App-based support for breast cancer patients to reduce psychological distress during therapy and survivorship - a multicentric randomized controlled trial.

Introduction: The negative impact of unmanaged psychological distress on quality of life and outcome in breast cancer survivors has been demonstrated. Fortunately, studies indicate that distress can effectively be addressed and even prevented using evidence-based interventions. In Germany prescription-based mobile health apps, known as DiGAs (digital health applications), that are fully reimbursed by health insurances, were introduced in 2020. In this study, the effectiveness of an approved breast cancer DiGA was investigated: The personalized coaching app PINK! Coach supports and accompanies breast cancer patients during therapy and follow-up. Methods: PINK! Coach was specifically designed for breast cancer (BC) patients from the day of diagnosis to the time of Follow-up (aftercare). The app offers individualized, evidence-based therapy and side-effect management, mindfulness-based stress reduction, nutritional and psychological education, physical activity tracking, and motivational exercises to implement lifestyle changes sustainably in daily routine. A prospective, intraindividual RCT (DRKS00028699) was performed with n = 434 patients recruited in 7 German breast cancer centers from September 2022 until January 2023. Patients with BC were included independent of their stage of diseases, type of therapy and molecular characteristics of the tumor. Patients were randomized into one of two groups: The intervention group got access to PINK! over 12 weeks; the control group served as a waiting-list comparison to "standard of care." The primary endpoint was psychological distress objectified by means of Patient Health Questionnaire-9 (PHQ-9). Subgroups were defined to investigate the app's effect on several patient groups such as MBC vs. EBC patients, patients on therapy vs. in aftercare, patients who received a chemotherapy vs. patients who did not. Results: Efficacy analysis of the primary endpoint revealed a significant reduction in psychological distress (least squares estimate -1.62, 95% confidence interval [1.03; 2.21]; p<0.001) among intervention group patients from baseline to T3 vs, control group. Subgroup analysis also suggested improvements across all clinical situations. Conclusion: Patients with breast cancer suffer from psychological problems including anxiety and depression during and after therapy. Personalized, supportive care with the app PINK! Coach turned out as a promising opportunity to significantly improve psychological distress in a convenient, accessible, and low-threshold manner for breast cancer patients independent of their stage of disease (EBC/MBC), therapy phase (aftercare or therapy) or therapy itself (chemotherapy/other therapy options). The app is routinely available in Germany as a DiGA. Clinical Trial Registration: DRKS Trial Registry (DRKS00028699).

Adherence to CPAP Treatment and the Risk of Recurrent Cardiovascular Events: A Meta-Analysis.

Importance: The effect of continuous positive airway pressure (CPAP) on secondary cardiovascular disease prevention is highly debated. Objective: To assess the effect of CPAP treatment for obstructive sleep apnea (OSA) on the risk of adverse cardiovascular events in randomized clinical trials. Data Sources: PubMed (MEDLINE), EMBASE, Current Controlled Trials: metaRegister of Controlled Trials, ISRCTN Registry, European Union clinical trials database, CENTRAL (Cochrane Central Register of Controlled Trials), and ClinicalTrials.gov databases were systematically searched through June 22, 2023. Study Selection: For qualitative and individual participant data (IPD) meta-analysis, randomized clinical trials addressing the therapeutic effect of CPAP on cardiovascular outcomes and mortality in adults with cardiovascular disease and OSA were included. Data Extraction and Synthesis: Two reviewers independently screened records, evaluated potentially eligible primary studies in full text, extracted data, and cross-checked errors. IPD were requested from authors of the selected studies (SAVE [NCT00738179], ISAACC [NCT01335087], and RICCADSA [NCT00519597]). Main Outcomes and Measures: One-stage and 2-stage IPD meta-analyses were completed to estimate the effect of CPAP treatment on risk of recurrent major adverse cardiac and cerebrovascular events (MACCEs) using mixed-effect Cox regression models. Additionally, an on-treatment analysis with marginal structural Cox models using inverse probability of treatment weighting was fitted to assess the effect of good adherence to CPAP (≥4 hours per day). Results: A total of 4186 individual participants were evaluated (82.1% men; mean [SD] body mass index, 28.9 [4.5]; mean [SD] age, 61.2 [8.7] years; mean [SD] apnea-hypopnea index, 31.2 [17] events per hour; 71% with hypertension; 50.1% receiving CPAP [mean {SD} adherence, 3.1 {2.4} hours per day]; 49.9% not receiving CPAP [usual care], mean [SD] follow-up, 3.25 [1.8] years). The main outcome was defined as the first MACCE, which was similar for the CPAP and no CPAP groups (hazard ratio, 1.01 [95% CI, 0.87-1.17]). However, an on-treatment analysis by marginal structural model revealed a reduced risk of MACCEs associated with good adherence to CPAP (hazard ratio, 0.69 [95% CI, 0.52-0.92]). Conclusions and Relevance: Adherence to CPAP was associated with a reduced MACCE recurrence risk, suggesting that treatment adherence is a key factor in secondary cardiovascular prevention in patients with OSA.

Efficacy of Endocrine Therapy Plus Trastuzumab and Pertuzumab vs De-escalated Chemotherapy in Patients with Hormone Receptor-Positive/ERBB2-Positive Early Breast Cancer: The Neoadjuvant WSG-TP-II Randomized Clinical Trial.

Importance: Combination of chemotherapy with (dual) ERBB2 blockade is considered standard in hormone receptor (HR)-positive/ERBB2-positive early breast cancer (EBC). Despite some promising data on endocrine therapy (ET) combination with dual ERBB2 blockade in HR-positive/ERBB2-positive BC, to our knowledge, no prospective comparison of neoadjuvant chemotherapy vs ET plus ERBB2 blockade in particular with focus on molecular markers has yet been performed. Objective: To determine whether neoadjuvant de-escalated chemotherapy is superior to endocrine therapy, both in combination with pertuzumab and trastuzumab, in a highly heterogeneous HR-positive/ERBB2-positive EBC. Design, Setting, and Participants: This prospective, multicenter, neoadjuvant randomized clinical trial allocated 207 patients with centrally confirmed estrogen receptor-positive and/or progesterone receptor-positive (>1%) HR-positive/ERBB2-positive EBC to 12 weeks of standard ET (n = 100) vs paclitaxel (n = 107) plus trastuzumab and pertuzumab. A total of 186 patients were required to detect a statistically significant difference in pathological complete response (pCR) (assumptions: 19% absolute difference in pCR; power, ≥80%; 1-sided Fisher exact test, 2.5% significance level). Interventions: Standard ET (aromatase inhibitor or tamoxifen) or paclitaxel, 80 mg/m2, weekly plus trastuzumab and pertuzumab every 21 days. Main Outcomes and Measures: The primary end point was pCR (ypT0/is, ypN0). Secondary end points included safety, translational research, and health-related quality of life. Omission of further chemotherapy was allowed in patients with pCR. PAM50 analysis was performed on baseline tumor biopsies. Results: Of the 207 patients included (median [range] age, 53 [25-83] years), 121 (58%) had cT2 to cT4 tumors, and 58 (28%) had clinically node-positive EBC. The pCR rate in the ET plus trastuzumab and pertuzumab arm was 23.7% (95% CI, 15.7%-33.4%) vs 56.4% (95% CI, 46.2%-66.3%) in the paclitaxel plus trastuzumab and pertuzumab arm (odds ratio, 0.24; 95% CI, 0.12-0.46; P < .001). Both immunohistochemical ERBB2 score of 3 or higher and ERBB2-enriched subtype were independent predictors for pCR in both arms. Paclitaxel was superior to ET only in the first through third quartiles but not in the highest ERBB2 quartile by messenger RNA. In contrast with the paclitaxel plus trastuzumab and pertuzumab arm, no decrease in health-related quality of life after 12 weeks was observed in the ET plus trastuzumab and pertuzumab arm. Conclusions and Relevance: The WSG-TP-II randomized clinical trial is, to our knowledge, the first prospective trial comparing 2 neoadjuvant de-escalation treatments in HR-positive/ERBB2-positive EBC and demonstrated an excellent pCR rate after 12 weeks of paclitaxel plus trastuzumab and pertuzumab that was clearly superior to the pCR rate after ET plus trastuzumab and pertuzumab. Trial Registration: ClinicalTrials.gov Identifier: NCT03272477.

Cardiovascular Outcomes in Adults with Coronary Artery Disease and Obstructive Sleep Apnea with versus without Excessive Daytime Sleepiness in the RICCADSA Cinical Trial.

Rationale: Recent randomized controlled trials did not show cardiovascular benefits of continuous positive airway pressure (CPAP) in adults with coronary artery disease (CAD) and obstructive sleep apnea (OSA) in intention-to-treat analyses. It has been argued that exclusion of patients with OSA with excessive daytime sleepiness (EDS), who may be most likely to benefit from CPAP treatment, may be a reason for the null results. Objectives: We addressed 1) the effect of concomitant EDS on adverse outcomes in patients with CAD and OSA; and 2) whether the cardiovascular benefit of CPAP adherence differs between individuals with versus without EDS. Methods: This was a secondary analysis of the RICCADSA (Randomized Intervention with CPAP in CAD and Obstructive Sleep Apnea) trial, conducted in Sweden between 2005 and 2013. Data were analyzed from 155 patients with CAD with OSA (apnea-hypopnea index ⩾ 15/h) and EDS (Epworth Sleepiness Scale score ⩾ 10), who were allocated to CPAP and 244 patients without EDS (ESS < 10), who were randomized to CPAP or no CPAP. Patients who were allocated to no CPAP or were nonadherent (CPAP usage < 4 h/night) were compared with adherent patients (CPAP usage ⩾ 4 h/night) at 1-year follow-up. Inverse probability of treatment weighting was applied to mimic randomization of EDS. The primary endpoint was the first event of repeat revascularization, myocardial infarction, stroke, or cardiovascular mortality. Results: The median follow-up was 52.2 months. The incidence of the primary endpoint did not differ significantly between the EDS versus no-EDS groups in the entire cohort. Within the adherent group, patients without EDS had a significantly decreased risk compared with patients with EDS (adjusted hazard ratio, 0.41; 95% confidence interval, 0.20-0.85; P = 0.02). Conclusions: Adverse cardiovascular outcomes did not differ by degrees of EDS for patients with CAD with OSA who were untreated or nonadherent to treatment. CPAP use, at least 4 h/night, was associated with reduced adverse outcomes in participants without EDS. Clinical trial registered with www.clinicaltrials.gov (NCT00519597).

De-Escalated Neoadjuvant Trastuzumab-Emtansine With or Without Endocrine Therapy Versus Trastuzumab With Endocrine Therapy in HR+/HER2+ Early Breast Cancer: 5-Year Survival in the WSG-ADAPT-TP Trial.

PURPOSE: Neoadjuvant chemotherapy is standard of care in human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (EBC), irrespective of the hormone receptor status. Trastuzumab-emtansine (T-DM1), antibody-drug conjugate, is highly effective in HER2+ EBC; however, no survival data are available for de-escalated antibody-drug conjugate-based neoadjuvant therapy without conventional chemotherapy. PATIENTS AND METHODS: In the WSG-ADAPT-TP (ClinicalTrials.gov identifier: NCT01779206) phase II trial, 375 centrally reviewed patients with hormone receptor-positive (HR+)/HER2+ EBC (clinical stage I-III) were randomly assigned to 12 weeks of T-DM1 with or without endocrine therapy (ET) or trastuzumab + ET once every 3 weeks (ratio 1:1:1). Adjuvant chemotherapy (ACT) omission was allowed in patients with pathologic complete response (pCR). In this study, we report the secondary survival end points and biomarker analysis. Patients who received at least one dose of study treatment were analyzed. Survival was analyzed using the Kaplan-Meier method, two-sided log-rank statistics, and Cox regression models stratified for nodal and menopausal status. P values < .05 were considered statistically significant. RESULTS: T-DM1, T-DM1 + ET, and trastuzumab + ET induced similar 5-year invasive disease-free survival (iDFS; 88.9%, 85.3%, 84.6%; Plog-rank = .608) and overall survival rates (97.2%, 96.4%, 96.3%; Plog-rank = .534). Patients with pCR versus non-pCR had improved 5-year iDFS rates (92.7% v 82.7%; hazard ratio, 0.40 [95% CI, 0.18 to 0.85]). Among the 117 patients with pCR, 41 did not receive ACT; 5-year iDFS rates were similar in those with (93.0% [95% CI, 84.0 to 97.0]) and without ACT (92.1% [95% CI, 77.5 to 97.4]; Plog-rank = .848). Translational research revealed that tumors with PIK3CA wild type, high immune marker expression, and luminal-A tumors (by PAM50) had an excellent prognosis with de-escalated anti-HER2 therapy. CONCLUSION: The WSG-ADAPT-TP trial demonstrated that pCR after 12 weeks of chemotherapy-free de-escalated neoadjuvant therapy was associated with excellent survival in HR+/HER2+ EBC without further ACT. Despite higher pCR rates for T-DM1 ± ET versus trastuzumab + ET, all trial arms had similar outcomes because of mandatory standard chemotherapy after non-pCR. WSG-ADAPT-TP demonstrated that such de-escalation trials in HER2+ EBC are feasible and safe for patients. Patient selection on the basis of biomarkers or molecular subtypes may increase the efficacy of systemic chemotherapy-free HER2-targeted approaches.

Impact of RNA Signatures on pCR and Survival after 12-Week Neoadjuvant Pertuzumab plus Trastuzumab with or without Paclitaxel in the WSG-ADAPT HER2+/HR- Trial.

PURPOSE: To identify associations of biological signatures and stromal tumor-infiltrating lymphocytes (sTIL) with pathological complete response (pCR; ypT0 ypN0) and survival in the Phase II WSG-ADAPT HER2+/HR- trial (NCT01817452). EXPERIMENTAL DESIGN: Patients with cT1-cT4c, cN0-3 HER2+/HR- early breast cancer (EBC) were randomized to pertuzumab+trastuzumab (P+T, n = 92) or P+T+paclitaxel (n = 42). Gene expression signatures were analyzed in baseline biopsies using NanoString Breast Cancer 360 panel (n = 117); baseline and on-treatment (week 3) sTIL levels were available in 119 and 76 patients, respectively. Impacts of standardized gene expression signatures on pCR and invasive disease-free survival (iDFS) were estimated by logistic and Cox regression. RESULTS: In all patients, ERBB2 [OR, 1.70; 95% confidence interval (CI), 1.08-2.67] and estrogen receptor (ER) signaling (OR, 1.72; 95% CI, 1.13-2.61) were favorable, whereas PTEN (OR, 0.57; 95% CI, 0.38-0.87) was unfavorable for pCR. After 60 months median follow-up, 13 invasive events occurred (P+T: n = 11, P+T+paclitaxel: n = 2), none following pCR. Gene signatures related to immune response (IR) and ER signaling were favorable for iDFS, all with similar HR about 0.43-0.55. These patterns were even more prominent in the neoadjuvant chemotherapy-free group, where additionally BRCAness signature was unfavorable (HR, 2.00; 95% CI, 1.04-3.84). IR signatures were strongly intercorrelated. sTILs (baseline/week 3/change) were not associated with pCR or iDFS, though baseline sTILs correlated positively with IR signatures. CONCLUSIONS: Distinct gene signatures were associated with pCR versus iDFS in HER2+/HR- EBC. The potential role of IR in preventing recurrence suggests that patients with upregulated IR signatures could be candidates for de-escalation concepts in HER2+ EBC.

De-escalated Neoadjuvant Chemotherapy in Early Triple-Negative Breast Cancer (TNBC): Impact of Molecular Markers and Final Survival Analysis of the WSG-ADAPT-TN Trial.

PURPOSE: Although optimal treatment in early triple-negative breast cancer (TNBC) remains unclear, de-escalated chemotherapy appears to be an option in selected patients within this aggressive subtype. Previous studies have identified several pro-immune factors as prognostic markers in TNBC, but their predictive impact regarding different chemotherapy strategies is still controversial. EXPERIMENTAL DESIGN: ADAPT-TN is a randomized neoadjuvant multicenter phase II trial in early patients with TNBC (n = 336) who were randomized to 12 weeks of nab-paclitaxel 125 mg/m2 + gemcitabine or carboplatin d 1,8 q3w. Omission of further (neo-) adjuvant chemotherapy was allowed only in patients with pathological complete response [pCR, primary endpoint (ypT0/is, ypN0)]. Secondary invasive/distant disease-free and overall survival (i/dDFS, OS) and translational research objectives included quantification of a predictive impact of markers regarding selection for chemotherapy de-escalation, measured by gene expression of 119 genes (including PAM50 subtype) by nCounter platform and stromal tumor-infiltrating lymphocytes (sTIL). RESULTS: After 60 months of median follow-up, 12-week-pCR was favorably associated (HR, 0.24; P = 0.001) with 5y-iDFS of 90.6% versus 62.8%. No survival advantage of carboplatin use was observed, despite a higher pCR rate [HR, 1.04; 95% confidence interval (CI), 0.68-1.59]. Additional anthracycline-containing chemotherapy was not associated with a significant iDFS advantage in pCR patients (HR, 1.29; 95% CI, 0.41-4.02). Beyond pCR rate, nodal status and high sTILs were independently associated with better iDFS, dDFS, and OS by multivariable analysis. CONCLUSIONS: Short de-escalated neoadjuvant taxane/platinum-based combination therapy appears to be a promising strategy in early TNBC for using pCR rate as an early decision point for further therapy (de-) escalation together with node-negative status and high sTILs. See related commentary by Sharma, p. 4840.

De-escalated neoadjuvant pertuzumab plus trastuzumab therapy with or without weekly paclitaxel in HER2-positive, hormone receptor-negative, early breast cancer (WSG-ADAPT-HER2+/HR-): survival outcomes from a multicentre, open-label, randomised, phase 2 trial.

BACKGROUND: Several de-escalation neoadjuvant strategies have been investigated to reduce the use of chemotherapy in HER2-positive early breast cancer using pathological complete response as a surrogate endpoint; there are few survival data from these trials. Here, we report 5-year survival data in the WSG-ADAPT-HER2+/HR- trial and address the effect of pathological complete response, early therapy response, and molecular subtype. METHODS: WSG-ASAPT-HER2+/HR-, a part of the ADAPT umbrella trial performed in patients with different subtypes of early breast cancer, was an investigator-initiated, multicentre, open-label, randomised, phase 2 trial done at 40 Breast Cancer Centres in Germany. Eligible patients were aged 18 years or older with histologically confirmed, unilateral, primary invasive, non-inflammatory early breast cancer, hormone receptor-negative and HER2-positive status, and an Eastern Cooperative Oncology Group performance status of 0 or 1 or a Karnofsky performance status of at least 80%. Patients were randomly assigned (5:2, block size 21, stratified by centre and clinical nodal status) to 12 weeks of either trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks) plus pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) or trastuzumab plus pertuzumab plus paclitaxel (80 mg/m2 weekly); all drugs were administered intravenously. The primary objective of the trial was to compare the number of patients with a pathological complete response at surgery (ie, no invasive tumour cells in breast and lymph nodes [ypT0/is ypN0], the primary endpoint) in early responders (ie, low cellularity or Ki67 decrease ≥30% after 3 weeks) in the trastuzumab plus pertuzumab group versus all patients (irrespective of an early response) in the trastuzumab plus pertuzumab plus paclitaxel group. Non-inferiority was defined as a pathological complete response no worse than 23% lower in the early-responder proportion of patients in the trastuzumab plus pertuzumab group than in the entire trastuzumab plus pertuzumab plus paclitaxel group. The primary endpoint has been reported previously. Additionally, the primary objective of the ADAPT umbrella trial was the evaluation of the effect of pathological complete response on invasive disease-free survival. At investigator's discretion, further chemotherapy could be omitted in patients with a pathological complete response. Secondary survival endpoints were 5-year invasive disease-free survival, relapse-free survival, locoregional relapse-free survival, distant disease-free survival, and overall survival. The effect of pathological complete response on survival was estimated by Cox regression analysis. All analyses are reported in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01817452, and is closed to recruitment. FINDINGS: Between March 3, 2014, and Oct 6, 2015, 134 patients were recruited and randomly assigned to treatment, 92 to trastuzumab plus pertuzumab and 42 to trastuzumab plus pertuzumab plus paclitaxel. Median follow-up in survivors was 59·9 months (IQR 53·4-61·4). There were no significant differences between the treatment groups in invasive disease-free survival, relapse-free survival, locoregional relapse-free survival, distant disease-free survival, and overall survival. In the trastuzumab plus pertuzumab plus paclitaxel group and in the trastuzumab plus pertuzumab group, the proportions of patients achieving 5-year survival respectively were 98% (95% CI 84-100) and 87% (78-93) for invasive disease-free survival (hazard ratio [HR] 0·32, 95% CI 0·07-1·49; p=0·15); 98% (95% CI 84-100) and 89% (79-94) for relapse-free survival (HR 0·41, 95% CI 0·09-1·91; p=0·25); 100% (95% CI not estimable) and 95% (88-98) for locoregional relapse-free survival (HR 0·41, 95% CI 0·05-3·75; p=0·43); 98% (95% CI 84-100) and 92% (83-96) for distant disease-free survival (HR 0·35, 95% CI 0·04-3·12; p=0·36), and 98% (95% CI 84-100) and 94% (86-97) for overall survival (HR 0·41, 95% CI 0·05-3·63; p=0·43). Pathological complete response was associated with improved invasive disease-free survival (HR 0·14, 95% CI 0·03-0·64; p=0·011). Two invasive disease-free survival events occurred after a pathological complete response (one in each treatment group). INTERPRETATION: The WSG-ADAPT-HER2+/HR- trial showed good survival rates in patients with a pathological complete response after de-escalated 12-week trastuzumab plus pertuzumab with or without weekly paclitaxel. Omission of further chemotherapy did not affect invasive disease-free survival in patients with a pathological complete response. 12 weeks of weekly paclitaxel plus dual HER2 blockade could be an efficacious de-escalated neoadjuvant regimen in patients with hormone receptor-negative, HER2-positive early breast cancer with high pathological complete response rates and good 5-year outcomes. Further trials of this approach are ongoing. FUNDING: Roche, Bayer. TRANSLATION: For the German translation of the abstract see Supplementary Materials section.

Risk for Pelvic Metastasis and Role of Pelvic Lymphadenectomy in Node-Positive Vulvar Cancer-Results from the AGO-VOP.2 QS Vulva Study.

The need for pelvic treatment in patients with node-positive vulvar cancer (VSCC) and the value of pelvic lymphadenectomy (LAE) as a staging procedure to plan adjuvant radiotherapy (RT) is controversial. In this retrospective, multicenter analysis, 306 patients with primary node-positive VSCC treated at 33 gynecologic oncology centers in Germany between 2017 and 2019 were analyzed. All patients received surgical staging of the groins; nodal status was as follows: 23.9% (73/306) pN1a, 23.5% (72/306) pN1b, 20.4% (62/306) pN2a/b, and 31.9% (97/306) pN2c/pN3. A total of 35.6% (109/306) received pelvic LAE; pelvic nodal involvement was observed in 18.5%. None of the patients with nodal status pN1a or pN1b and pelvic LAE showed pelvic nodal involvement. Taking only patients with nodal status ≥pN2a into account, the rate of pelvic involvement was 25%. In total, adjuvant RT was applied in 64.4% (197/306). Only half of the pelvic node-positive (N+) patients received adjuvant RT to the pelvis (50%, 10/20 patients); 41.9% (122/291 patients) experienced recurrent disease or died. In patients with histologically-confirmed pelvic metastases after LAE, distant recurrences were most frequently observed (7/20 recurrences). Conclusions: A relevant risk regarding pelvic nodal involvement was observed from nodal status pN2a and higher. Our data support the omission of pelvic treatment in patients with nodal status pN1a and pN1b.

Adjuvant radiotherapy and local recurrence in vulvar cancer - a subset analysis of the AGO-CaRE-1 study.

BACKGROUND: The impact of adjuvant radiotherapy (RT) to the vulva with regard to prognosis and local recurrence in patients with vulvar squamous cell cancer (VSCC) is poorly described. PATIENTS AND METHODS: In the AGO-CaRE-1 study 1618 patients with primary VSCC FIGO stage ≥ IB, treated between 1998-2008, were documented. In this retrospective subanalysis, 360 patients were included based on the following criteria: nodal involvement (pN+), known RT treatment and known radiation fields. RESULTS: The majority had pT1b/pT2 tumors (n=299; 83.1%). In 76.7%, R0 resection was achieved. 57/360 (15.8%) N+ patients were treated with adjuvant RT to the groins/pelvis and 146/360 (40.5%) received adjuvant RT to the vulva and groins/pelvis. 157/360 (43.6%) patients did not receive any adjuvant RT. HPV status was available in 162/360 patients (45.0%), 75/162 tumors were HPV+(46.3%), 87/162 (53.7%) HPV-. During a median follow-up of 17.2 months, recurrence at the vulva only occurred in 25.5% of patients without adjuvant RT, in 22.8% of patients with adjuvant RT to groins/pelvis and in 15.8% of patients with adjuvant RT to the vulva and groins/pelvis respectively. The risk reducing effect of local RT was independent of the resection margin status. 50% disease free survival time (50% DFST) indicated a stronger impact of adjuvant RT to the vulva in HPV+ compared to HPV- patients (50% DFST 20.7 months vs. 17.8 months). CONCLUSION: Adjuvant RT to the vulva was associated with a lower risk for local recurrence in N+ VSCC independent of the resection margin status. This observation was more pronounced in patients with HPV+ tumors in comparison to HPV- tumors.

TP53 mutations are associated with primary endocrine resistance in luminal early breast cancer.

BACKGROUND: Whereas the genomic landscape of endocrine-resistant breast cancer has been intensely characterized in previously treated cases with local or distant recurrence, comparably little is known about genomic alterations conveying primary non-responsiveness to endocrine treatment in luminal early breast cancer. METHODS: In this study, 622 estrogen receptor-expressing breast cancer cases treated with short-term preoperative endocrine therapy (pET) from the WSG-ADAPT trial (NCT01779206) were analyzed for genetic alterations associated with impaired endocrine proliferative response (EPR) to 3-week pET with tamoxifen or aromatase inhibitors. EPR was categorized as optimal (post-pET Ki67 <10%) versus slightly, moderately, and severely impaired (post-pET Ki67 10%-19%, 20%-34%, and ≥35%, respectively). Recently described gene mutations frequently found in previously treated advanced breast cancer were analyzed (ARID1A, BRAF, ERBB2, ESR1, GATA3, HRAS, KRAS, NRAS, PIK3CA, and TP53) by next-generation sequencing. Amplifications of CCND1, FGFR1, ERBB2, and PAK1 were determined by digital PCR or fluorescence in situ hybridization. RESULTS: ERBB2 amplification (p = 0.0015) and mutations of TP53 (p < 0.0001) were significantly associated with impaired EPR. Impaired EPR in TP53-mutated breast cancer cases was independent from the Oncotype DX Recurrence Score group and was seen both with tamoxifen- and aromatase inhibitor-based pET (p = 0.0005 each). CONCLUSION: We conclude that impaired EPR to pET is suitable to identify cases with primary endocrine resistance in early luminal breast cancer and that TP53-mutated luminal cancers might not be sufficiently treated by endocrine therapy alone.

The use of breast ultrasound for prediction of pathologic complete response in different subtypes of early breast cancer within the WSG-ADAPT subtrials.

OBJECTIVE: We assessed the value of breast ultrasound (US) performed at week 3 and 6 and at the end (EOT) of neoadjuvant therapy (NAT) for prediction of pathologic complete response (pCR, ypT0/is ypN0) in patients with HR+/HER2+, HR-/HER2-or HR-/HER2+ early breast cancer enrolled in the WSG-ADAPT subtrials. METHODS: US was performed at week 3 and 6 of NAT and at EOT in 401, 517, and 553 patients, respectively. Tumors with complete or partial response by US (RECIST 1.1) were classified as responders and those with stable or progressive disease as non-responders. RESULTS: pCR rate was higher in US responders than in non-responders. US tended to yield the highest positive predictive value in HR-/HER2+ (69%) and HR-/HER2-tumors (65%) at week 3, and the highest negative predictive value in HR+/HER2+ tumors at week 6 and at EOT (88.9% and 86.9%, respectively) and in HR-/HER2-tumors at EOT (87.9%). Multivariable analysis of patients with US at week 3 and 6 identified tumor subtype (HR-/HER2+ vs HR+/HER2+; odds ratio (OR) 2.77, 95%CI 1.45-5.29, and OR 4.17, 95%CI 2.26-7.68, respectively) and each 10% change in lesion dimension on US from baseline (OR 1.15, 95%CI 1.08-1.24, and OR 1.25, 95%CI 1.16-1.35, respectively) as parameters associated with pCR. CONCLUSIONS: Our data support the use of week 3 and EOT US for prediction of pCR in response-guided NAT and in planning of breast-conserving surgery. Change in tumor diameter on US as a continuous variable could be a valuable alternative to categorical RECIST 1.1 criteria.

Magnetic resonance imaging and ultrasound for prediction of residual tumor size in early breast cancer within the ADAPT subtrials.

BACKGROUND: Prediction of histological tumor size by post-neoadjuvant therapy (NAT) ultrasound and magnetic resonance imaging (MRI) was evaluated in different breast cancer subtypes. METHODS: Imaging was performed after 12-week NAT in patients enrolled into three neoadjuvant WSG ADAPT subtrials. Imaging performance was analyzed for prediction of residual tumor measuring ≤10 mm and summarized using positive (PPV) and negative (NPV) predictive values. RESULTS: A total of 248 and 588 patients had MRI and ultrasound, respectively. Tumor size was over- or underestimated by < 10 mm in 4.4% and 21.8% of patients by MRI and in 10.2% and 15.8% by ultrasound. Overall, NPV (proportion of correctly predicted tumor size ≤10 mm) of MRI and ultrasound was 0.92 and 0.83; PPV (correctly predicted tumor size > 10 mm) was 0.52 and 0.61. MRI demonstrated a higher NPV and lower PPV than ultrasound in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-positive and in HR-/HER2+ tumors. Both methods had a comparable NPV and PPV in HR-/HER2- tumors. CONCLUSIONS: In HR+/HER2+ and HR-/HER2+ breast cancer, MRI is less likely than ultrasound to underestimate while ultrasound is associated with a lower risk to overestimate tumor size. These findings may help to select the most optimal imaging approach for planning surgery after NAT. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01815242 (registered on March 21, 2013), NCT01817452 (registered on March 25, 2013), and NCT01779206 (registered on January 30, 2013).

Role of Pelvic Lymph Node Resection in Vulvar Squamous Cell Cancer: A Subset Analysis of the AGO-CaRE-1 Study.

BACKGROUND: As the population at risk for pelvic nodal involvement remains poorly described, the role of pelvic lymphadenectomy (LAE) in vulvar squamous cell cancer (VSCC) has been a matter of discussion for decades. METHODS: In the AGO-CaRE-1 study, 1618 patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB or higher primary VSCC treated at 29 centers in Germany between 1998 and 2008 were documented. In this analysis, only patients with pelvic LAE (n = 70) were analyzed with regard to prognosis and correlation between inguinal and pelvic lymph node involvement. RESULTS: The majority of patients had T1b/T2 tumors (n = 47; 67.1%), with a median diameter of 40 mm (2-240 mm); 54/70 patients (77.1%) who received pelvic LAE had positive groin nodes. For 42 of these 54 patients, the number of affected groin nodes had been documented as a median of 3; 14/42 (33.3%) of these patients had histologically confirmed pelvic nodal metastases (median number of affected pelvic nodes 3 [1-12]). In these 14 patients, the median number of affected groin nodes was 7 (1-30), with a groin metastases median maximum diameter of 42.5 mm (12-50). Receiver operating characteristic analysis showed an area under the curve of 0.85, with 83.3% sensitivity and 92.6% specificity for the prediction of pelvic involvement in cases of six or more positive groin nodes. No cases of pelvic nodal involvement without groin metastases were observed. Prognosis in cases of pelvic metastasis was poor, with a median progression-free survival of only 12.5 months. CONCLUSION: For the majority of node-positive patients with VSCC, pelvic nodal staging appears unnecessary since a relevant risk for pelvic nodal involvement only seems to be present in highly node-positive disease.

Age, treatment and prognosis of patients with squamous cell vulvar cancer (VSCC) - analysis of the AGO-CaRE-1 study.

BACKGROUND: Despite an increasing incidence with simultaneous decreasing age of onset, vulvar squamous cell carcinoma (VSCC) is still a disease that mainly effects the elderly population. Data on the association of age with prognosis and treatment patterns in VSCC are sparse. METHODS: This is an analysis of the AGO-CaRE-1 cohort. Patients with VSCC (FIGO stage ≥1B), treated at 29 cancer centers in Germany from 1998 to 2008, were included in a centralized database (n = 1618). In this subgroup analysis patients were analyzed according to age [<50 yrs. (n = 220), 50-69 yrs. (n = 506), ≥70 yrs. (n = 521)] with regard to treatment patterns and prognosis. Only patients with documented age, surgical groin staging and known nodal status were included (n = 1247). Median follow-up was 27.5 months. RESULTS: At first diagnosis, women ≥70 yrs. presented with more advanced tumor stages (<0.001), larger tumor diameter (<0.001), poorer ECOG status (<0.001), more frequent HPV negative tumors (p = 0.03) as well as a higher rate of nodal involvement (<0.001). Disease recurrence occurred significantly more often in elderly patients (p = 0.001) and age as well as ECOG status, microscopic residual resection, tumor stage, grading, and (chemo)radiation were independent prognostic factors for death or recurrence in multivariate analysis. 2-year disease-free survival rates were 59.3% (≥70 yrs), 65.8% (50-69 yrs) and 81.1% (<50 yrs), respectively (p < 0.001). CONCLUSIONS: Older women with VSCC present with advanced tumor stages at first diagnosis and have an increased risk of recurrence as well as a decreased 2-year DFS in comparison to younger patients. Potential reasons could be self-awareness and/or more aggressive tumor biology due to HPV independent disease.

The effect of family history on screening procedures and prognosis in breast cancer patients - Results of a large population-based case-control study.

BACKGROUND: The potential benefit of additional breast cancer screening examinations in moderate risk patients (patients with a history of breast cancer in one or two family members) remains unclear. METHODS: A large population-based case-control study on breast cancer in postmenopausal women in Germany recruited 2002-2005 (3813 cases and 7341 age-matched controls) was used to assess the association of family history with breast cancer risk. Analysis of family history, participation in screening procedures, and tumor size regarding prognosis in patients was based on follow-up data until 2015. RESULTS: A first degree family history of breast cancer was associated with higher breast cancer risk (OR 1.39, p < 0.001). Patients with a first degree family history of breast cancer were more likely to have had >10 mammograms (MG) (42.7% vs. 24.9%, p < 0.001) and showed a higher rate of imaging-detected tumors (MG or ultrasound) (45.8% vs. 31.9%, p < 0.001). A smaller tumor size at initial diagnosis (below 2 cm) was more likely in patients with a positive family history (OR 1.45, p < 0.001) and a higher number of MG (≥10 MG: OR 2.29). After accounting for tumor characteristics, mammogram regularity (HR 0.72, p < 0.001) and imaging-assisted tumor detection (HR 0.66, p < 0.001) were associated with better overall survival but not with a positive family history. DISCUSSION: Patients with a positive family history had a higher rate of imaging detected tumors with smaller size at initial diagnosis compared to patients without affected family members. Screening was associated with improved survival after a breast cancer diagnosis, irrespective of a positive family history.

p53 and p16 expression profiles in vulvar cancer: a translational analysis by the Arbeitsgemeinschaft Gynäkologische Onkologie Chemo and Radiotherapy in Epithelial Vulvar Cancer study group.

BACKGROUND: There are 2 known pathways for tumorigenesis of vulvar squamous cell carcinoma-a human papillomavirus-dependent pathway characterized by p16 overexpression and a human papillomavirus-independent pathway linked to lichen sclerosus, characterized by TP53 mutation. A correlation of human papillomavirus dependency with a favorable prognosis has been proposed. OBJECTIVE: The objective of the study was to further understand the role of human papillomavirus and p53 status in vulvar squamous cell carcinoma and characterize its clinical relevance. STUDY DESIGN: The Arbeitsgemeinschaft Gynaecological Oncology Chemo and Radiotherapy in Epithelial Vulvar Cancer-1 study is a retrospective cohort study of 1618 patients with primary vulvar squamous cell carcinoma Fédération Internationale de Gynécologie et d'Obstétrique stage ≥1B treated at 29 gynecologic cancer centers in Germany between 1998 and 2008. For this translational substudy, formalin-fixed paraffin-embedded tissue was collected. A tissue microarray was constructed (n=652 samples); p16 and p53 expression was determined by immunohistochemistry. Human papillomavirus status and subtype were analyzed by polymerase chain reaction. RESULTS: p16 immunohistochemistry was positive in 166 of 550 tumors (30.2%); p53 staining in 187 of 597 tumors (31.3%). Only tumors with available information regarding p16 and p53 immunohistochemistry and without p53 silent expression pattern were further analyzed (n=411); 3 groups were defined: p53+ (n=163), p16+/p53- (n=132), and p16-/p53- (n=116). Human papillomavirus DNA was detected in 85.6% of p16+/p53- tumors; human papillomavirus-16 was the most common subtype (86.3%). Patients with p16+ tumors were younger (64 vs 72 years for p53+, respectively, 69 years for p16-/p53- tumors; P<.0001) and showed lower rates of lymph-node involvement (28.0% vs 42.3% for p53+, respectively, 30.2% for p16-/p53- tumors; P=.050). Notably, 2-year-disease-free and overall survival rates were significantly different among the groups: disease-free survival, 47.1% (p53+), 60.2% (p16-/p53-), and 63.9% (p16+/p53-) (P<.001); overall survival, 70.4% (p53+), 75.4% (p16-/p53-), and 82.5% (p16+/p53-) (P=.002). In multivariate analysis, the p16+/p53- phenotype showed a consistently improved prognosis compared with the other groups (hazard ratio, 0.66; 95% confidence interval, 0.44-0.99; P=.042). CONCLUSION: p16 overexpression is associated with an improved prognosis whereas p53 positivity is linked to an adverse outcome. Our data support the hypothesis of a clinically relevant third subgroup of vulvar squamous cell carcinoma with a p53-/p16- phenotype showing an intermediate prognosis that needs to be further characterized.

Pelvic Lymphadenectomy in Vulvar Cancer - Does it make sense?

Since the publication of the updated German guideline in 2015, the recommendations for performing pelvic lymphadenectomy (LAE) in patients with vulvar cancer (VSCC) have changed considerably. The guideline recommends surgical lymph node staging in all patients with a higher risk of pelvic lymph node involvement. However, the current data do not allow the population at risk to be clearly defined, therefore, the indication for pelvic lymphadenectomy is still not clear. There are currently two published German patient populations who had pelvic LAE which can be used to investigate both the prognostic effect of histologically verified pelvic lymph node metastasis and the relation between inguinal and pelvic lymph node involvement. A total of 1618 patients with primary FIGO stage ≥ IB VSCC were included in the multicenter AGO CaRE-1 study (1998 - 2008), 70 of whom underwent pelvic LAE. During a retrospective single-center evaluation carried out at the University Medical Center Hamburg-Eppendorf (UKE), a total of 514 patients with primary VSCC treated between 1996 - 2018 were evaluated, 21 of whom underwent pelvic LAE. In both cohorts, around 80% of the patients who underwent pelvic LAE were inguinally node-positive, with a median number of three affected groin lymph nodes. There were no cases of pelvic lymph node metastasis without inguinal lymph node metastasis in either of the two cohorts. Between 33 - 35% of the inguinal node-positive patients also had pelvic lymph node metastasis; the median number of affected groin lymph nodes in these patients was high (> 4), and the maximum median diameter of the largest inguinal metastasis was > 40 mm in both cohorts. Pelvic lymph node staging and pelvic radiotherapy is therefore probably not necessary for the majority of node-positive patients with VSCC, as the relevant risk of pelvic lymph node involvement was primarily found in node-positive patients with high-grade disease. More, ideally prospective data collections are necessary to validate the relation between inguinal and pelvic lymph node involvement.

Effect of Obstructive Sleep Apnea and CPAP Treatment on Cardiovascular Outcomes in Acute Coronary Syndrome in the RICCADSA Trial.

We aimed to address the impact of OSA and its treatment with continuous positive airway pressure (CPAP) on major adverse cardiovascular and cerebrovascular events (MACCE) in patients with acute coronary syndrome (ACS). In this current analysis of the revascularized ACS subgroup (n = 353) of the Randomized Intervention with CPAP in Coronary Artery Disease and Obstructive Sleep Apnea (RICCADSA) trial (Trial Registry: ClinicalTrials.gov; No: NCT00519597), participants with non-sleepy OSA (apnea-hypopnea-index [AHI] ≥ 15 events/h on a home sleep apnea testing, and Epworth Sleepiness Scale [ESS] score < 10; n = 171) were randomized to CPAP (n = 86) or no-CPAP (n = 85). The sleepy OSA patients (AHI ≥ 15 events/h and ESS ≥ 10) who were offered CPAP, and the ones with no-OSA (AHI < 5 events/h) were included in the observational arm. A post-hoc analysis was done to compare untreated OSA (no-CPAP; n = 78) and nonadherent sleepy/non-sleepy OSA (n = 96) with the reference group without OSA (n = 81). The primary endpoint (the first event of repeat revascularization, myocardial infarction, stroke or cardiovascular mortality) during a median 4.7-year follow-up was evaluated in time-dependent Cox proportional hazards models adjusted for confounding factors. The incidence of MACCE did not differ significantly in intention-to-treat population. On-treatment analysis showed a significant risk reduction in those who used CPAP for ≥4 vs. <4 h/day or did not receive treatment (adjusted hazard ratio [HR] 0.17; 95% confidence interval [CI] 0.03-0.81; p = 0.03). Compared with the reference group, nonadherent/untreated OSA was associated with an increased cardiovascular risk (adjusted HR 1.97, 95% CI 1.03-3.77; p = 0.04). We conclude that OSA is an independent risk factor for adverse cardiovascular outcomes in patients with ACS. CPAP treatment may reduce this risk, if the device is used at least 4 h/day.