes (parallel, diagonal, orthograde) with wire guidance and then classified into either "visibility good", "visibility moderate" or "visibility poor" with regard to the alignment of the transducer. Additionally, "real-life conditions" were simulated, in which the markers were searched without any wires guidance. RESULTS: It was observed that, while not all markers are detectable in fatty tissue, markers with spherical shape (non-embedded Inconel or Nitinol) or rectangular-shaped Titanium markers with embedded material have a clear advantage. 3D-shaped markers can always be detected in all three axes, which is of particular importance in the axilla with its pyramid shape and fatty tissue. CONCLUSION: The shape and the embedding of the material play a crucial role for visibility and efficacy of the marker, as reliable marking of suspicious and pathological axillary lymph nodes is essential for TAD.

The SOX2 Status of Disseminated Tumor Cells in Breast Cancer Patients Treated With Neoadjuvant Chemotherapy.

BACKGROUND/AIM: Detection of disseminated tumor cells (DTCs) after systemic treatment predicts poor prognosis in breast cancer patients. The aim of our study was to assess the expression of stem-cell marker SOX2 on DTCs and in the primary tumor of patients treated with neoadjuvant chemotherapy (NAT). MATERIALS AND METHODS: In 170 DTC-positive patients after NAT an additional slide of bone marrow aspirate was stained by double immunofluorescence to detect SOX2-positive DTCs. The SOX2 status of the primary tumor was assessed using the same antibody. RESULTS: The SOX2-status of DTCs was determined in 62 patients and 20 of those (32%) had SOX2 positive DTCs. The SOX2 status of DTCs was not associated with any of the clinicopathological factors. A total of 36% of the patients with a SOX2-negative tumor showed SOX2-positive persistent DTCs. CONCLUSION: SOX2-positive DTCs can be detected in breast cancer patients after NAT, even in patients with SOX2-negative primary tumors. This suggests that these populations may have evolved independently of each other.

Challenges and Opportunities for Real-World Evidence in Metastatic Luminal Breast Cancer.

BACKGROUND: The therapeutic armamentarium for patients with metastatic breast cancer is becoming more and more specific. Recommendations from clinical trials are not available for all treatment situations and patient subgroups, and it is therefore important to collect real-world data. SUMMARY: To develop recommendations for up-to-date treatments and participation in clinical trials for patients with metastatic breast cancer, the Prospective Academic Translational Research PRAEGNANT Network was established to optimize the quality of oncological care in the advanced therapeutic setting. The main aim of PRAEGNANT is to systematically record medical care for patients with metastatic breast cancer in the real-life setting, including the outcome and side effects of different treatment strategies, to monitor quality-of-life changes during therapy, to identify patients eligible for participation in clinical studies, and to allow targeted therapies based on the molecular structures of breast carcinomas. KEY MESSAGES: This article describes the PRAEGNANT network and sheds light on the question of whether the various end points from clinical trials can be transferred to the real-world treatment situation.

Erratum: Prognostic relevance of high pretreatment CA125 levels in primary serous ovarian cancer.

[This corrects the article DOI: 10.3892/mco.2020.2170.].

Mutations in BRCA1/2 and Other Panel Genes in Patients With Metastatic Breast Cancer -Association With Patient and Disease Characteristics and Effect on Prognosis.

PURPOSE: Among patients with metastatic breast cancer (mBC), the frequency of germline mutations in cancer susceptibility genes and the clinical relevance of these mutations are unclear. In this study, a prospective cohort of patients with mBC was used to determine mutation rates for breast cancer (BC) predisposition genes, to evaluate the clinical characteristics of patients with mutations, and to assess the influence of mutations on patient outcome. PATIENTS AND METHODS: Germline DNA from 2,595 patients with mBC enrolled in the prospective PRAEGNANT registry was evaluated for mutations in cancer predisposition genes. The frequencies of mutations in known BC predisposition genes were compared with results from a prospective registry of patients with nonmetastatic BC sequenced using the same QIAseq method and with public reference controls. Associations between mutation status and tumor characteristics, progression-free survival, and overall survival were assessed. RESULTS: Germline mutations in 12 established BC predisposition genes (including BRCA1 and BRCA2) were detected in 271 (10.4%) patients. A mutation in BRCA1 or BRCA2 was seen in 129 patients (5.0%). BRCA1 mutation carriers had a higher proportion of brain metastasis (27.1%) compared with nonmutation carriers (12.8%). Mutations were significantly enriched in PRAEGNANT patients with mBC compared with patients with nonmetastatic BC (10.4% v 6.6%, P < .01). Mutations did not significantly modify progression-free survival or overall survival for patients with mBC. CONCLUSION: Multigene panel testing may be considered in all patients with mBC because of the high frequency of germline mutations in BRCA1/2 and other BC predisposition genes. Although the prognosis of mutation carriers and nonmutation carriers with mBC was similar, differences observed in tumor characteristics have implications for treatment and for future studies of targeted therapies.