Prepectoral versus subpectoral implant-based breast reconstruction after skin-sparing mastectomy or nipple-sparing mastectomy (OPBC-02/ PREPEC): a pragmatic, multicentre, randomised, superiority trial.

INTRODUCTION: The emphasis on aesthetic outcomes and quality of life (QoL) has motivated surgeons to develop skin-sparing or nipple-sparing mastectomy (SSM/ NSM) for breast cancer treatment or prevention. During the same operation, a so-called immediate breast reconstruction is performed. The breast can be reconstructed by positioning of a breast implant above (prepectoral) or below (subpectoral) the pectoralis major muscle or by using the patients' own tissue (autologous reconstruction). The optimal positioning of the implant prepectoral or subpectoral is currently not clear. Subpectoral implant-based breast reconstruction (IBBR) is still standard care in many countries, but prepectoral IBBR is increasingly performed. This heterogeneity in breast reconstruction practice is calling for randomised clinical trials (RCTs) to guide treatment decisions. METHODS AND ANALYSIS: International, pragmatic, multicentre, randomised, superiority trial. The primary objective of this trial is to test whether prepectoral IBBR provides better QoL with respect to long-term (24 months) physical well-being (chest) compared with subpectoral IBBR for patients undergoing SSM or NSM for prevention or treatment of breast cancer. Secondary objectives will compare prepectoral versus subpectoral IBBR in terms of safety, QoL and patient satisfaction, aesthetic outcomes and burden on patients. Total number of patients to be included: 372 (186 per arm). ETHICS AND DISSEMINATION: This study will be conducted in compliance with the Declaration of Helsinki. Ethical approval has been obtained for the lead investigator's site by the Ethics Committee 'Ethikkommission Nordwest- und Zentralschweiz' (2020-00256, 26 March 2020). The results of this study will be published in a peer-reviewed medical journal, independent of the results, following the Consolidated Standards of Reporting Trials standards for RCTs and good publication practice. Metadata describing the type, size and content of the datasets will be shared along with the study protocol and case report forms on public repositories adhering to the FAIR (Findability, Accessibility, Interoperability, and Reuse) principles. TRIAL REGISTRATION NUMBER: NCT04293146.

Correction: Residual Axillary Burden After Neoadjuvant Chemotherapy (NACT) in Early Breast Cancer in Patients with a priori Clinically Occult Nodal Metastases - a transSENTINA Analysis.

[This corrects the article DOI: 10.1055/a-1298-3453.].

Survival Analysis After Neoadjuvant Chemotherapy With Trastuzumab or Lapatinib in Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer in the GeparQuinto (G5) Study (GBG 44).

Purpose The GeparQuinto phase III trial demonstrated a lower pathologic complete response (pCR; pT0 ypN0) rate when lapatinib was added to standard anthracycline-taxane chemotherapy compared with trastuzumab in patients with human epidermal growth factor receptor 2 (HER2) -positive breast cancer. Here, we report the long-term outcomes. Methods Patients with HER2-positive tumors (n = 615) received neoadjuvant treatment with epirubicin (E) plus cyclophosphamide (C), followed by docetaxel (T) in combination with either lapatinib (L) or trastuzumab (H; ECH-TH arm: n = 307; ECL-TL arm: n = 308). All patients received adjuvant trastuzumab for a total of 12 months and 18 months in the ECH-TH and ECL-TL arms, respectively. Median follow-up was 55 months. Results Three-year disease-free survival (DFS), distant DFS (DDFS), and overall survival (OS) were not significantly different between the two treatment arms. Long-term outcomes correlated with pCR (DFS: hazard ratio [HR], 0.63; P = .042; DDFS: HR, 0.55; P = .021; and OS: HR, 0.31; P = .004). A benefit only for OS was observed in patients who were treated with trastuzumab and achieved pCR versus no pCR (HR, 0.15; P = .010), whereas no difference was found in patients with pCR versus without pCR in the lapatinib arm. DFS and DDFS remained unchanged in both treatment arms according to hormone receptor status, whereas OS was significantly better in hormone receptor-positive patients who were treated with neoadjuvant lapatinib (HR, 0.32; P = .019), followed by adjuvant trastuzumab. No difference was observed in hormone receptor-negative patients; however, the small number of events limits this interpretation. Within the hormone receptor-negative cohort, pCR was significantly associated with DFS, DDFS, and OS ( P = .002, .005, and .002, respectively). Conclusion pCR correlated with long-term outcome. In patients with hormone receptor-positive tumors, prolonged anti-HER2 treatment-neoadjuvant lapatinib for 6 months, followed by adjuvant trastuzumab for 12 months-significantly improved survival compared with anti-HER2 treatment with trastuzumab alone.

Using ultrasound and palpation for predicting axillary lymph node status following neoadjuvant chemotherapy - Results from the multi-center SENTINA trial.

BACKGROUND: With the growing importance of neoadjuvant systemic therapy (NST) the assessment of post neoadjuvant axillary status is of increasing importance especially in patients who presented initially with suspicious nodes (cN1). This study aims to investigate the predictive value of palpation and axillary ultrasound of formerly cN1 patients following NST. PATIENTS AND METHODS: The SENTINA trial (SENTinel NeoAdjuvant) is a 4-arm prospective multicenter study designed to evaluate the role of sentinel node biopsy (SLNB) in the context of neoadjuvant systemic treatment (NST) of breast cancer patients. RESULTS: 1240 patients from 103 institutions entered the trial. 715 (arm C n = 592; arm D n = 123) patients, who presented initially cN1 underwent clinical evaluation of lymph node status following NST. Palpation alone demonstrated a sensitivity of 8.3%, specifity of 94.8% and a negative predictive value (NPV) of 46.6%. Ultrasound alone revealed a sensitivity of 23.9%, specificity 91.7%, and a NPV of 50.3%.The investigators combined classification (palpation and ultrasound) resulted in a sensitivity of 24.4%, specificity 91.4%, and a NPV of 50.3%. Investigators classified the axilla nodes as being unsuspicious (cN0) following NST in 592/715 patients; of them 298 (50.3%) were pN0, 151 (25.5%) had 1-2 histologically involved nodes and 143 (24.2%) had >2 histologically involved nodes. CONCLUSION: The diagnostic accuracy of ultrasound and palpation following NST is unacceptably low and additional tools for evaluation of the axillary lymph node status following NST are urgently needed.

Surgical outcome after neoadjuvant chemotherapy and bevacizumab: results from the GeparQuinto study (GBG 44).

PURPOSE: Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, has shown increased pathological complete response rates when added to neoadjuvant chemotherapy. In various cancer types, bevacizumab treatment was accompanied by an increased risk of bleedings and other surgical complications. We assessed associated surgical complications. METHODS: In the GeparQuinto trial, 1,948 patients were randomized to receive four cycles epirubicin/cyclophosphamide (EC, 90/600 mg/m(2) q3w) followed by four cycles docetaxel (D, 100 mg/m(2) q3w) each with (ECB-DB) or without (EC-D) bevacizumab (B, 15 mg/kg q3w) concurrent with chemotherapy. Surgery had to be performed not earlier than 28 days after the last bevacizumab infusion, but within days 21 and 35 after the last chemotherapy. RESULTS: In 743 (38.1 %) patients, a surgical complication (bleedings, hematomas, necrosis, wound infections, abscess) was documented prospectively. Baseline characteristics of the patients were well balanced between both arms. The breast-conserving surgery (BCS) rate (N = 502) was 69.1 % (EC-D) and 71.9 % (ECB-DB; p = 0.464). The first surgical procedure was performed at a median of 29 (EC-D) and 34 days (ECB-DB) after last chemotherapy with or without bevacizumab infusion (p < 0.001). Surgical complications were documented in 38 (10.9 %; EC-D) and 59 (15.0 %; ECB-DB) patients (p = 0.103). Surgical complications were significantly higher after ECD-DB only in patients treated with BCS (N = 53; p = 0.029) or in those requiring repeat surgery in order achieve clear margins (N = 23; p = 0.037) compared to the EC-D group. CONCLUSIONS: Addition of bevacizumab to neoadjuvant chemotherapy might be associated with an increased risk for surgical complications in patients treated with BCS or after repeated surgeries.

FemZone trial: a randomized phase II trial comparing neoadjuvant letrozole and zoledronic acid with letrozole in primary breast cancer patients.

BACKGROUND: The objective of this prospectively randomized phase II trial (Trial registration: EUCTR2004-004007-37-DE) was to compare the clinical response of primary breast cancer patients to neoadjuvant therapy with letrozole alone (LET) or letrozole and zoledronic acid (LET + ZOL). METHODS: Patients were randomly assigned to receive either LET 2.5 mg/day (n = 79) or the combination of LET 2.5 mg/day and a total of seven infusions of ZOL 4 mg every 4 weeks (n = 89) for 6 months. Primary endpoint was clinical response rate as assessed by mammogram readings. The study was terminated prematurely due to insufficient recruitment. We report here on an exploratory analysis of this data. RESULTS: Central assessment of tumor sizes during the treatment period was available for 131 patients (66 LET, 65 LET + ZOL). Clinical responses (complete or partial) were seen in 54.5% (95% CI: 41.8-66.9) of the patients in the LET arm and 69.2% (95% CI: 56.6-80.1) of those in the LET + ZOL arm (P = 0.106). A multivariate model showed an OR of 1.72 (95% CI: 0.83-3.59) for the experimental arm. CONCLUSION: No increase in the clinical response rate was observed with the addition of ZOL to a neoadjuvant treatment regimen with LET. However a trend towards a better reponse in the LET + ZOL arm could be observed. This trend is consistent with previous studies that have investigated the addition of ZOL to chemotherapy, and it may support the evidence for a direct antitumor action of zoledronic acid.

Absence of pharmacokinetic drug-drug interaction of pertuzumab with trastuzumab and docetaxel.

Pertuzumab is a novel antihuman epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody. Combined with trastuzumab plus docetaxel, pertuzumab improved progression-free and overall survival versus trastuzumab plus docetaxel in the phase III CLEOPATRA trial (NCT00567190) in first-line HER2-positive metastatic breast cancer. Thirty-seven patients participated in a pharmacokinetic (PK)/corrected QT interval substudy of CLEOPATRA, which evaluated potential PK drug-drug interaction (DDI). PK parameters were calculated using noncompartmental methods, and DDI analyses were carried out. In the presence of trastuzumab and docetaxel, the mean pertuzumab Cmin and Cmax in cycle 3 were 63.6 and 183 µg/ml, respectively. The pertuzumab concentrations observed were consistent with simulations from a validated population PK model, indicating that trastuzumab and docetaxel did not alter pertuzumab PK. Comparison of geometric least-squares mean PK parameters between arms showed no impact of pertuzumab on the PK of trastuzumab or docetaxel. In conclusion, no PK DDI was observed when pertuzumab, trastuzumab, and docetaxel were combined for the treatment of HER2-positive metastatic breast cancer.

Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer.

BACKGROUND: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor A, has shown clinical efficacy in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. We evaluated the efficacy, measured according to the rate of pathological complete response (absence of invasive and intraductal disease in the breast and the axillary lymph nodes), and the safety of adding bevacizumab to neoadjuvant chemotherapy in patients with early-stage breast cancer. METHODS: We randomly assigned 1948 patients with a median tumor size of 40 mm on palpation to receive neoadjuvant epirubicin and cyclophosphamide followed by docetaxel, with or without concomitant bevacizumab. Patients with untreated HER2-negative breast cancer were eligible if they had large tumors, hormone-receptor-negative disease, or hormone-receptor-positive disease with palpable nodes or positive findings on sentinel-node biopsy, and no increased cardiovascular or bleeding risk. RESULTS: Overall, the rates of pathological complete response were 14.9% with epirubicin and cyclophosphamide followed by docetaxel and 18.4% with epirubicin and cyclophosphamide followed by docetaxel plus bevacizumab (odds ratio with addition of bevacizumab, 1.29; 95% confidence interval, 1.02 to 1.65; P=0.04); the corresponding rates of pathological complete response were 27.9% and 39.3% among 663 patients with triple-negative tumors (P=0.003) and 7.8% and 7.7% among 1262 patients with hormone-receptor-positive tumors (P=1.00). Breast-conserving surgery was possible in 66.6% of the patients in both groups. The addition of bevacizumab, as compared with neoadjuvant therapy alone, was associated with a higher incidence of grade 3 or 4 toxic effects (febrile neutropenia, mucositis, the hand-foot syndrome, infection, and hypertension) but with a similar incidence of surgical complications. CONCLUSIONS: The addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response among patients with HER2-negative early-stage breast cancer. Efficacy was restricted primarily to patients with triple-negative tumors, in whom the pathological complete response is considered to be a reliable predictor of long-term outcome. (Funded by Sanofi-Aventis and Roche, Germany; ClinicalTrials.gov number, NCT00567554.).

Re-Challenging Taxanes in Recurrent Breast Cancer in Patients Treated with (Neo-)Adjuvant Taxane-Based Therapy.

SUMMARY: Background: Docetaxel and paclitaxel are among the most active substances for the treatment of breast cancer. As both drugs are used today in adjuvant regimens, efficacy data from pivotal trials in the metastatic setting in taxane-naive populations cannot reliably be used as references. Patients and Methods: The Taxane Re-Challenge Cohort Study identified participants from 6 prospective (neo-)adjuvant taxane-based studies with recurrent disease and collected data on their subsequent treatment. Out of 381 recurrent patients, 106 (27.8%) were re-challenged with a taxane-based treatment as first- or later-line therapy for recurrent disease. Results: Taxanes were used as first-line therapy in 74 patients and showed a response rate of 48.6% (including complete responses in 27.0%). The response rate was dependent on the disease-free interval (<1 year: 34.8%; 1-2 years: 42.9%; >2 years: 63.3%; p = 0.04) and visceral metastasis (present: 62.5%; not present 32.4%; p = 0.01). Patients without visceral metastasis and with a disease-free interval of >2 years achieved the longest overall survival. Hormone and HER2 receptor status were not predictive; however, triple-negative tumors responded in 50.0%. The overall response rate of later-line taxane-based treatment was 28.2%. Conclusion: Re-challenging taxanes appears to be effective and therefore represents a reasonable option in this population.

Effect of neoadjuvant anthracycline-taxane-based chemotherapy in different biological breast cancer phenotypes: overall results from the GeparTrio study.

In order to explore the effect of neoadjuvant chemotherapy (NACT) on clinical mid-course and pathological complete response (pCR) at surgery in different biological breast cancer subtypes. The GeparTrio study included 2,072 patients with operable or locally advanced breast cancer. After two cycles with docetaxel, doxorubicin and cyclophosphamide (TAC) patients were randomized according to their clinical response. Clinical and biological factors were assessed for predicting clinically mid-course response and pCR at surgery. The overall pCR rate, defined as no invasive residuals in breast and axilla, was 20.5%. The highest pCR rate of 57% was observed in patients below 40 years of age with triple negative or grade 3 tumors. Independent factors for mid-course response and pCR were: young age, non-T4 tumors, high grade, and hormone receptor status, the strongest single predictive factor. Within the biological subtypes, grading was an independent factor to predict pCR for luminal tumors, clinical tumor stage for the HER2 like tumors and age for the triple negative ones. Grading gave independent information for mid-course response within the triple negative group. No factor predicted mid-course response within the other groups. Grading and age can identify subgroups within the luminal and triple negative patients who have an increased benefit from NACT.

Monitoring serum HER2 levels during neoadjuvant trastuzumab treatment within the GeparQuattro trial.

In the context of neoadjuvant therapy (NT) for breast cancer patients, different targeted therapy approaches are currently evaluated in clinical trials. Serum markers could help to monitor and optimize such treatment strategies. We investigated human epidermal growth factor receptor 2 serum (sHER2) levels in 175 breast cancer patients participating in the GeparQuattro trial. This study incorporated NT approaches and additional trastuzumab treatment for all patients with HER2-positive tumors. Human epidermal growth factor receptor 2 serum levels were measured by enzyme-linked immunosorbent assay (ELISA) before initiation of NT and after NT (pre-surgery) in a HER2-positive (n = 90) and a HER2-negative patient cohort (n = 85). Median pre-chemotherapy sHER2 levels were higher in patients with positive HER2 status of the primary tumor than in patients with negative HER2 status (14.9 ng/ml vs. 7.7 ng/ml, P < 0.001). A pre-chemotherapy sHER2 cut-off level of 10 ng/ml had the best sensitivity and specificity in discriminating between HER2-positive and HER2-negative primary tumors. In HER2-positive patients, we found a significant positive association between pathological complete remission (pCR) and elevated sHER2 levels (above 15 ng/ml, P = 0.045) and a decrease of sHER2 levels during NT (P = 0.02), which was also significant in multivariate analysis (OR = 3.29, 95% CI 1.001-10.89, P = 0.049). In HER2-negative patients, we observed no association between sHER2 levels and pCR (P > 0.05). Monitoring sHER2 levels in the presence of anti-HER2 treatment might be an adjunct to the clinical evaluation during NT.

Baseline characteristics and prevalence of HPV 6, 11, 16, 18 in young German women participating in phase III clinical trials of a quadrivalent HPV (6/11/16/18) vaccine.

INTRODUCTION: As limited data among German women exist about HPV, Chlamydia trachomatis (CT) and Neisseria gonorrhoeae, we report the prevalence of these genital infections and general baseline demographics of the young German women enrolled in the phase III trials of the quadrivalent HPV vaccine. MATERIALS AND METHODS: German females (n = 437; 9-23 years) were recruited among 3 international phase 3 studies of an HPV-6/11/16/18 vaccine. We present baseline characteristics, prevalence of HPV-6/11/16/18 and, for women aged 16-23, abnormal cervical cytology and sexually transmitted diseases. RESULTS: Chlamydia trachomatis and Neisseria gonorrhoeae prevalence was 5 and 0.3%, respectively. Approximately 17% of participants had HPV-6, 11, 16, or 18 DNA or antibodies. All subjects <17 years were naïve to the four vaccine types. DISCUSSION: The results of the vaccine trials have demonstrated that it is worth administering prophylactic HPV vaccines before sexual debut; however, none of these sexually active German women were positive to all four types and most were positive to only one type. Thus, all women had the potential to benefit from vaccination with a quadrivalent HPV vaccine.

Options and limits of surgery after pre-operative chemotherapy in breast cancer.

The primary administration of chemotherapy leads to a reduction in size of tumors, increasing the possibility of breast-conserving surgery in both locally advanced, inoperable and primary operable mamma carcinomas. This, however, increases the rate of local relapse and the rate of mastectomy over the course of the disease, even although the EUSOMA guidelines are not exceeded. Whether the pre-surgical administration of chemotherapy with pathological complete remission actually increases the disease-free rate and overall survival remains to be determined. Further clinical studies are required to establish the reliability of sentinel lymph-node biopsy; currently, axillary lymphadenectomy is still the standard therapy. The response of the tumor to therapy, in correlation with predictive factors and the molecular-genetic profile, could make more individualized treatment regimes possible in the future.

Postoperative therapy modalities for cervical carcinoma.

Currently, the standard therapy for cervical carcinoma of FIGO stage IIB following adequate radical surgery is simultaneous radiochemotherapy with a platinous chemotherapeutic agent. According to the current state of scientific knowledge, all patients of FIGO stages IIA-IB with at least one additional risk factor (adenocarcinoma, pN1, L1, V1, pT1b2) also benefit from adjuvant radiochemotherapy. Various studies have shown that it is possible to successfully carry out a platinous radiochemotherapy. However, one disadvantage is that a number of patients have to break off therapy because of treatment-related toxicities. It has also been proven that a low hemoglobin level during radiochemotherapy is a negative prognostic factor for overall survival. The data regarding a possible survival advantage following an increase in the hemoglobin content in the blood of cancer patients by erythropoietin administration is still contradictory. As a result, the administration of new cytostatics, platinous combination chemotherapies, sequential instead of simultaneous regimens and appropriate supportive therapies have to be taken into account. Several studies are currently being conducted into the effectiveness of such new therapies on both life expectancy and quality of life (e.g., Cervix-NOGGO-AGO-Uterus 7-study).

Subareolar injection of technetium-99m nanocolloid yields reliable data on the axillary lymph node tumour status in breast cancer patients with previous manipulations on the primary tumour: a prospective study of 117 patients.

According to recently published guidelines, histological clarification by interventional techniques should be undertaken before planning the surgical management of patients with breast carcinoma. In patients with previous manipulations on the primary tumour, peritumoural injection in the context of preoperative scintigraphic detection of the sentinel lymph nodes is not possible. The aim of this prospective study was to clarify whether subareolar injection of nanocolloid can yield reliable data on the axillary lymph node tumour status in breast cancer patients with previous manipulations on the primary tumour. To date, 117 women (age 31-80 years) with breast carcinoma have been enrolled. All of these patients had undergone a biopsy (n=88) or surgery on the primary tumour (n=29) and were without clinical suspicion of lymph node metastases. Subareolar injection of 40 MBq technetium-99m nanocolloid was carried out in at least eight deposits around the areolar margin [one deposit in the middle of each quadrant and one deposit at each quadrant intersection (0.05 ml/deposit)]. Immediately after injection, dynamic and static lymphoscintigraphy of the axillary, thoracic and cervical areas was performed in various views with a gamma camera (LEAP collimator, 256x256 matrix). Lymphatic drainage was directed exclusively to the ipsilateral axilla. Sentinel lymph node biopsy and elective dissection of axillary lymph nodes were performed in all patients. All lymph nodes removed were examined by histology and immunohistochemistry. In 26 patients, lymph node metastases were found in the sentinel lymph nodes. In six of them, non-sentinel lymph nodes also showed tumour involvement. In the remaining 91 patients, lymph node metastases could be found neither in sentinel lymph nodes nor in non-sentinel lymph nodes. In conclusion, subareolar nanocolloid injection can yield reliable information on the axillary lymph node tumour status in patients with previous manipulations on the primary tumour in the breast.