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BRCA1/BRCA2 genes play a central role in DNA repair and their mutations increase sensitivity to DNA-damaging agents. There are conflicting data regarding the prognostic value of BRCA germline mutations in breast cancer (BC) patients. We collected clinical, pathological and genetic data of a cohort 925 BC patients preselected for genetic screening and treated with neoadjuvant or adjuvant chemotherapy, of whom 266 were BRCA carriers. Overall, 171 women carried a BRCA1 mutation, 95 carried a BRCA2 mutation, and 659 were non-carriers. In the entire cohort, there was a prolonged disease-free survival (DFS) for BRCA carriers (hazard ratio (HR) = 0.63; 95% confidence interval (CI), 0.44–0.90 for BRCA1; HR = 0.72; 95%CI, 0.47–1.1 for BRCA2 ; p  = 0.020) and a trend toward prolonged disease-specific survival (DSS; HR = 0.65; 95%CI, 0.40–1.1 for BRCA1 ; HR = 0.78; 95%CI, 0.44–1.38 for BRCA2 ; p  = 0.19) though not statistically significant. In the TNBC group, BRCA carriers had prolonged DFS (adjusted HR = 0.50; 95%CI, 0.28–0.89 for BRCA1; adjusted HR = 0.37; 95%CI, 0.11–1.25, for BRCA2; p  = 0.034) and DSS (adjusted HR = 0.42; 95%CI, 0.21–0.82 for BRCA1; adjusted HR = 0.45; 95%CI, 0.11–1.9 for BRCA2; p  = 0.023). In the non-TNBC group, the BRCA1 or BRCA2 mutations did not have any impact on survival. These results suggest that BRCA1/BRCA2 germline mutations are associated with prolonged survival only if women were diagnosed with TNBC.

Breast cancer is the most frequently diagnosed cancer among women worldwide. Despite the fact that breast cancer is more frequent after fifty years of age, breast cancer among young women has recently drawn particular attention due to an increase in incidence in several western countries. With the exception of individuals with a high genetic risk, breast cancer occurring in younger women remains poorly understood. This project aims at investigating the patient, tumour and treatment characteristics as well as the long-term health outcomes of these women by evaluating numerous variables that were collected from their pathology and medical files, including the social environment, family history, fertility and pregnancy. We constituted a population-based cohort from the Geneva Cancer Registry of 1586 patients with breast cancer who were aged less than 46 years at the time of diagnosis. Breast cancer was diagnosed before the age of 35 years in 225 women (14.2%), between 35 and 39 years of age in 368 women (23.2%) and between 40 and 45 years of age in 993 women (62.6%). Most of the patients were diagnosed with luminal A or luminal B molecular subtypes (32.8 and 37.5%, respectively), stage I or II tumours (75.2%), and estrogen (74.8%) and progesterone (67.5%) positive receptors. During the study period, 16.7% of these women developed loco-regional recurrences and 25.4% developed distant metastases; the majority (66.3%) did not have a recurrence. Regarding mortality, 474 (29.9%) women died during the study period, 347 (73.2%) from breast cancer. The results of this study will help filling the knowledge gap about treatment of young breast cancer patients and having a child after breast cancer, and will provide clinicians and public health professionals' with additional information to improve quality of care and decrease the impact of breast cancer in young women.

Advanced triple negative breast cancer (TNBC) is an aggressive, but initially chemo-sensitive disease. The prognosis is poor and more than three quarters of patients experience progression 12 months after the initiation of conventional first-line chemotherapy. Approximately two thirds of TNBC express epidermal growth factor receptor 1 (EGFR). We have developed an anti-EGFR targeted nanocontainer drug by inserting anti-EGFR antibody fragments into the membrane of pegylated liposomes (anti-EGFR-ILs-dox). The payload consists of doxorubicin, a standard drug for TNBC. In a first-in-human phase I trial in 26 patients with various advanced solid malignancies, anti-EGFR-ILs-dox has shown little toxicity and encouraging efficacy. In this single-arm phase II trial, we assessed the efficacy of anti-EGFR-ILs-dox as first-line therapy in patients with advanced, EGFR + TNBC. The primary endpoint was progression-free survival at 12 months (PFS12m). Secondary endpoints included overall response rate (ORR), duration of response (DOR), time to progression (TTP), overall survival (OS) and adverse events (AEs). 48 patients received anti-EGFR-ILs-dox 50 mg/m 2 iv, on day one of a 28 days-cycle until progression. The Kaplan–Meier estimate for PFS12m was 13% (one-sided 90% CI 7%, 95% CI [5%, 25%]), median PFS was 3.5 months (95% CI 1.9, 5.4). The trial has not reached its primary endpoint. There were no new toxicity signals. Based on these results, anti-EGFR-ILs-dox should not be further developed for TNBC. It remains an open question whether anti-EGFR-ILs-dox would offer more opportunities in other EGFR-expressing malignancies, where targeting this receptor has already shown anticancer effects. Trial registration: This trial was registered at clinicaltrials.gov: NCT02833766. Registered 14/07/2016.

Purpose This study aimed to compare changes in postural control in different testing conditions involving sensory disturbances, quality of life and neurotoxicity concerns in women with cancer before and after chemotherapy with taxanes. The second aim was to compare postural control between chemotherapy-induced peripheral neuropathy (CIPN) severity subgroups. Method The 33 participants with breast cancer (age 48.15 ± 9.88 years) were tested during the month preceding (baseline) and the month after the end of chemotherapy. Postural control was assessed on a force platform (100 Hz) in different conditions: eyes open/closed, rigid/foam surface, with/without tendon vibration, dual task, and limits of stability. CIPN severity and neurotoxicity concerns were also evaluated. Paired t-tests or Wilcoxon sign rank tests were used, and a Benjamini-Hochberg correction was applied. Results After chemotherapy, greater postural adjustments were required to maintain balance in the reference condition ( p ≤ 0.02), and in conditions with visual ( p ≤ 0.02), foam ( p ≤ 0.04), and dual task disturbances ( p ≤ 0.01), but not in the vibration and limits of stability conditions. No difference was found between the CIPN subgroups. The neurotoxicity score worsened after chemotherapy (-8.61 ± 7.53, p ≤ 0.01). Conclusions Postural control was impaired after chemotherapy, particularly in conditions with visual disturbances and dual task. Anteroposterior center of pressure displacements with mediolateral ground reaction forces were particularly increased. Clinical implications Systematic assessment of postural control with eyes closed in women with breast cancer would help to identify chemotherapy-induced postural control disorders and determine treatment needs. Trial registration Clinical Trial Registration number NCT04692168. Registration date: 28.12.2020

Background Treatment of patients with residual disease after neoadjuvant chemotherapy for breast cancer is an unmet clinical need. We hypothesised that tumour subclones showing expansion in residual disease after chemotherapy would contain mutations conferring drug resistance. Methods We studied oestrogen receptor and/or progesterone receptor-positive, HER2-negative tumours from 42 patients in the EORTC 10994/BIG 00-01 trial who failed to achieve a pathological complete response. Genes commonly mutated in breast cancer were sequenced in pre and post-treatment samples. Results Oncogenic driver mutations were commonest in PIK3CA (38% of tumours), GATA3 (29%), CDH1 (17%), TP53 (17%) and CBFB (12%); and amplification was commonest for CCND1 (26% of tumours) and FGFR1 (26%). The variant allele fraction frequently changed after treatment, indicating that subclones had expanded and contracted, but there were changes in both directions for all of the commonly mutated genes. Conclusions We found no evidence that expansion of clones containing recurrent oncogenic driver mutations is responsible for resistance to neoadjuvant chemotherapy. The persistence of classic oncogenic mutations in pathways for which targeted therapies are now available highlights their importance as drug targets in patients who have failed chemotherapy but provides no support for a direct role of driver oncogenes in resistance to chemotherapy. ClinicalTrials.gov EORTC 10994/BIG 1-00 Trial registration number NCT00017095.

Background We explored, within the EORTC10994 study, the outcomes for patients with molecular apocrine (MA) breast cancer, and defined immunohistochemistry (IHC) as androgen-receptor (AR) positive, oestrogen (ER) and progesterone (PR) negative. We also assessed the concordance between IHC and gene expression arrays (GEA) in the identification of MA cancers. Methods Centrally assessed biopsies for AR, ER, PR, HER2 and Ki67 by IHC were classified into six subtypes: MA, triple-negative (TN) basal-like, luminal A, luminal B HER2 negative, luminal B HER2 positive and “other”. The two main objectives were the pCR rates and survival outcomes in the overall MA subtype (and further divided by HER2 status) and the remaining five subtypes. Results IHC subtyping was obtained in 846 eligible patients. Ninety-three (11%) tumours were classified as the MA subtype. Both IHC and GEA data were available for 64 patients. In this subset, IHC concordance was 88.3% in identifying MA tumours compared with GEA. Within the MA subtype, pCR was observed in 33.3% of the patients (95% CI: 29.4–43.9) and the 5-year recurrence-free interval was 59.2% (95% CI: 48.2–68.6). Patients with MA and TN basal-like tumours have lower survival outcomes. Conclusions Irrespective of their HER2 status, the prognosis for MA tumours remains poor and adjuvant trials evaluating anti-androgens should be considered.

IntroductionChemotherapy-induced peripheral neuropathy is a frequent side effect of some chemotherapies that can cause postural control disorders and has a serious impact on quality of life (QoL). An enhanced understanding of postural control dysfunction could help build a systematic and accurate assessment as well as specific exercises to limit the impact on QoL. This study aims to assess the influence of chemotherapy on postural control and the QoL for women with gynaecological cancer.Methods and analysisThis prospective observational study will include 37 participants with cancer treated using neurotoxic chemotherapy. Their postural control in various conditions (rigid and foam surfaces, eyes open and closed, with and without tendon vibration, and dual tasks), limits of stability, QoL and modified Total Neuropathy Score will be assessed. A linear mixed model will compare postural control pre-chemotherapy and post-chemotherapy.Ethics and disseminationThis study was approved by an ethical review board in Geneva (CCER-2020-01639). The study findings will be disseminated through conference presentations and publications in peer-reviewed journals.Trial registration numberNCT04692168.

Purpose The primary aim was to determine the effect of a physical activity (PA) program with education sessions on walking capacity and fatigue in people with cancer. The secondary objective was to assess the factors that moderated the program’s effect on walking capacity and fatigue among sociodemographic, physical capacity and symptom-related factors. Satisfaction with the program was also evaluated. Method A retrospective, observational study of data from a 12-week program of twice-weekly group PA sessions combined with education sessions was conducted. The 6-min walk test (6MWT), the Multidimensional Fatigue Inventory (MFI-20) and program satisfaction were assessed. Paired t-tests were applied to assess changes in 6MWT and MFI-20. Multiple linear regressions were applied to determine the influence of age, gender, initial walking capacity and fatigue on the effects of the program. Results Among the 264 participants (age 57.36 ± 12.43 years; 189 women; 134 with breast cancer), 125 (47%) completed the program. Walking capacity (+ 41.63 ± 91.00 m) and fatigue (-2.01 ± 3.77) were improved after the program ( p  < 0.001). Age and gender did not influence the program’s effect; however, lower initial walking capacity and higher fatigue scores were associated with larger improvements after the program. Satisfaction with the program was high among participants who completed it. Conclusions Walking capacity and fatigue improved significantly after the PA program, but the drop-out rate was high. The program could be individualized based on an individual's initial walking capacity or fatigue score to enhance its effectiveness.

Objective To evaluate the performance of 18F-fluorodeoxyglucose (FDG) positron emission tomography magnetic resonance imaging (PET/MR) for preoperative breast cancer staging. Methods Preoperative PET/MR exams of 58 consecutive women with breast cancer were retrospectively reviewed. Histology and mean follow-up of 26 months served as gold standard. Four experienced readers evaluated primary lesions, lymph nodes and distant metastases with contrast-enhanced MRI, qualitative/quantitative PET, and combined PET/MR. ROC curves were calculated for all modalities and their combinations. Results The study included 101 breast lesions (83 malignant, 18 benign) and 198 lymph node groups, (34 malignant, 164 benign). Two patients had distant metastases. Areas under the curve (AUC) for breast cancer were 0.9558, 0.8347 and 0.8855 with MRI, and with qualitative and quantitative PET/MR, respectively ( p  = 0.066). Sensitivity for primary cancers with MRI and quantitative PET/MR was 100 % and 77 % ( p  = 0.004), and for lymph nodes 88 % and 79 % ( p  = 0.25), respectively. Specificity for MRI and PET/MR for primary cancers was 67 % and 100 % ( p  = 0.03) and for lymph nodes 98 % and 100 % ( p  = 0.25). Conclusions In breast cancer patients, MRI alone has the highest sensitivity for primary tumours. For nodal metastases, both MRI and PET/MR are highly specific. Key points • MRI alone and PET/MR have a similar overall diagnostic performance. • MRI alone has a higher sensitivity than PET/MR for local tumour assessment. • Both MRI and PET/MR have a limited sensitivity for nodal metastases. • Positive lymph nodes on MRI or PET/MR do not require presurgical biopsy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.