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Investigators of registry-based studies report improved survival for breast-conserving surgery plus radiotherapy compared with mastectomy in early breast cancer. As these studies did not present long-term overall and breast cancer-specific survival, the effect of breast-conserving surgery plus radiotherapy might be overestimated. In this study, we aimed to evaluate 10 year overall and breast cancer-specific survival after breast-conserving surgery plus radiotherapy compared with mastectomy in Dutch women with early breast cancer. In this population-based study, we selected all women from the Netherlands Cancer Registry diagnosed with primary, invasive, stage T1–2, N0–1, M0 breast cancer between Jan 1, 2000, and Dec 31, 2004, given either breast-conserving surgery plus radiotherapy or mastectomy, irrespective of axillary staging or dissection or use of adjuvant systemic therapy. Primary outcomes were 10 year overall survival in the entire cohort and breast cancer-specific survival in a representative subcohort of patients diagnosed in 2003 with characteristics similar to the entire cohort. We estimated breast cancer-specific survival by calculating distant metastasis-free and relative survival for every tumour and nodal category. We did multivariable Cox proportional hazard analysis to estimate hazard ratios (HRs) for overall and distant metastasis-free survival. We estimated relative survival by calculating excess mortality ratios using life tables of the general population. We did multiple imputation to account for missing data. Of the 37 207 patients included in this study, 21 734 (58%) received breast-conserving surgery plus radiotherapy and 15 473 (42%) received mastectomy. The 2003 representative subcohort consisted of 7552 (20%) patients, of whom 4647 (62%) received breast-conserving surgery plus radiotherapy and 2905 (38%) received mastectomy. For both unadjusted and adjusted analysis accounting for various confounding factors, breast-conserving surgery plus radiotherapy was significantly associated with improved 10 year overall survival in the whole cohort overall compared with mastectomy (HR 0·51 [95% CI 0·49–0·53]; p<0·0001; adjusted HR 0·81 [0·78–0·85]; p<0·0001), and this improvement remained significant for all subgroups of different T and N stages of breast cancer. After adjustment for confounding variables, breast-conserving surgery plus radiotherapy did not significantly improve 10 year distant metastasis-free survival in the 2003 cohort overall compared with mastectomy (adjusted HR 0·88 [0·77–1·01]; p=0·07), but did in the T1N0 subgroup (adjusted 0·74 [0·58–0·94]; p=0·014). Breast-conserving surgery plus radiotherapy did significantly improve 10 year relative survival in the 2003 cohort overall (adjusted 0·76 [0·64–0·91]; p=0·003) and in the T1N0 subgroup (adjusted 0·60 [0·42–0·85]; p=0·004) compared with mastectomy. Adjusting for confounding variables, breast-conserving surgery plus radiotherapy showed improved 10 year overall and relative survival compared with mastectomy in early breast cancer, but 10 year distant metastasis-free survival was improved with breast-conserving surgery plus radiotherapy compared with mastectomy in the T1N0 subgroup only, indicating a possible role of confounding by severity. These results suggest that breast-conserving surgery plus radiotherapy is at least equivalent to mastectomy with respect to overall survival and may influence treatment decision making for patients with early breast cancer. None.

Primary chemotherapy in breast cancer poses a dilemma with regard to adjuvant locoregional radiotherapy, as guidelines for locoregional radiotherapy were originally based on pathology results of primary surgery. We aimed to evaluate the oncological safety of de-escalated locoregional radiotherapy in patients with cT1–2N1 breast cancer treated with primary chemotherapy, according to a predefined, consensus-based study guideline. In this prospective registry study (RAPCHEM, BOOG 2010–03), patients referred to one of 17 participating radiation oncology centres in the Netherlands between Jan 1, 2011, and Jan 1, 2015, with cT1–2N1 breast cancer (one to three suspicious nodes on imaging before primary chemotherapy, of which at least one had been pathologically confirmed), and who were treated with primary chemotherapy and surgery of the breast and axilla were included in the study. The study guideline comprised three risk groups for locoregional recurrence, with corresponding locoregional radiotherapy recommendations: no chest wall radiotherapy and no regional radiotherapy in the low-risk group, only local radiotherapy in the intermediate-risk group, and locoregional radiotherapy in the high-risk group. Radiotherapy consisted of a biologically equivalent dose of 25 fractions of 2 Gy, with or without a boost. During the study period, the generally applied radiotherapy technique in the Netherlands was forward-planned or inverse-planned intensity modulated radiotherapy. 5-year follow-up was assessed, taking into account adherence to the study guideline, with locoregional recurrence rate as primary endpoint. We hypothesised that 5-year locoregional recurrence rate would be less than 4% (upper-limit 95% CI 7·8%). This study was registered at ClinicalTrials.gov, NCT01279304, and is completed. 838 patients were eligible for 5-year follow-up analyses: 291 in the low-risk group, 370 in the intermediate-risk group, and 177 in the high-risk group. The 5-year locoregional recurrence rate in all patients was 2·2% (95% CI 1·4–3·4). The 5-year locoregional recurrence rate was 2·1% (0·9–4·3) in the low-risk group, 2·2% (1·0–4·1) in the intermediate-risk group, and 2·3% (0·8–5·5) in the high-risk group. If the study guideline was followed, the locoregional recurrence rate was 2·3% (0·8–5·3) for the low-risk group, 1·0% (0·2–3·4) for the intermediate-risk group, and 1·4% (0·3–4·5) for the high-risk group. In this study, the 5-year locoregional recurrence rate was less than 4%, which supports our hypothesis that it is oncologically safe to de-escalate locoregional radiotherapy based on locoregional recurrence risk, in selected patients with cT1–2N1 breast cancer treated with primary chemotherapy, according to this predefined, consensus-based study guideline. Dutch Cancer Society. For the Dutch translation of the abstract see Supplementary Materials section.

Introduction The presence of tumor-infiltrating lymphocytes (TILs) is correlated with good prognosis and outcome after (immuno)therapy in triple-negative and HER2-positive breast cancer. However, the role of TILs in luminal breast cancer is less clear. Emerging evidence has now demonstrated that genetic aberrations in malignant cells influence the immune landscape of tumors. Phosphatidylinositol 3-kinase (PI3K) is the most common altered pathway in ER-positive breast cancer. It is unknown whether changes in the PI3K pathway result in a different composition of the breast tumor microenvironment. Here we present the retrospective analysis of a prospective randomized trial in ER-positive breast cancer on the prognostic and predictive value of specific tumor-associated lymphocytes in the context of PI3K alterations. Methods We included 563 ER-positive tumors from a multicenter trial for stage I to III postmenopausal breast cancer patients, who were randomized to tamoxifen or no adjuvant therapy. The amount of CD8-, CD4-, and FOXP3-positive cells was evaluated by immunohistochemistry and quantified by imaging-analysis software. We analyzed the associations between PIK3CA hotspot mutations, PTEN expression, phosphorylated proteins of the PI3K and MAPK pathway (p-AKT, p-ERK1/2, p-4EBP1, p-p70S6K), and recurrence-free interval after adjuvant tamoxifen or no adjuvant treatment. Results CD8-positive lymphocytes were significantly more abundant in PIK3CA -mutated tumors (OR = 1.65; 95% CI 1.03–2.68). While CD4 and FOXP3 were not significantly associated with prognosis, patients with tumors classified as CD8-high had increased risk of recurrence (HR = 1.98; 95% CI 1.14–3.41; multivariable model including PIK3CA status, treatment arm, and other standard clinicopathological variables). Lymphocytes were more often present in tumors with increased PI3K downstream phosphorylation. This was most pronounced for FOXP3-positive cells. Conclusion These exploratory analyses of a prospective trial in luminal breast cancer suggest high CD8 infiltration is associated with unfavorable outcome and that PI3K pathway alterations might be associated with the composition of the tumor microenvironment.

Breast cancer is a heterogeneous disease, manifesting in a broad differentiation in phenotypes and morphologic profiles, resulting in variable clinical behavior. Between 10 and 20% of all breast cancers are triple negative. Triple-negative breast cancer (TNBC) lacks the expression of human epidermal growth factor receptor 2 (HER2) and hormone receptors; therefore, to date, chemotherapy remains the backbone of treatment. TNBC tends to be aggressive and has a high histological grade, resulting in a poor 5-year prognosis. It has a high prevalence of BRCA1 mutations and an increased Ki-67 expression. This subtype usually responds well to taxanes and/or platinum compounds and poly (ADP-ribose) polymerase (PARP) inhibitors. Studies with PARP inhibitors have demonstrated promising results in the treatment of BRCA -mutated breast and ovarian cancer, and PARP inhibitors have been studied as monotherapy and in combination with cytotoxic therapy or radiotherapy. PARP inhibitor efficacy on poly (ADP-ribose) polymer (PAR) formation in vivo can be quantified by pharmacodynamic assays that measure PAR activity in peripheral blood mononuclear cells (PBMC). Biomarkers such as TP53 , ATM , PALB2 and RAD51C might be prognostic or predictive indicators for treatment response, and could also provide targets for novel treatment strategies. In summary, this review provides an overview of the treatment options for basal-like TNBC, including PARP inhibitors, and focuses on the pharmacotherapeutic options in these patients.

The optimal chemotherapy backbone for dual HER2 blockade in the neoadjuvant setting for early breast cancer is unknown. We investigated whether the addition of anthracyclines would improve pathological complete response compared with a carboplatin–taxane regimen, when given in combination with the HER2-targeted agents trastuzumab and pertuzumab. The TRAIN-2 study is an open-label, randomised, controlled, phase 3 trial being done in 37 hospitals in the Netherlands. We recruited patients aged 18 years or older with previously untreated, histologically confirmed stage II–III HER2-positive breast cancer. Patients were randomly allocated using central randomisation software (1:1 ratio) with minimisation without a random component, stratified by tumour stage, nodal stage, oestrogen receptor status, and age, to receive 5-fluorouracil (500 mg/m2), epirubicin (90 mg/m2), and cyclophosphamide (500 mg/m2) every 3 weeks for three cycles followed by paclitaxel (80 mg/m2 on days 1 and 8) and carboplatin (area under the concentration–time curve [AUC] 6 mg/mL per min on day 1 or optionally, as per hospital preference, AUC 3 mg/mL per min on days 1 and 8) every 3 weeks for six cycles, or to receive nine cycles of paclitaxel and carboplatin at the same dose and schedule as in the anthracycline group. Patients in both study groups received trastuzumab (6 mg/kg, loading dose 8 mg/kg) and pertuzumab (420 mg, loading dose 840 mg) concurrently with all chemotherapy cycles. The primary endpoint was the proportion of patients who achieved a pathological complete response in breast and axilla (ypT0/is ypN0) in the intention-to-treat population. Safety was analysed in patients who received at least one treatment cycle according to actual treatment received. This trial is registered with ClinicalTrials.gov, number NCT01996267, and follow-up for long-term outcome is ongoing. Between Dec 9, 2013, and Jan 14, 2016, 438 patients were enrolled and randomly assigned to the two treatment groups (219 patients to each group), of whom 418 were evaluable for the primary endpoint (212 in the anthracycline group and 206 in the non-anthracycline group). The median follow-up for all patients was 19 months (IQR 16–23 months). A pathological complete response was recorded in 141 (67%, 95% CI 60–73) of 212 patients in the anthracycline group and in 140 (68%, 61–74) of 206 in the non-anthracycline group (p=0·95). One patient randomly allocated to the non-anthracycline group did receive anthracyclines and was thus included in the anthracycline group for safety analyses; therefore, for the safety analyses there were 220 patients in the anthracycline group and 218 in the non-anthracycline group. Serious adverse events were reported in 61 (28%) of 220 patients in the anthracycline group and in 49 (22%) of 218 in the non-anthracycline group. The most common adverse events of any cause were grade 3 or worse neutropenia (in 131 [60%] of 220 patients in the anthracycline group vs 118 [54%] of 218 in the non-anthracycline group), grade 3 or worse diarrhoea (26 [12%] vs 37 [18%]), and grade 2 or worse peripheral neuropathy (66 [30%] vs 68 [31%]), with no substantial differences between the groups. Grade 3 or worse febrile neutropenia was more common in the anthracycline group than in the non-anthracycline group (23 [10%] vs three [1%], p<0·0001). Symptomatic left ventricular systolic dysfunction was rare in both groups (two [1%] of 220 vs 0 of 218). One patient in the anthracycline group died because of a pulmonary embolism, which was possibly treatment related. In view of the high proportion of pathological complete responses recorded in both groups and the fact that febrile neutropenia was more frequent in the anthracycline group, omitting anthracyclines from neoadjuvant treatment regimens might be a preferred approach in the presence of dual HER2 blockade in patients with early HER2-positive breast cancer. Long-term follow-up is required to confirm these results. Roche Netherlands.

Key Points Preclinical and clinical data indicate that endocrine treatment for breast cancer might have an adverse effect on cognition Many studies exploring the influence of endocrine therapy on cognition are underpowered and have flawed designs, precluding any definite conclusions on the existence and clinical impact of such effects Studies with a pretreatment neuropsychological assessment are essential to determine the potential cognitive effects of endocrine treatment and to identify patients who might be at risk of treatment-associated cognitive decline Current guidelines permit the choice between different endocrine regimens in the treatment of breast cancer; thus, potential treatment-selective cognitive effects might influence treatment decision-making on an individualized basis Many breast cancer survivors experience long-term adverse effects of adjuvant systemic therapy, including cognitive decline. The decline of cognitive functions can have a detrimental impact on quality of life and might interfere with independent living. This Review discusses the tissue-selective side effects of endocrine therapies and specifically their impact on cognitive function. The critical issues that need to be addressed to best assess the cognitive effects of endocrine treatment in patients with breast cancer are highlighted. The number of breast cancer survivors is gradually increasing and a subset of these patients experience long-term adverse effects of adjuvant systemic therapy, including cognitive decline. Surprisingly, relatively little is known about the long-term adverse effects of endocrine treatment on cognition. As 75% of all patients with breast cancer are eligible to receive hormonal treatment, understanding the potential neurocognitive adverse effects of such therapy is of utmost importance. Concerns about adverse cognitive effects of adjuvant endocrine therapy are timely, as recently updated guidelines recommend increasing the length of such therapy from 5 years to 10 years for a subset of patients. The decline of cognitive functions can have a detrimental impact on quality of life and might interfere with independent living. This Review discusses the tissue-selective side effects of endocrine therapies and specifically their impact on cognitive function, on the basis of clinical data; the neurobiological effects of endocrine therapies as observed in preclinical models are also discussed. We highlight the critical issues that need to be addressed in future preclinical and clinical studies in order to best assess the cognitive effects of endocrine treatment in patients with breast cancer.

Immune checkpoint blockade (ICB) is currently approved for patients with triple-negative breast cancer (TNBC), whereas responses to ICB are also observed in a small subgroup of Estrogen Receptor (ER)-positive breast cancer. The cut-off for ER-positivity (≥1%) is based on likelihood of endocrine treatment response, but ER-positive breast cancer represents a very heterogeneous group. This raises the question whether selection based on ER-negativity should be revisited to select patients for ICB treatment in the context of clinical trials. Stromal tumor-infiltrating lymphocytes (sTILs) and other immune parameters are higher in TNBC compared to ER-positive breast cancer, but it is unknown whether lower ER levels are associated with more inflamed tumor microenvironments (TME). We collected a consecutive series of primary tumors from 173 HER2-negative breast cancer patients, enriched for tumors with ER expression between 1 and 99% and found levels of stromal TILs, CD8 + T cells, and PD-L1 positivity in breast tumors with ER 1–9% and ER 10–50% to be comparable to tumors with ER 0%. Expression of immune-related gene signatures in tumors with ER 1–9% and ER 10–50% was comparable to ER 0%, and higher than in tumors with ER 51–99% and ER 100%. Our results suggest that the immune landscape of ER low tumors (1–9%) and ER intermediate tumors (10–50%) mimic that of primary TNBC.

Most studies for identifying biomarkers for oestrogen receptor-α (ERα)-positive breast cancer have been performed using material from consecutive series of patients treated with tamoxifen. Consequently, the predictive value of any biomarker identified is confounded by its prognostic value. In this Review, the authors discuss how different biomarkers might enable the prediction of broad endocrine or agent-specific resistance. Personalized medicine for oestrogen receptor-α (ERα)-positive breast cancer requires predictive biomarkers for broad endocrine resistance as well as biomarkers capable of predicting resistance to a specific agent. In addition, biomarkers could be used to select patients that might benefit from the addition of treatments that do not target ERα. However, biomarker identification studies seem to be far from consistent and identified biomarkers seldom face an introduction into clinical practice. Importantly, most of the studies that seek to identify biomarkers have been performed using material from consecutive series of patients treated with tamoxifen (the most commonly prescribed ERα antagonist). Consequently, the predictive value of any biomarker identified is confounded by its prognostic value. Another important issue is the lack of differentiation between premenopausal and postmenopausal patients with breast cancer. The hormonal environment of a tumour in patients who are premenopausal is intrinsically distinct from those arising in postmenopausal women. Biomarkers of different biological mechanisms might enable the prediction of either broad endocrine resistance or resistance to a specific agent in each of these patient subtypes. Ultimately, improvements to study design are needed to establish the clinical validity of the most promising biomarkers to predict benefit from endocrine therapy. Key Points Predictive biomarkers for resistance to tamoxifen and/or aromatase inhibitors are essential to select the optimal adjuvant treatment for oestrogen receptor-α (ERα)-positive breast cancer and increase patient survival rates As oestrogen signalling is different between premenopausal and postmenopausal patients with breast cancer, these subgroups should be analysed separately when testing the clinical validity of potential predictive biomarkers Although additional activated signalling pathways circumvent ERα signalling in vitro , a validated biomarker that predicts the activation status of these pathways and resistance to endocrine therapies is not yet clinically available Targeted agents to these signalling pathways have shown promise in metastatic breast cancer and might provide an additional treatment modality in personalized breast cancer treatment

Male breast cancer (MBC) is rare and poorly characterized. Like the female counterpart, most MBCs are hormonally driven, but relapse after hormonal treatment is also noted. The pan-hormonal action of steroid hormonal receptors, including estrogen receptor alpha (ERα), androgen receptor (AR), progesterone receptor (PR), and glucocorticoid receptor (GR) in this understudied tumor type remains wholly unexamined. This study reveals genomic cross-talk of steroid hormone receptor action and interplay in human tumors, here in the context of MBC, in relation to the female disease and patient outcome. Here we report the characterization of human breast tumors of both genders for cistromic make-up of hormonal regulation in human tumors, revealing genome-wide chromatin binding landscapes of ERα, AR, PR, GR, FOXA1, and GATA3 and enhancer-enriched histone mark H3K4me1. We integrate these data with transcriptomics to reveal gender-selective and genomic location-specific hormone receptor actions, which associate with survival in MBC patients. Male breast cancer (MBC) is rare and largely hormonally driven. Here, the authors examine the action of steroid hormone receptors in male and female breast cancers and find gender selective hormone receptor action that associates with the survival of MBC patients.