Spatial predictors of immunotherapy response in triple-negative breast cancer.

Immune checkpoint blockade (ICB) benefits some patients with triple-negative breast cancer, but what distinguishes responders from non-responders is unclear1. Because ICB targets cell-cell interactions2, we investigated the impact of multicellular spatial organization on response, and explored how ICB remodels the tumour microenvironment. We show that cell phenotype, activation state and spatial location are intimately linked, influence ICB effect and differ in sensitive versus resistant tumours early on-treatment. We used imaging mass cytometry3 to profile the in situ expression of 43 proteins in tumours from patients in a randomized trial of neoadjuvant ICB, sampled at three timepoints (baseline, n = 243; early on-treatment, n = 207; post-treatment, n = 210). Multivariate modelling showed that the fractions of proliferating CD8+TCF1+T cells and MHCII+ cancer cells were dominant predictors of response, followed by cancer-immune interactions with B cells and granzyme B+ T cells. On-treatment, responsive tumours contained abundant granzyme B+ T cells, whereas resistant tumours were characterized by CD15+ cancer cells. Response was best predicted by combining tissue features before and on-treatment, pointing to a role for early biopsies in guiding adaptive therapy. Our findings show that multicellular spatial organization is a major determinant of ICB effect and suggest that its systematic enumeration in situ could help realize precision immuno-oncology.

Ten-year survival of neoadjuvant dual HER2 blockade in patients with HER2-positive breast cancer.

BACKGROUND: Dual anti-HER2-targeted therapy in breast cancer (BC) significantly increased the rate of pathological complete response (pCR) compared to single blockade when added to chemotherapy. However, limited data exist on the long-term impact on survival of the additional increase in pCR. METHODS: Neoadjuvant lapatinib and/or trastuzumab treatment optimisation (NCT00553358) is an international, randomised, open-label, phase III study investigating the addition of lapatinib to chemotherapy plus trastuzumab in HER2-positive early BC. Ten-year event-free survival (EFS), overall survival (OS) and safety were assessed on intention-to-treat population. The association between pCR and EFS or OS was investigated in landmark population. RESULTS: A total of 455 patients were randomised to receive lapatinib (154), trastuzumab (149) or the combination (152). Ten-year EFS estimates were 63% (95% confidence interval [CI], 54%-71%) in the lapatinib group, 64% (95% CI, 55%-72%) in the trastuzumab group and 67% (95% CI, 58%-74%) in the combination group. Ten-year OS rates were 76% (95% CI, 67%-83%), 75% (95% CI, 66%-82%) and 80% (95% CI, 73%-86%) in the lapatinib, trastuzumab and combination groups, respectively. Women who achieved a pCR had improved EFS (hazard ratio 0.48, 95% CI, 0.31-0.73) and OS (hazard ratio 0.37, 95% CI, 0.20-0.63) compared with those who did not. The numerical difference in survival according to pCR status was greater in women treated with the combination and those with hormone-receptor-negative tumours. There were no new or long-term safety concerns. CONCLUSIONS: Patients with HER2-positive BC showed a durable survival benefit of neoadjuvant anti-HER2, irrespective of treatment arm. Patients who achieve pCR have significantly better outcomes than patients without pCR.

The Senologic International Society Survey on Ductal Carcinoma In Situ: Present and Future.

Objective: Therapeutic management of ductal carcinoma in situ (DCIS) is heterogeneous among countries worldwide, and some treatment indications are still controversial. To investigate DCIS management in different countries; identify both consensual practices and controversial topics; and survey opinions about the future management of DCIS. Materials and Methods: The Senologic International Society network members participated to an online survey using a questionnaire, between November 2021 and February 2022. Results: Twenty-two responses from 20 different countries showed that organized breast cancer screening programs were present for 87% participants, and DCIS cases represented 13.7% of all breast cancers. Most participants used the grade classification (100%), the morphological classification (78%) and performed immunohistochemistry assays (73%). In case of conservative treatment, the mean re-excision rate was 10.3% and clear margins of mean 2.5 mm were considered healthy. Radical mastectomy rate was 35.5% with a breast reconstruction rate of 53%. Tumor bed boost indications were heterogeneous, and 73% of participants indicated hormone therapy for hormone-positive DCIS. Surgery and radiotherapy omission for some low-risk DCIS were considered by 73% of participants. Multigene assays were used by 43% of participants. Concerning future changes in DCIS management, participants mostly answered surgical de-escalation (48%), radiotherapy de-escalation (35) and/or active surveillance for some cases (22%). Conclusion: This survey provided an overview of the current practices of DCIS management worldwide. It showed that some areas are rather consensual: incidence increases over time, treatment in young women, pathological classifications, definition of healthy margins, the skin-sparing mastectomy and immediate breast reconstruction. However, some topics are still debated and result in heterogeneous practices, such as evolution in the age of diagnosis, the benefit of de-escalation in low-risk DCIS among elderly women, indications for hormone therapy, radiotherapy omission, or multigene assays. Further evidence is needed to reach consensus on these points, and innovative approaches are still under evaluation in clinical trials. The International Senologic Society, by its members, encourages precision medicine and personalized treatments for DCIS, to avoid overtreatment and overdiagnosis, and provide better healthcare to women with DCIS.

Immunology and immunotherapy in breast cancer.

Immuno-oncology is a rapidly developing field in medicine. Drug combination therapies have already been studied in many clinical trials on various tumor types. In recent years, a checkpoint inhibition therapy with monoclonal antibodies targeting PD-1 and its ligand PD-L1 has been developed. Breast cancer had been examined in the field of immune-oncology relatively recently. This review focuses on clinical evidence regarding immune checkpoint inhibition for curative treatment of various breast cancer subtypes. In addition, we present the results of studies demonstrating the prognostic and predictive value of levels of tumorinfiltrating lymphocytes (CD4 and CD8), their quantitative ratios, and their correlation with regulatory genes (PD-1, PD-L1, and FOX-P3).

The TRAR gene classifier to predict response to neoadjuvant therapy in HER2-positive and ER-positive breast cancer patients: an explorative analysis from the NeoSphere trial.

As most erb-b2 receptor tyrosine kinase 2 (HER2)-positive breast cancer (BC) patients currently receive dual HER2-targeting added to neoadjuvant chemotherapy, improved methods for identifying individual response, and assisting postsurgical salvage therapy, are needed. Herein, we evaluated the 41-gene classifier trastuzumab advantage risk model (TRAR) as a predictive marker for patients enrolled in the NeoSphere trial. TRAR scores were computed from RNA of 350 pre- and 166 post-treatment tumor specimens. Overall, TRAR score was significantly associated with pathological complete response (pCR) rate independently of other predictive clinico-pathological variables. Separate analyses according to estrogen receptor (ER) status showed a significant association between TRAR score and pCR in ER-positive specimens but not in ER-negative counterparts. Among ER-positive BC patients not achieving a pCR, those with TRAR-low scores in surgical specimens showed a trend for lower distant event-free survival. In conclusion, in HER2-positive/ER-positive BC, TRAR is an independent predictor of pCR and represents a promising tool to select patients responsive to anti-HER2-based neoadjuvant therapy and to assist treatment escalation and de-escalation strategies in this setting.

Copy Number Aberration Analysis to Predict Response to Neoadjuvant Anti-HER2 Therapy: Results from the NeoALTTO Phase III Clinical Trial.

PURPOSE: The heterogeneity of response to anti-HER2 agents represents a major challenge in patients with HER2-positive breast cancer. To better understand the sensitivity and resistance to trastuzumab and lapatinib, we investigated the role of copy number aberrations (CNA) in predicting pathologic complete response (pCR) and survival outcomes in the NeoALTTO trial. EXPERIMENTAL DESIGN: The neoadjuvant phase III NeoALTTO trial enrolled 455 patients with HER2-positive early-stage breast cancer. DNA samples from 269 patients were assessed for genome-wide copy number profiling. Recurrent CNAs were found with GISTIC2.0. RESULTS: CNA estimates were obtained for 184 patients included in NeoALTTO. Among those, matched transcriptome and whole-exome data were available for 154 and 181 patients, respectively. A significant association between gene copy number and pCR was demonstrated for ERBB2 amplification. Nevertheless, ERBB2 amplification ceased to be predictive once ERBB2 expression level was considered. GISTIC2.0 analysis revealed 159 recurrent CNA regions. Lower copy number levels of the 6q23-24 locus predicted absence of pCR in the whole cohort and in the estrogen receptor-positive subgroup. 6q23-24 deletion was significantly more frequent in TP53 wild-type (WT) compared with TP53-mutated, resulting in copy number levels significantly associated with lack of pCR only in the TP53 WT subgroup. Interestingly, a gene-ontology analysis highlighted several immune processes correlated to 6q23-24 copy number. CONCLUSIONS: Our analysis identified ERBB2 copy number as well as 6q23-24 CNAs as predictors of response to anti-HER2-based treatment. ERBB2 expression outperformed ERBB2 amplification. The complexity of the 6q23-24 region warrants further investigation.

TiLoop Bra Assisted Breast Reconstruction - Our Experience.

Additional covering of the lower pole with allomaterial or its synthetic analogues during immediate breast reconstruction is being perfomed at the N.N. Petrov National Medical Research Oncology Center, Ministry of Healthcare of Russian Federation for last 7 years. Initially, epidermal flap was the only option for lower pole coverage, later ADM was used as part of clinical approbation. Average complication rate ranges from 20-35% due to blood circulatory (supply) disorders. Since 2018, a titanized mesh (TiLoop Bra) been used as a additional coverage of the lower pole. Methods: From July 2018 to April 2019, 103 breast reconstructions were performed using TiLoop-BRA mesh. All operations were performed due to malignant tumors of breast, of which in 94 operations were performed for unilateral breast carcinoma, 9 for bilateral breast carcinoma.74 patients received neoadjuvant therapy, 31 received adjuvant therapy, 17 patients required radiation therapy. Results: Overall complications rates significally decreased. Complete loss of breast implant and mesh endoprosthesis 5.88%, Capsular contracture 17.65 %, Only mesh removal due to painful syndrome 5.88%,* Red breast * syndrome (by analogy with ADM) 5.88%.

Derived Neutrophil-to-Lymphocyte Ratio Predicts Pathological Complete Response to Neoadjuvant Chemotherapy in Breast Cancer.

BACKGROUND: Derived neutrophil-to-lymphocyte ratio (dNLR) is a biomarker associated with clinical outcome in breast cancer (BC). We analyzed the association of dNLR with pathological complete response (pCR) in triple-negative BC (TNBC) patients receiving neoadjuvant chemotherapy (CT). METHODS: This is a retrospective analysis of two randomized studies involving early stage/locally advanced TNBC patients receiving anthracycline/taxane-based CT+/-carboplatin (GEICAM/2006-03) or nab-paclitaxel/paclitaxel followed by anthracycline regimen (ETNA). dNLR was calculated as the ratio of neutrophils to the difference between total leukocytes and neutrophils in peripheral blood before CT (baseline) and at the end of treatment (EOT). Logistic regression analyses were used to explore dNLR association with pCR. RESULTS: In total, 308 TNBC patients were analyzed, 216 from ETNA and 92 from GEICAM/2006-03. Baseline median dNLR was 1.61 (interquartile range (IQR): 1.25-2.04) and at EOT 1.53 (IQR: 0.96-2.22). Baseline dNLR showed positive correlation with increased tumor size (p-value = 1e-04). High baseline dNLR, as continuous variable or using median cutoff, was associated with lower likelihood of pCR in univariate analysis. High EOT dNLR as continuous variable or using quartiles was also associated with lower pCR rate in uni- and multivariate analyses. CONCLUSIONS: High baseline and EOT dNLR correlates with lower benefit from neoadjuvant CT in TNBC.

Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study.

BACKGROUND: CLEOPATRA was a phase 3 study comparing the efficacy and safety of pertuzumab, trastuzumab, and docetaxel with placebo, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer. In the primary analysis and subsequent reports, progression-free and overall survival were significantly improved in the pertuzumab group compared with the placebo group. Here, we report the end-of-study analysis of CLEOPATRA. METHODS: This was a double-blind, randomised, placebo-controlled, phase 3 trial that was done at 204 centres in 25 countries. Eligible patients were 18 years or older, had HER2-positive, metastatic breast cancer, had not received previous chemotherapy or biological treatment for their metastatic disease, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. All study drugs were given intravenously, every 3 weeks. Patients were assigned to receive either pertuzumab or placebo at a loading dose of 840 mg, and 420 mg thereafter; plus trastuzumab at 8 mg/kg loading dose and 6 mg/kg thereafter; and docetaxel at 75 mg/m2, escalating to 100 mg/m2 if tolerated. Pertuzumab or placebo and trastuzumab were given until disease progression; docetaxel was given for six cycles, or longer at the investigators' discretion. Randomisation (1:1) was done by use of an interactive voice-response system and was stratified by geographical region (Asia, Europe, North America, or South America) and previous treatment (previous adjuvant or neoadjuvant chemotherapy vs none). The primary endpoint was independent review facility-assessed progression-free survival, which has been reported previously. Since the confirmatory overall survival analysis had also occurred before this prespecified end-of-study analysis, analyses presented here are descriptive. Overall survival analyses were based on the intention-to-treat population with crossover patients analysed in the placebo group; analyses were not adjusted for crossover to the pertuzumab group and are likely to be conservative. Safety analyses were based on treatment received; crossover patients were counted in the placebo group up to the day before first pertuzumab dose. This trial is registered with ClinicalTrials.gov, number NCT00567190. FINDINGS: Between Feb 12, 2008, and July 7, 2010, 1196 patients were assessed for eligibility, of whom 808 were enrolled and randomly assigned. 402 patients were assigned to receive docetaxel plus trastuzumab plus pertuzumab, and 406 patients were assigned to receive docetaxel plus trastuzumab plus placebo. Clinical cutoff for this analysis was Nov 23, 2018. Between July 2012 and clinical cutoff, 50 patients crossed from the placebo to the pertuzumab group. Median follow-up was 99·9 months in the pertuzumab group (IQR 92·9-106·4) and 98·7 months (90·9-105·7) in the placebo group. Median overall survival was 57·1 months (95% CI 50-72) in the pertuzumab group and 40·8 months (36-48) in the placebo group (hazard ratio 0·69, 95% CI 0·58-0·82); 8-year landmark overall survival rates were 37% (95% CI 31-42) in the pertuzumab group and 23% (19-28) in the placebo group. The most common grade 3-4 adverse event was neutropenia (200 [49%] of 408 patients in the pertuzumab group, 183 [46%] of 396 patients in the placebo group). Five (1%) of 408 patients in the pertuzumab group and six (2%) of 396 patients in the placebo group had treatment-related deaths. One new serious adverse event suggestive of congestive heart failure (pertuzumab group) and one new symptomatic left ventricular systolic dysfunction (post-crossover) occurred since the previous analysis. INTERPRETATION: Our analysis shows that the previously observed improvements in overall survival with pertuzumab, trastuzumab, and docetaxel versus placebo, trastuzumab, and docetaxel were maintained after a median of more than 8 years of follow-up. The long-term safety and cardiac safety profiles of pertuzumab, trastuzumab, and docetaxel were maintained in the overall safety population and within crossover patients. HER2-targeted therapy has changed the natural history of HER2-positive metastatic breast cancer, with the dual blockade of pertuzumab and trastuzumab, with docetaxel, demonstrating an 8-year landmark overall survival rate of 37%. FUNDING: F Hoffmann-La Roche and Genentech.

A phase 1b/2, open-label, dose-escalation, and dose-confirmation study of eribulin mesilate in combination with capecitabine.

BACKGROUND: Capecitabine and eribulin are widely used as single agents in metastatic breast cancer (MBC) and have nonoverlapping toxicities. METHODS: In phase 1b (dose escalation), patients with advanced, treatment-refractory, solid tumours received eribulin mesilate intravenously in 21-day cycles according to schedule 1 (day 1) or schedule 2 (days 1, 8) with twice-daily oral capecitabine (1000 mg/m2 days 1-14). In phase 2 (dose confirmation), women with advanced/MBC and ≤3 prior chemotherapies received eribulin mesilate at the maximum tolerated dose (MTD) per the preferred schedule plus capecitabine. Primary objectives were MTD and dose-limiting toxicities (DLTs; phase 1b) and objective response rate (ORR; phase 2). Secondary objectives included progression-free survival (PFS), safety, and pharmacokinetics. RESULTS: DLTs occurred in 4/19 patients (schedule 1) and 2/15 patients (schedule 2). Eribulin pharmacokinetics were dose proportional, irrespective of schedule or capecitabine coadministration. The MTD of eribulin was 1.6 mg/m2 day 1 for schedule 1 and 1.4 mg/m2 days 1 and 8 for schedule 2. ORR in phase 2 (eribulin 1.4 mg/m2 days 1, 8 plus capecitabine) was 43% and median PFS 7.2 months. The most common treatment-related adverse events were neutropenia, leukopenia, alopecia, nausea, and lethargy. CONCLUSIONS: The combination of capecitabine and eribulin showed promising efficacy with manageable tolerability in patients with MBC.

Phase III, Randomized, Double-Blind Study Comparing the Efficacy, Safety, and Immunogenicity of SB3 (Trastuzumab Biosimilar) and Reference Trastuzumab in Patients Treated With Neoadjuvant Therapy for Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer.

Purpose This phase III study compared SB3, a trastuzumab (TRZ) biosimilar, with reference TRZ in patients with human epidermal growth factor receptor 2-positive early breast cancer in the neoadjuvant setting ( ClinicalTrials.gov identifier: NCT02149524). Patients and Methods Patients were randomly assigned to receive neoadjuvant SB3 or TRZ for eight cycles concurrently with chemotherapy (four cycles of docetaxel followed by four cycles of fluorouracil, epirubicin, and cyclophosphamide) followed by surgery, and then 10 cycles of adjuvant SB3 or TRZ. The primary objective was comparison of breast pathologic complete response (bpCR) rate in the per-protocol set; equivalence was declared if the 95% CI of the ratio was within 0.785 to 1.546 or the 95% CI of the difference was within ± 13%. Secondary end points included comparisons of total pathologic complete response rate, overall response rate, event-free survival, overall survival, safety, pharmacokinetics, and immunogenicity. Results Eight hundred patients were included in the per-protocol set (SB3, n = 402; TRZ, n = 398). The bpCR rates were 51.7% and 42.0% with SB3 and TRZ, respectively. The adjusted ratio of bpCR was 1.259 (95% CI, 1.085 to 1.460), which was within the predefined equivalence margins. The adjusted difference was 10.70% (95% CI, 4.13% to 17.26%), with the lower limit contained within and the upper limit outside the equivalence margin. The total pathologic complete response rates were 45.8% and 35.8% and the overall response rates were 96.3% and 91.2% with SB3 and TRZ, respectively. Overall, 96.6% and 95.2% of patients experienced one or more adverse event, 10.5% and 10.7% had a serious adverse event, and 0.7% and 0.0% had antidrug antibodies (up to cycle 9) with SB3 and TRZ, respectively. Conclusion Equivalence for efficacy was demonstrated between SB3 and TRZ on the basis of the ratio of bpCR rates. Safety and immunogenicity were comparable.

Comparing Neoadjuvant Nab-paclitaxel vs Paclitaxel Both Followed by Anthracycline Regimens in Women With ERBB2/HER2-Negative Breast Cancer-The Evaluating Treatment With Neoadjuvant Abraxane (ETNA) Trial: A Randomized Phase 3 Clinical Trial.

IMPORTANCE: Studies of neoadjuvant chemotherapy regimens using anthracyclines followed by taxanes have reported a doubling of pathological complete remission (pCR) rates compared with anthracycline-based regimens alone. A reverse sequence did not reduce activity. Nab-paclitaxel is an albumin-bound nanoparticle of paclitaxel that allows for safe infusion without premedication, and its use led to a significantly higher rate of pCR in the GeparSepto trial. OBJECTIVE: To determine whether nab-paclitaxel improves the outcomes of early and locally advanced human epidermal growth factor receptor 2 (ERBB2/HER2)-negative breast cancer compared with paclitaxel when delivered in a neoadjuvant setting. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter, open-label study, in collaboration with Grupo Español de Investigación en Cáncer de Mama (GEICAM) and Breast Cancer Research Center-Western Australia (BCRC-WA), patients with newly diagnosed and centrally confirmed ERBB2/HER2-negative breast cancer were recruited. Participants were randomly allocated to paclitaxel, 90 mg/m2 (349 patients), or nab-paclitaxel, 125 mg/m2 (346 patients). The 2 drugs were given on weeks 1, 2, and 3 followed by 1 week of rest for 4 cycles before 4 cycles of an anthracycline regimen per investigator choice. MAIN OUTCOMES AND MEASURES: The primary end point was the rate of pCR, defined as absence of invasive cells in the breast and axillary nodes (ie, ypT0/is ypN0) at the time of surgery. A secondary end point was to assess tolerability and safety of the 2 regimens. RESULTS: From May 2013 to March 2015, 814 patients were registered to the study; 695 patients met central confirmation eligibility and were randomly allocated to receive either paclitaxel (349), or nab-paclitaxel (346) (median age, 50 years; range, 25-79 years). The intention-to-treat analysis of the primary end point pCR revealed that the improved pCR rate after nab-paclitaxel (22.5%) was not statistically significant compared with paclitaxel (18.6%; odds ratio [OR], 0.77; 95% CI, 0.52-1.13; P = .19). Overall, 38 of 335 patients (11.3%) 11.3% of patients had at least 1 serious adverse event in the paclitaxel arm and 54 of 337 patient (16.0%) in the nab-paclitaxel arm. Peripheral neuropathy of grade 3 or higher occurred in 6 of 335 patients (1.8%) and in 15 of 337 (4.5%), respectively. CONCLUSIONS AND RELEVANCE: The improved rate of pCR after nab-paclitaxel was not statistically significant. The multivariate analysis revealed that tumor subtype (triple-negative vs luminal B-like) was the most significant factor (OR, 4.85; 95% CI, 3.28-7.18) influencing treatment outcome. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01822314.

5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial.

BACKGROUND: In the primary analysis of the NeoSphere trial, patients given neoadjuvant pertuzumab, trastuzumab, and docetaxel showed a significantly improved pathological complete response compared with those given trastuzumab and docetaxel after surgery. Here, we report 5-year progression-free survival, disease-free survival, and safety. METHODS: In this multicentre, open-label, phase 2 randomised trial in hospitals and medical clinics, treatment-naive adults with locally advanced, inflammatory, or early-stage HER2-positive breast cancer were randomly assigned (1:1:1:1) to receive four neoadjuvant cycles of trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m(2) every 3 weeks, increasing to 100 mg/m(2) from cycle 2 if tolerated; group A), pertuzumab (840 mg loading dose, followed by 420 mg every 3 weeks) and trastuzumab plus docetaxel (group B), pertuzumab and trastuzumab (group C), or pertuzumab and docetaxel (group D). After surgery, patients received three cycles of FEC (fluorouracil 600 mg/m(2), epirubicin 90 mg/m(2), and cyclophosphamide 600 mg/m(2)) every 3 weeks (patients in group C received four cycles of docetaxel prior to FEC), and trastuzumab 6 mg/kg every 3 weeks to complete 1 year's treatment (17 cycles in total). Randomisation was done by a central centre using dynamic allocation, stratified by operable, locally advanced, and inflammatory breast cancer, and by oestrogen and/or progesterone receptor positivity. Safety analyses were done according to treatment received. The primary endpoint (pathological complete response) was previously reported; secondary endpoints reported here are 5-year progression-free survival (analysed in the intention-to-treat population) and disease-free survival (analysed in patients who had surgery). Secondary and exploratory analyses were not powered for formal statistical hypothesis testing, and therefore results are for descriptive purposes only. The study ended on Sept 22, 2014 (last patient, last visit). This study is registered with ClinicalTrials.gov, number NCT00545688. FINDINGS: Between Dec 17, 2007, and Dec 22, 2009, 417 eligible patients were randomly assigned to group A (107 patients), group B (107 patients), group C (107 patients), or group D (96 patients). One patient in group A withdrew before treatment. One patient assigned to group D received group A treatment, one patient assigned to group D received group B treatment, and one patient assigned to group B received group C treatment. At clinical cutoff, 87 patients had progressed or died. 5-year progression-free survival rates were 81% (95% CI 71-87) for group A, 86% (77-91) for group B, 73% (64-81) for group C, and 73% (63-81) for group D (hazard ratios 0·69 [95% CI 0·34-1·40] group B vs group A, 1·25 [0·68-2·30] group C vs group A, and 2·05 [1·07-3·93] group D vs group B). Disease-free survival results were consistent with progression-free survival results and were 81% (95% CI 72-88) for group A, 84% (72-91) for group B, 80% (70-86) for group C, and 75% (64-83) for group D. Patients who achieved total pathological complete response (all groups combined) had longer progression-free survival compared with patients who did not (85% [76-91] in patients who achieved total pathological response vs 76% [71-81] in patients who did not achieve total pathological response; hazard ratio 0·54 [95% CI 0·29-1·00]). There were no new or long-term safety concerns and tolerability was similar across groups (neoadjuvant and adjuvant treatment periods combined). The most common grade 3 or worse adverse events were neutropenia (group A: 71 [66%] of 107 patients; group B: 59 [55%] of 107; group C: 40 [37%] of 108; group D: 60 [64%] of 94), febrile neutropenia (group A: 10 [9%]; group B: 12 [11%]; group C: 5 [5%]; group D: 15 [16%]), and leucopenia (group A: 13 [12%]; group B: 6 [6%]; group C: 4 [4%]; group D: 8 [9%]). The number of patients with one or more serious adverse event was similar across groups (19-22 serious adverse events per group in 18-22% of patients). INTERPRETATION: Progression-free survival and disease-free survival at 5-year follow-up show large and overlapping CIs, but support the primary endpoint (pathological complete response) and suggest that neoadjuvant pertuzumab is beneficial when combined with trastuzumab and docetaxel. Additionally, they suggest that total pathological complete response could be an early indicator of long-term outcome in early-stage HER2-positive breast cancer. FUNDING: F Hoffmann-La Roche.

RECIST for Response (Clinical and Imaging) in Neoadjuvant Clinical Trials in Operable Breast Cancer.

Although approximately 70% of breast cancer patients demonstrate a clinical response on neoadjuvant systemic therapy on physical examination or on anatomic radiographic imaging, only 3%-40% achieve a pathologic complete response (pCR). Magnetic resonance imaging (MRI) is superior to physical examination, ultrasound, and mammography in response evaluation during neoadjuvant systemic therapy. The accuracy of breast MRI to predict pCR has a moderate sensitivity, but high specificity. The accuracy of anatomic imaging to assess residual disease and predict pCR depended on anatomic radiographic imaging cancer subtypes. Response monitoring using breast is accurate in triple-negative or HER2-positive tumors. It was inaccurate in estrogen receptor-positive/HER2-negative subtype. Another approach currently under investigation is dynamic contrast-enhanced MRI and diffusion weighted-imaging, (18)F-fluorodeoxyglucose positron emission tomography, fluorodeoxyglucose positron emission tomography/computed tomography.

International Expert Consensus on Primary Systemic Therapy in the Management of Early Breast Cancer: Highlights of the Fifth Symposium on Primary Systemic Therapy in the Management of Operable Breast Cancer, Cremona, Italy (2013).

Expert consensus-based recommendations regarding key issues in the use of primary (or neoadjuvant) systemic treatment (PST) in patients with early breast cancer are a valuable resource for practising oncologists. PST remains a valuable therapeutic approach for the assessment of biological antitumor activity and clinical efficacy of new treatments in clinical trials. Neoadjuvant trials provide endpoints, such as pathological complete response (pCR) to treatment, that potentially translate into meaningful improvements in overall survival and disease-free survival. Neoadjuvant trials need fewer patients and are less expensive than adjuvant trial, and the endpoint of pCR is achieved in months, rather than years. For these reasons, the neoadjuvant setting is ideal for testing emerging targeted therapies in early breast cancer. Although pCR is an early clinical endpoint, its role as a surrogate for long-term outcomes is the key issue. New and better predictors of treatment efficacy are needed to improve treatment and outcomes. After PST, accurate management of post-treatment residual disease is mandatory. The surgery of the sentinel lymph-node could be an acceptable option to spare the axillary dissection in case of clinical negativity (N0) of the axilla at the diagnosis and/or after PST. No data exists yet to support the modulation of the extent of locoregional radiation therapy on the basis of the response attained after PST although trials are underway.

Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer.

BACKGROUND: In patients with metastatic breast cancer that is positive for human epidermal growth factor receptor 2 (HER2), progression-free survival was significantly improved after first-line therapy with pertuzumab, trastuzumab, and docetaxel, as compared with placebo, trastuzumab, and docetaxel. Overall survival was significantly improved with pertuzumab in an interim analysis without the median being reached. We report final prespecified overall survival results with a median follow-up of 50 months. METHODS: We randomly assigned patients with metastatic breast cancer who had not received previous chemotherapy or anti-HER2 therapy for their metastatic disease to receive the pertuzumab combination or the placebo combination. The secondary end points of overall survival, investigator-assessed progression-free survival, independently assessed duration of response, and safety are reported. Sensitivity analyses were adjusted for patients who crossed over from placebo to pertuzumab after the interim analysis. RESULTS: The median overall survival was 56.5 months (95% confidence interval [CI], 49.3 to not reached) in the group receiving the pertuzumab combination, as compared with 40.8 months (95% CI, 35.8 to 48.3) in the group receiving the placebo combination (hazard ratio favoring the pertuzumab group, 0.68; 95% CI, 0.56 to 0.84; P<0.001), a difference of 15.7 months. This analysis was not adjusted for crossover to the pertuzumab group and is therefore conservative. Results of sensitivity analyses after adjustment for crossover were consistent. Median progression-free survival as assessed by investigators improved by 6.3 months in the pertuzumab group (hazard ratio, 0.68; 95% CI, 0.58 to 0.80). Pertuzumab extended the median duration of response by 7.7 months, as independently assessed. Most adverse events occurred during the administration of docetaxel in the two groups, with long-term cardiac safety maintained. CONCLUSIONS: In patients with HER2-positive metastatic breast cancer, the addition of pertuzumab to trastuzumab and docetaxel, as compared with the addition of placebo, significantly improved the median overall survival to 56.5 months and extended the results of previous analyses showing the efficacy of this drug combination. (Funded by F. Hoffmann-La Roche and Genentech; CLEOPATRA ClinicalTrials.gov number, NCT00567190.).

CEREBEL (EGF111438): A Phase III, Randomized, Open-Label Study of Lapatinib Plus Capecitabine Versus Trastuzumab Plus Capecitabine in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer.

PURPOSE: CEREBEL compared the incidence of CNS metastases as first site of relapse in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer receiving lapatinib-capecitabine or trastuzumab-capecitabine. PATIENTS AND METHODS: Patients without baseline CNS metastases were randomly assigned (1:1) to receive lapatinib-capecitabine (lapatinib 1,250 mg per day; capecitabine 2,000 mg/m(2) per day on days 1 to 14 every 21 days) or trastuzumab-capecitabine (trastuzumab loading dose of 8 mg/kg followed by an infusion of 6 mg/kg every 3 weeks; capecitabine 2,500 mg/m(2) per day on days 1 to 14 every 21 days). The primary end point was incidence of CNS metastases as first site of relapse. Secondary end points included progression-free survival (PFS) and overall survival (OS). RESULTS: The study was terminated early with 540 enrolled patients (271 received lapatinib-capecitabine, and 269 received trastuzumab-capecitabine). Incidence of CNS metastases as first site of relapse was 3% (eight of 251 patients) for lapatinib-capecitabine and 5% (12 of 250 patients) for trastuzumab-capecitabine (treatment differences, -1.6%; 95% CI, -2% to 5%; P = .360). PFS and OS were longer with trastuzumab-capecitabine versus lapatinib-capecitabine (hazard ratio [HR] for PFS, 1.30; 95% CI, 1.04 to 1.64; HR for OS, 1.34; 95% CI, 0.95 to 1.64). Serious adverse events were reported in 13% (34 of 269 patients) and 17% (45 of 267 patients) of patients in the lapatinib-capecitabine and trastuzumab-capecitabine arms, respectively. CONCLUSION: CEREBEL is inconclusive for the primary end point, and no difference was detected between lapatinb-capecitabine and trastuzumab-capecitabine for the incidence of CNS metastases. A better outcome was observed with trastuzumab-capecitabine in the overall population. However, lapatinib-capecitabine efficacy may have been affected by previous exposure to a trastuzumab regimen and/or when treatment was given as first- or second-line therapy in the metastatic setting.

Primary results of ROSE/TRIO-12, a randomized placebo-controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer.

PURPOSE: Currently, antiangiogenic strategies in metastatic breast cancer have demonstrated modest improvements in progression-free survival (PFS) but not improved quality or duration of survival, warranting evaluation of new agents in a placebo-controlled setting. Ramucirumab is a human immunoglobulin G1 antibody that binds vascular endothelial growth factor receptor-2 and blocks ligand-stimulated activation. The ROSE/TRIO-012 trial evaluated ramucirumab with docetaxel in unresectable, locally recurrent, or metastatic breast cancer. PATIENTS AND METHODS: In this double-blind, placebo-controlled, randomized, multinational phase III trial, 1,144 patients with human epidermal growth factor receptor 2 (HER2) -negative breast cancer who had not received cytotoxic chemotherapy in the advanced setting were randomly assigned at a two-to-one ratio to receive docetaxel 75 mg/m(2) plus ramucirumab 10 mg/kg or docetaxel 75 mg/m(2) plus placebo once every 3 weeks. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria. Patients were stratified by previous taxane therapy, visceral metastasis, hormone receptor status, and geographic region. An independent data monitoring committee oversaw the trial. The primary end point was investigator-assessed PFS. RESULTS: Median PFS in patients treated with ramucirumab plus docetaxel was 9.5 months, compared with 8.2 months in patients who received placebo plus docetaxel (hazard ratio [HR], 0.88; P = .077). Median overall survival was 27.3 months in patients who received ramucirumab plus docetaxel, compared with 27.2 months in patients who received placebo plus docetaxel (HR, 1.01; P = .915). Toxicities seen at significantly higher rates in patients receiving ramucirumab included fatigue, hypertension, febrile neutropenia, palmar-plantar erythrodysesthesia syndrome, and stomatitis. CONCLUSION: Addition of ramucirumab to docetaxel in HER2-negative advanced breast cancer did not meaningfully improve important clinical outcomes.

Comparison of two treatment strategies for irradiation of regional lymph nodes in patients with breast cancer: Lymph flow guided portals versus standard radiation fields.

AIM AND BACKGROUND: Radiotherapy being an essential part of breast cancer treatment, we evaluate various radiotherapy strategies in patients with breast cancer. MATERIALS AND METHODS: Lymph node (LN) scintigraphy was performed in 172 primary patients with BC. LN visualization started 30-360 min after intratumoral injection of 75-150 MBq of 99mTc-nanocolloids. Our standard recommendation for postoperative radiotherapy in patients with LN invasion by BC were as follows: for patients with external localization of tumour - breast + axillary (Ax) + sub-supraclavicular (SSCL) regions; with internal localization - all above + internal mammary nodes (IM). Proposed strategy of lymph flow guided radiotherapy is based on the assumption that only regions that contain 'hot' LNs must be included in a treatment volume. RESULTS: Among 110 patients with external localization of BC, Ax LNs were visualized in all cases and in 62 patients it was the only region with 'hot' LN. Twenty-three patients (20.9%) had drainage to Ax + SSCL, 12 (10.9%) - Ax + IM, 13 (11.8%) - Ax + SSCL + IM regions. After the visualization of lymph flow patterns, standard treatment volume was changed in 87/110 cases (79.1%): in 56.4%, reduced, in 22.7%, enlarged or changed. In 62 patients with tumours in internal quadrants, we revealed the following patterns of lymph-flow: only to the Ax region in 23 (37.1%); Ax + IM, 13 (21%); Ax + SSCL, 15 (24.2%); Ax + IM + ISSCL, 11 (17.7%) cases. After lymph-flow visualization, the standard irradiation volume was reduced in 53/62 (85.5%) cases. CONCLUSION: Visualization of an individual lymph flow pattern from BC can be used for the optimization of standard fields used for irradiation of regional LNs.

Trabectedin as a single-agent treatment of advanced breast cancer after anthracycline and taxane treatment: a multicenter, randomized, phase II study comparing 2 administration regimens.

BACKGROUND: The purpose of this study was to assess the efficacy and safety of trabectedin for advanced breast cancer. PATIENTS AND METHODS: In an open-label, phase II, multicenter study, women with advanced breast cancer previously treated with ≤ 2 lines of chemotherapy for advanced disease, including both anthracyclines and taxanes, were randomized (1:1) to 3-hour infusions of trabectedin 1.3 mg/m(2) once every 3 weeks (1/3 treatment arm) or 0.58 mg/m(2) every week for 3 of 4 weeks (3/4 treatment arm). The primary end point was objective response. Secondary end points included time to progression (TTP), progression-free survival (PFS), and overall survival (OS). RESULTS: Fifty-two women (median age, 50 years; median chemotherapy agents, 4) were enrolled. Relative trabectedin dose intensities were 81% and 76% in the 1/3 and 3/4 treatment arms, respectively. Objective response rates were 12% (3 of 25) and 4% (1 of 27), respectively. Stable disease was observed in 14 (56%) and 11 (41%) patients in the 1/3 and 3/4 treatment arms, respectively, with median durations of 3.5 and 3.7 months. Median TTP and PFS were higher in the 1/3 treatment arm (3.1 months each) than in the 3/4 treatment arm (2.0 months each). At a median follow-up of 7 months in both treatment arms, median OS was not reached in the 1/3 treatment arm and was 9.4 months in the 3/4 treatment arm. The most frequent drug-related adverse events in the 1/3 and 3/4 treatment arms, respectively, were alanine aminotransferase (ALT) level increases (68% vs. 63%), nausea (56% vs. 59%), and asthenia (56% vs. 48%). Neutropenia and increases in ALT levels were the most frequent grade 3/4 events. Both types of events were usually transient and reversible. CONCLUSION: In the population studied, trabectedin showed a manageable safety profile for both regimens analyzed. There were higher objective response rates and a longer PFS in the 1/3 treatment arm compared with the 3/4 treatment arm.