GLORIA: phase III, open-label study of adagloxad simolenin/OBI-821 in patients with high-risk triple-negative breast cancer.

Triple-negative breast cancer (TNBC) has the highest rate of distant metastasis and poorest overall survival among breast cancer subtypes. In a phase II study, adagloxad simolenin (AdaSim), a synthetic Globo H conjugate vaccine administered with adjuvant OBI-821, was shown to induce IgM and IgG anti-Globo H humoral responses in patients with metastatic breast cancer overexpressing the glycosphingolipid Globo H. GLORIA is an ongoing phase III, randomized, open-label clinical trial to evaluate the safety and efficacy of AdaSim and the quality of life (QoL) of patients receiving AdaSim plus standard of care (SOC) versus SOC alone in high-risk, early-stage TNBC. The primary end point is invasive progression-free survival; secondary end points include overall survival, QoL, breast cancer-free interval, distant disease-free survival, safety, and tolerability.

Patients with triple-negative breast cancer generally do very poorly with the current available therapies. A vaccine with a totally different mechanism of action is being investigated in these patients to see how they do with this new therapy. This trial is a very early investigation and is currently ongoing. Clinical Trial Registration: NCT03562637 (ClinicalTrials.gov).

Au@Pt Core-Shell Nanoparticle Bioconjugates for the Therapy of HER2+ Breast Cancer and Hepatocellular Carcinoma. Model Studies on the Applicability of 193mPt and 195mPt Radionuclides in Auger Electron Therapy.

193mPt and 195mPt radionuclides are therapeutically attractive Auger electron emitters with notably high Auger electron yield per decay. The present paper summarizes the first step of research on the applications of core-shell (Au@Pt) nanoparticles for electron Auger therapy of HER2+ (human epidermal growth factor receptor 2) breast cancer and hepatocellular carcinoma. Gold nanoparticles (30 nm) were synthesized covered with a platinum shell at high efficiency (>80%) and were further evaluated for in vitro studies such as binding affinity, internalization and cytotoxicity. To find the mechanism(s) responsible for platinum cytotoxicity in HepG2 cells, the platinum concentration in isolated cell nuclei and cytoplasm was determined using ICP-MS (inductively coupled plasma mass spectrometry). Lack of platinum in cell nuclei suggests that the cytotoxic effect is associated with the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Studies carried out on the SKOV-3 cell line with the use of a synthesized targeting bioconjugate (Au@Pt-PEG-trastuzumab) revealed a high affinity of this preparation to HER2+ cells, its internalization, its placement in the perinuclear area and partial intranuclear location. The specific binding for HER2 negative cells, MDA-MB-231, was negligible and Au@Pt-PEG-trastuzumab did not enter these cells. The results obtained are promising and warrant future investigation of Auger electron therapy using 193mPt and 195mPt based radiopharmaceuticals.

Trastuzumab emtansine with or without pertuzumab versus trastuzumab with taxane for human epidermal growth factor receptor 2-positive advanced breast cancer: Final results from MARIANNE.

BACKGROUND: In the phase 3 MARIANNE trial, trastuzumab emtansine (T-DM1) with or without pertuzumab showed noninferior progression-free survival and better tolerability than trastuzumab plus a taxane (HT) for the first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. This article reports the final descriptive overall survival (OS) analysis, updated safety data, and additional patient-reported outcomes and biomarker analyses. METHODS: OS was assessed in 1095 patients with HER2-positive breast cancer and no prior therapy for advanced disease who had been randomized to HT, T-DM1 plus a placebo (hereafter T-DM1), or T-DM1 plus pertuzumab (T-DM1+pertuzumab). A post hoc exploratory landmark analysis of OS, baseline patient and disease characteristics, and tumor biomarkers in patients with and without an objective tumor response (OR) according to the Response Evaluation Criteria in Solid Tumors within 6.5 months of randomization was conducted. RESULTS: The median OS was similar across groups (50.9, 53.7, and 51.8 months for the HT, T-DM1, and T-DM1+pertuzumab groups, respectively). Among patients with an OR, the median OS was longer with T-DM1 (64.4 months) and T-DM1+pertuzumab (not reached) versus HT (56.3 months). No baseline characteristics or biomarkers were strongly associated with OR. The incidence of grade 3 or higher adverse events was greater with HT (55.8%) than T-DM1 (47.1%) or T-DM1+pertuzumab (48.6%). The median time to clinically meaningful deterioration (a 3-point or greater change) in neurotoxicity symptoms was shorter with HT (2.1 months) and T-DM1+pertuzumab (4.2 months) than T-DM1 (6.2 months). Fewer patients reported alopecia and diarrhea and were bothered by treatment side effects in the T-DM1 arm. CONCLUSIONS: These results support T-DM1 as a first-line treatment for patients with HER2-positive metastatic breast cancer who are deemed unsuitable for taxane-based therapy.

Correction to: Relationship between tumor biomarkers and efficacy in MARIANNE, a phase III study of trastuzumab emtansine ± pertuzumab versus trastuzumab plus taxane in HER2-positive advanced breast cancer.

Following publication of the original article [1], the authors reported the following errors in the article.

Relationship between tumor biomarkers and efficacy in MARIANNE, a phase III study of trastuzumab emtansine ± pertuzumab versus trastuzumab plus taxane in HER2-positive advanced breast cancer.

BACKGROUND: The phase III EMILIA and TH3RESA trials demonstrated clinical benefits of trastuzumab emtansine (T-DM1) therapy in patients with previously treated HER2-positive metastatic breast cancer (MBC). Data from these and other trials showed that T-DM1-associated survival benefits were observed across biomarker subgroups tested in these trials. Prespecified, exploratory analyses of the phase III MARIANNE study examined the effects of HER2-related biomarkers on PFS in patients administered T-DM1 in the first-line MBC setting. METHODS: In MARIANNE, patients with previously untreated HER2-positive MBC were randomized (1:1:1) to trastuzumab plus taxane, T-DM1 plus placebo, or T-DM1 plus pertuzumab. Biomarker subgroups included HER2 and HER3 mRNA expression levels (≤median vs. >median), HER2 staining intensity (IHC 3+ vs. 2+ vs. 0/1+), PIK3CA status (mutated vs. non-mutated), PTEN H-score (≤median vs. >median), and PTEN protein expression level (0 vs. 1+ vs. 2+ vs. 3+ vs. 4+). PFS was analyzed descriptively for each subgroup using Kaplan-Meier methodology. Additional exploratory post-hoc analyses evaluated the effects of HER2 heterogeneity. Multivariate analyses were also performed. RESULTS: Median PFS was numerically longer for patients with HER2 mRNA levels >median versus ≤median across treatment arms. In general, there were no predictive biomarkers of benefit for either T-DM1 treatment arm; most hazard ratios were close to 1 with wide confidence intervals that included the value 1. Focal HER2 expression (IHC 3+ or IHC 2+) was present in 3.8% of patients and was associated with numerically shorter PFS in the T-DM1-containing treatment arms versus trastuzumab plus taxane. Compared with non-mutated PIK3CA, mutated PIK3CA was associated with numerically shorter median PFS across treatment groups. Post-hoc multivariate analysis showed HER2 mRNA expression and mutated PIK3CA were prognostic for PFS (P ≤ 0.001 for both biomarkers). CONCLUSIONS: In MARIANNE, biomarkers related to the HER2 pathway did not have predictive value for PFS when comparing T-DM1 (with or without pertuzumab) with trastuzumab plus taxane. However, HER2 mRNA level and PIK3CA mutation status showed prognostic value. Evaluation of other potential biomarkers, including immune markers, is ongoing. TRIAL REGISTRATION: Registration number: NCT01120184 . Date of registration: April 28, 2010 (registered prospectively).

Biomarker analysis of the NeoSphere study: pertuzumab, trastuzumab, and docetaxel versus trastuzumab plus docetaxel, pertuzumab plus trastuzumab, or pertuzumab plus docetaxel for the neoadjuvant treatment of HER2-positive breast cancer.

BACKGROUND: NeoSphere showed significantly higher pathologic complete response (pCR) with neoadjuvant pertuzumab, trastuzumab, and docetaxel compared with trastuzumab plus docetaxel, pertuzumab plus trastuzumab, or pertuzumab plus docetaxel. We assessed associations between human epidermal growth factor receptor 2 (HER2) pathway-related biomarkers and clinical outcome in response to these regimens. METHODS: Tumor, serum, and whole blood samples were collected at baseline and post neoadjuvant treatment before surgery. Associations between biomarkers and pCR, and between biomarkers and clinical variables were assessed in the overall and estrogen receptor (ER)-positive and ER-negative populations. Changes in serum marker levels between baseline and post-neoadjuvant treatment were examined. RESULTS: No markers were associated with pCR across all groups; however, significant associations were observed for two markers in individual groups. High HER2 was significantly associated with higher pCR rates (P = 0.001) and a significant treatment interaction (P = 0.0236) with pertuzumab, trastuzumab, and docetaxel (odds ratio 2.07, P = 0.01). Low serum transforming growth factor alpha (TGFα) was associated with higher pCR rates with pertuzumab plus trastuzumab (P = 0.04) without a significant treatment interaction. Presence of truncated HER2 did not affect pCR. A non-significant decreased pCR benefit was observed consistently across groups in patients with mutated PIK3CA while the treatment benefit from pertuzumab was maintained when comparing the trastuzumab plus docetaxel and pertuzumab, trastuzumab, and docetaxel groups. Notably, PIK3CA exon 9 mutations were associated with residual disease (pooled groups), which was not found for exon 20 mutations. Serum HER2 extracellular domain levels were significantly increased between baseline and post-neoadjuvant treatment in the non-trastuzumab-treated group, and decreased in the trastuzumab-containing groups (likely due to trastuzumab's mechanism of action). Differences in biomarker profiles according to ER status were observed. CONCLUSIONS: The observed associations of HER2 protein levels with sensitivity to pertuzumab, and of PIK3CA exon 9 mutation to lack of sensitivity to HER2-targeted monoclonal antibody treatment, warrant further investigation. Previously reported findings of truncated forms of HER2 as resistance markers to HER2-targeted treatment could not be confirmed in NeoSphere. Conventional HER2 assessment should continue and HER2 remains the only biomarker suitable for patient selection in this population. TRIAL REGISTRATION: Clinicaltrials.gov, NCT00545688 . Registered on 16 October 2007.

Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer (TURANDOT): primary endpoint results of a randomised, open-label, non-inferiority, phase 3 trial.

BACKGROUND: The randomised phase 3 TURANDOT trial compared two approved bevacizumab-containing regimens for HER2-negative metastatic breast cancer in terms of efficacy, safety, and quality of life. The interim analysis did not confirm non-inferior overall survival (stratified hazard ratio [HR] 1·04; 97·5% repeated CI [RCI] -∞ to 1·69). Here we report final results of our study aiming to show non-inferior overall survival with first-line bevacizumab plus capecitabine versus bevacizumab plus paclitaxel for locally recurrent or metastatic breast cancer. METHODS: In this multinational, open-label, randomised phase 3 TURANDOT trial, patients aged 18 years or older who had an Eastern Cooperative Oncology Group performance status 0-2 and measurable or non-measurable HER2-negative locally recurrent or metastatic breast cancer who had received no previous chemotherapy for locally recurrent or metastatic breast cancer were stratified and randomly assigned (1:1) using permuted blocks of size six to either bevacizumab plus paclitaxel (bevacizumab 10 mg/kg on days 1 and 15 plus paclitaxel 90 mg/m(2) on days 1, 8, and 15 every 4 weeks) or bevacizumab plus capecitabine (bevacizumab 15 mg/kg on day 1 plus capecitabine 1000 mg/m(2) twice daily on days 1-14 every 3 weeks) until disease progression, unacceptable toxicity, or withdrawal of consent. Stratification factors were oestrogen or progesterone receptor status, country, and menopausal status. The primary objective was to show non-inferior overall survival with bevacizumab plus capecitabine versus bevacizumab plus paclitaxel in the per-protocol population by rejecting the null hypothesis of inferiority (HR ≥1·33) using a stratified Cox proportional hazard model. This trial is registered with ClinicalTrials.gov, number NCT00600340. FINDINGS: Between Sept 10, 2008, and Aug 30, 2010, 564 patients were randomised, representing the intent-to-treat population. The per-protocol population comprised 531 patients (266 in the bevacizumab plus paclitaxel group and 265 in the bevacizumab plus capecitabine group). At the final overall survival analysis after 183 deaths (69%) in 266 patients receiving bevacizumab plus paclitaxel and 201 (76%) in 265 receiving bevacizumab plus capecitabine in the per-protocol population, median overall survival was 30·2 months (95% CI 25·6-32·6 months) versus 26·1 months (22·3-29·0), respectively. The stratified HR was 1·02 (97·5% RCI -∞ to 1·26; repeated p=0·0070), indicating non-inferiority. The unstratified Cox model (HR 1·13 [97·5% RCI -∞ to 1·39]; repeated p=0·061) did not support the primary analysis. Intent-to-treat analyses were consistent with the per-protocol results. The most common grade 3 or worse adverse events were neutropenia (54 [19%] of 284 patients in the bevacizumab plus paclitaxel group vs 5 [2%] of 277 patients in the bevacizumab plus capecitabine group), hand-foot syndrome (1 [<1%] vs 43 [16%]), peripheral neuropathy (39 [14%] vs 1 [<1%]), leucopenia (20 [7%] vs 1 [<1%]), and hypertension (12 [4%] vs 16 [6%]). Serious adverse events were reported in 65 (23%) of 284 patients receiving bevacizumab plus paclitaxel and 68 (25%) of 277 receiving bevacizumab plus capecitabine. Deaths in two (1%) of 284 patients in the bevacizumab plus paclitaxel group were deemed by the investigator to be treatment-related. No treatment-related deaths occurred in the bevacizumab plus capecitabine group. INTERPRETATION: Bevacizumab plus capecitabine represents a valid first-line treatment option for HER2-negative locally recurrent or metastatic breast cancer, offering good tolerability without compromising overall survival compared with bevacizumab plus paclitaxel. Although progression-free survival with the bevacizumab plus capecitabine combination is inferior to that noted with bevacizumab plus paclitaxel, we suggest that physicians should consider possible predictive risk factors for overall survival, individual's treatment priorities, and the differing safety profiles. FUNDING: Roche.

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.

Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.

BACKGROUND: The anti-human epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody trastuzumab improves the outcome in patients with HER2-positive metastatic breast cancer. However, most cases of advanced disease eventually progress. Pertuzumab, an anti-HER2 humanized monoclonal antibody that inhibits receptor dimerization, has a mechanism of action that is complementary to that of trastuzumab, and combination therapy with the two antibodies has shown promising activity and an acceptable safety profile in phase 2 studies involving patients with HER2-positive breast cancer. METHODS: We randomly assigned 808 patients with HER2-positive metastatic breast cancer to receive placebo plus trastuzumab plus docetaxel (control group) or pertuzumab plus trastuzumab plus docetaxel (pertuzumab group) as first-line treatment until the time of disease progression or the development of toxic effects that could not be effectively managed. The primary end point was independently assessed progression-free survival. Secondary end points included overall survival, progression-free survival as assessed by the investigator, the objective response rate, and safety. RESULTS: The median progression-free survival was 12.4 months in the control group, as compared with 18.5 months in the pertuzumab group (hazard ratio for progression or death, 0.62; 95% confidence interval, 0.51 to 0.75; P<0.001). The interim analysis of overall survival showed a strong trend in favor of pertuzumab plus trastuzumab plus docetaxel. The safety profile was generally similar in the two groups, with no increase in left ventricular systolic dysfunction; the rates of febrile neutropenia and diarrhea of grade 3 or above were higher in the pertuzumab group than in the control group. CONCLUSIONS: The combination of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival, with no increase in cardiac toxic effects. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, NCT00567190.).

Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial.

BACKGROUND: For women with oestrogen receptor (ER)-positive early breast cancer, treatment with tamoxifen for 5 years substantially reduces the breast cancer mortality rate throughout the first 15 years after diagnosis. We aimed to assess the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years. METHODS: In the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, 12,894 women with early breast cancer who had completed 5 years of treatment with tamoxifen were randomly allocated to continue tamoxifen to 10 years or stop at 5 years (open control). Allocation (1:1) was by central computer, using minimisation. After entry (between 1996 and 2005), yearly follow-up forms recorded any recurrence, second cancer, hospital admission, or death. We report effects on breast cancer outcomes among the 6846 women with ER-positive disease, and side-effects among all women (with positive, negative, or unknown ER status). Long-term follow-up still continues. This study is registered, number ISRCTN19652633. FINDINGS: Among women with ER-positive disease, allocation to continue tamoxifen reduced the risk of breast cancer recurrence (617 recurrences in 3428 women allocated to continue vs 711 in 3418 controls, p=0·002), reduced breast cancer mortality (331 deaths vs 397 deaths, p=0·01), and reduced overall mortality (639 deaths vs 722 deaths, p=0·01). The reductions in adverse breast cancer outcomes appeared to be less extreme before than after year 10 (recurrence rate ratio [RR] 0·90 [95% CI 0·79­1·02] during years 5­9 and 0·75 [0·62­0·90] in later years; breast cancer mortality RR 0·97 [0·79­1·18] during years 5­9 and 0·71 [0·58­0·88] in later years). The cumulative risk of recurrence during years 5­14 was 21·4% for women allocated to continue versus 25·1% for controls; breast cancer mortality during years 5­14 was 12·2% for women allocated to continue versus 15·0% for controls (absolute mortality reduction 2·8%). Treatment allocation seemed to have no effect on breast cancer outcome among 1248 women with ER-negative disease, and an intermediate effect among 4800 women with unknown ER status. Among all 12,894 women, mortality without recurrence from causes other than breast cancer was little affected (691 deaths without recurrence in 6454 women allocated to continue versus 679 deaths in 6440 controls; RR 0·99 [0·89­1·10]; p=0·84). For the incidence (hospitalisation or death) rates of specific diseases, RRs were as follows: pulmonary embolus 1·87 (95% CI 1·13­3·07, p=0·01 [including 0·2% mortality in both treatment groups]), stroke 1·06 (0·83­1·36), ischaemic heart disease 0·76 (0·60­0·95, p=0·02), and endometrial cancer 1·74 (1·30­2·34, p=0·0002). The cumulative risk of endometrial cancer during years 5­14 was 3·1% (mortality 0·4%) for women allocated to continue versus 1·6% (mortality 0·2%) for controls (absolute mortality increase 0·2%). INTERPRETATION: For women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis. FUNDING: Cancer Research UK, UK Medical Research Council, AstraZeneca UK, US Army, EU-Biomed.

Adjuvant trastuzumab in HER2-positive breast cancer.

BACKGROUND: Trastuzumab improves survival in the adjuvant treatment of HER-positive breast cancer, although combined therapy with anthracycline-based regimens has been associated with cardiac toxicity. We wanted to evaluate the efficacy and safety of a new nonanthracycline regimen with trastuzumab. METHODS: We randomly assigned 3222 women with HER2-positive early-stage breast cancer to receive doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks (AC-T), the same regimen plus 52 weeks of trastuzumab (AC-T plus trastuzumab), or docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH). The primary study end point was disease-free survival. Secondary end points were overall survival and safety. RESULTS: At a median follow-up of 65 months, 656 events triggered this protocol-specified analysis. The estimated disease-free survival rates at 5 years were 75% among patients receiving AC-T, 84% among those receiving AC-T plus trastuzumab, and 81% among those receiving TCH. Estimated rates of overall survival were 87%, 92%, and 91%, respectively. No significant differences in efficacy (disease-free or overall survival) were found between the two trastuzumab regimens, whereas both were superior to AC-T. The rates of congestive heart failure and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the TCH group (P<0.001). Eight cases of acute leukemia were reported: seven in the groups receiving the anthracycline-based regimens and one in the TCH group subsequent to receiving an anthracycline outside the study. CONCLUSIONS: The addition of 1 year of adjuvant trastuzumab significantly improved disease-free and overall survival among women with HER2-positive breast cancer. The risk-benefit ratio favored the nonanthracycline TCH regimen over AC-T plus trastuzumab, given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia. (Funded by Sanofi-Aventis and Genentech; BCIRG-006 ClinicalTrials.gov number, NCT00021255.).

Delays in diagnosis and treatment of breast cancer: a multinational analysis.

BACKGROUND: Reducing treatment delay improves outcomes in breast cancer. The aim of this study was to determine factors influencing patient- and system-related delays in commencing breast cancer treatment in different countries. METHODS: A total of 6588 female breast cancer patients from 12 countries were surveyed. Total delay time was determined as the sum of the patient-related delay time (time between onset of the first symptoms and the first medical visit) and system-related delay time (time between the first medical visit and the start of therapy). RESULTS: The average patient-related delay time and total delay time were 4.7 (range: 3.4-6.2) weeks and 14.4 (range: 11.5-29.4) weeks, respectively. Longer patient-related delay times were associated with distrust and disregard, and shorter patient-related delay times were associated with fear of breast cancer, practicing self-examination, higher education level, being employed, having support from friends and family and living in big cities. The average system-related delay time was 11.1 (range: 8.3-24.7) weeks. Cancer diagnosis made by an oncologist versus another physician, higher education level, older age, family history of female cancers and having a breast lump as the first cancer sign were associated with shorter system-related delay times. Longer patient-related delay times and higher levels of distrust and disregard were predictors of longer system-related delay times. CONCLUSIONS: The delay in diagnosis and treatment of breast cancer remains a serious problem. Several psychological and behavioural patient attributes strongly determine both patient-related delay time and system-related delay time, but their strength is different in particular countries.

Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer: interim efficacy results of the randomised, open-label, non-inferiority, phase 3 TURANDOT trial.

BACKGROUND: Randomised phase 3 trials in metastatic breast cancer have shown that combining bevacizumab with either paclitaxel or capecitabine significantly improves progression-free survival and response rate compared with chemotherapy alone but the relative efficacy of bevacizumab plus paclitaxel versus bevacizumab plus capecitabine has not been investigated. We compared the efficacy of the two regimens. METHODS: In this open-label, non-inferiority, phase 3 trial, patients with HER2-negative metastatic breast cancer who had received no chemotherapy for advanced disease were randomised (by computer-generated sequence; 1:1 ratio; block size six; stratified by hormone receptor status, country, and menopausal status) to receive either intravenous bevacizumab (10 mg/kg on days 1 and 15) plus intravenous paclitaxel (90 mg/m(2) on days 1, 8, and 15) repeated every 4 weeks (paclitaxel group) or intravenous bevacizumab (15 mg/kg on day 1) plus oral capecitabine (1000 mg/m(2) twice daily on days 1-14) repeated every 3 weeks (capecitabine group) until disease progression or unacceptable toxic effects. Treatment allocation was not masked because of the differences in routes of administration and cycle lengths. The primary objective was to show non-inferior overall survival with bevacizumab plus capecitabine versus bevacizumab plus paclitaxel. We report results of an interim overall survival analysis, which was planned for after 175 deaths in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT00600340. FINDINGS: Between Sept 10, 2008, and Aug 30, 2010, we randomised 564 patients (paclitaxel group n=285; capecitabine group n=279) from 51 centres in 12 countries. The per-protocol population consisted of 533 patients (paclitaxel group n=268; capecitabine group n=265). After median follow-up of 18·6 months (IQR 14·9-24·7), 181 patients in the per-protocol population had died (89 [33%] in the paclitaxel group; 92 [35%] in the capecitabine group). The hazard ratio [HR] for overall survival was 1·04 (97·5% repeated CI -∞ to 1·69; p=0·059); the non-inferiority criterion of the interim analysis (interim α=0·00105) was not met. More patients who received bevacizumab plus paclitaxel had an objective response than did those who received bevacizumab plus capecitabine (125 [44%] of 285 patients vs 76 [27%] of 279; p<0·0001). Similarly, progression-free survival was significantly longer in the paclitaxel group than in the capecitabine group (median progression-free survival 11·0 months [95% CI 10·4-12·9] vs 8·1 months [7·1-9·2]; HR 1·36 [95% CI 1·09-1·68], p=0·0052). The most common adverse events of grade 3 or higher were neutropenia (51 [18%]), peripheral neuropathy (39 [14%]), and leucopenia (20 [7%]) in the paclitaxel group and hand-foot syndrome (44 [16%]), hypertension (16 [6%]), and diarrhoea (15 [5%]) in the capecitabine group. One treatment-related death occurred in the paclitaxel group; no deaths in the capecitabine group were deemed to be treatment-related. INTERPRETATION: In this planned interim analysis, the non-inferiority criterion was not met and overall survival results are inconclusive. Final results are expected in 2014. Progression-free survival was better, and more patients achieved an objective response, with bevacizumab plus paclitaxel than with bevacizumab plus capecitabine. Efficacy results in both groups were consistent with previous reports. FUNDING: Central European Cooperative Oncology Group; Roche.

Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive breast cancer: 10-year follow-up of the phase 3 randomised BCIRG 001 trial.

BACKGROUND: We compared standard adjuvant anthracycline chemotherapy with anthracycline-taxane combination chemotherapy in women with operable node-positive breast cancer. Here we report the final, 10-year follow-up analysis of disease-free survival, overall survival, and long-term safety. METHODS: BCIRG 001 was an open label, phase 3, multicentre trial in which 1491 patients aged 18-70 years with node-positive, early breast cancer and a Karnofsky score of 80% or more were randomly assigned to adjuvant treatment with docetaxel, doxorubicin, and cyclophosphamide (TAC) or fluorouracil, doxorubicin, and cyclophosphamide (FAC) every 3 weeks for six cycles. Randomisation was stratified according to institution and number of involved axillary lymph nodes per patient (one to three vs four or more). Disease-free survival was the primary endpoint and was defined as the interval between randomisation and breast cancer relapse, second primary cancer, or death, whichever occurred first. Efficacy analyses were based on the intention-to-treat principle. BCIRG 001 is registered with ClinicalTrials.gov, number NCT00688740. FINDINGS: Enrolement took place between June 11, 1997 and June 3, 1999; 745 patients were assigned to receive TAC and 746 patients were assigned to receive FAC. After a median follow-up of 124 months (IQR 90-126), disease-free survival was 62% (95% CI 58-65) for patients in the TAC group and 55% (51-59) for patients in the FAC group (hazard ratio [HR] 0·80, 95% CI 0·68-0·93; log-rank p=0·0043). 10-year overall survival was 76% (95% CI 72-79) for patients in the TAC group and 69% (65-72) for patients in the FAC group (HR 0·74, 0·61-0·90; log-rank p=0·0020). TAC improved disease-free survival relative to FAC irrespective of nodal, hormone receptor, and HER2 status, although not all differences were significant in these subgroup analyses. Grade 3-4 heart failure occurred in 26 (3%) patients in the TAC group and 17 (2%) patients in the FAC group, and caused death in two patients in the TAC group and four patients in the FAC group. A substantial decrease in left ventricular ejection fraction (defined as a relative decrease from baseline of 20% or more) was seen in 58 (17%) patients who received TAC and 41 (15%) patients who received FAC. Six patients who received TAC developed leukaemia or myelodysplasia, as did three patients who received FAC. INTERPRETATION: Our results provide evidence that the initial therapeutic outcomes seen at the 5-year follow-up with a docetaxel-containing adjuvant regimen are maintained at 10 years. However, a substantial percentage of patients had a decrease in left ventricular ejection fraction, probably caused by anthracycline therapy, which warrants further investigation. FUNDING: Sanofi.

Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial.

BACKGROUND: The addition of bevacizumab to chemotherapy improves progression-free survival in metastatic breast cancer and pathological complete response rates in the neoadjuvant setting. Micrometastases are dependent on angiogenesis, suggesting that patients might benefit from anti-angiogenic strategies in the adjuvant setting. We therefore assessed the addition of bevacizumab to chemotherapy in the adjuvant setting for women with triple-negative breast cancer. METHODS: For this open-label, randomised phase 3 trial we recruited patients with centrally confirmed triple-negative operable primary invasive breast cancer from 360 sites in 37 countries. We randomly allocated patients aged 18 years or older (1:1 with block randomisation; stratified by nodal status, chemotherapy [with an anthracycline, taxane, or both], hormone receptor status [negative vs low], and type of surgery) to receive a minimum of four cycles of chemotherapy either alone or with bevacizumab (equivalent of 5 mg/kg every week for 1 year). The primary endpoint was invasive disease-free survival (IDFS). Efficacy analyses were based on the intention-to-treat population, safety analyses were done on all patients who received at least one dose of study drug, and plasma biomarker analyses were done on all treated patients consenting to biomarker analyses and providing a measurable baseline plasma sample. This trial is registered with ClinicalTrials.gov, number NCT00528567. FINDINGS: Between Dec 3, 2007, and March 8, 2010, we randomly assigned 1290 patients to receive chemotherapy alone and 1301 to receive bevacizumab plus chemotherapy. Most patients received anthracycline-containing therapy; 1638 (63%) of the 2591 patients had node-negative disease. At the time of analysis of IDFS, median follow-up was 31·5 months (IQR 25·6-36·8) in the chemotherapy-alone group and 32·0 months (27·5-36·9) in the bevacizumab group. At the time of the primary analysis, IDFS events had been reported in 205 patients (16%) in the chemotherapy-alone group and in 188 patients (14%) in the bevacizumab group (hazard ratio [HR] in stratified log-rank analysis 0·87, 95% CI 0·72-1·07; p=0·18). 3-year IDFS was 82·7% (95% CI 80·5-85·0) with chemotherapy alone and 83·7% (81·4-86·0) with bevacizumab and chemotherapy. After 200 deaths, no difference in overall survival was noted between the groups (HR 0·84, 95% CI 0·64-1·12; p=0·23). Exploratory biomarker assessment suggests that patients with high pre-treatment plasma VEGFR-2 might benefit from the addition of bevacizumab (Cox interaction test p=0·029). Use of bevacizumab versus chemotherapy alone was associated with increased incidences of grade 3 or worse hypertension (154 patients [12%] vs eight patients [1%]), severe cardiac events occurring at any point during the 18-month safety reporting period (19 [1%] vs two [<0·5%]), and treatment discontinuation (bevacizumab, chemotherapy, or both; 256 [20%] vs 30 [2%]); we recorded no increase in fatal adverse events with bevacizumab (four [<0·5%] vs three [<0·5%]). INTERPRETATION: Bevacizumab cannot be recommended as adjuvant treatment in unselected patients with triple-negative breast cancer. Further follow-up is needed to assess the potential effect of bevacizumab on overall survival.

Obesity and survival in operable breast cancer patients treated with adjuvant anthracyclines and taxanes according to pathological subtypes: a pooled analysis.

INTRODUCTION: Obesity is an unfavorable prognostic factor in breast cancer (BC) patients regardless of menopausal status and treatment received. However, the association between obesity and survival outcome by pathological subtype requires further clarification. METHODS: We performed a retrospective analysis including 5,683 operable BC patients enrolled in four randomized clinical trials (GEICAM/9906, GEICAM/9805, GEICAM/2003-02, and BCIRG 001) evaluating anthracyclines and taxanes as adjuvant treatments. Our primary aim was to assess the prognostic effect of body mass index (BMI) on disease recurrence, breast cancer mortality (BCM), and overall mortality (OM). A secondary aim was to detect differences of such prognostic effects by subtype. RESULTS: Multivariate survival analyses adjusting for age, tumor size, nodal status, menopausal status, surgery type, histological grade, hormone receptor status, human epidermal growth factor receptor 2 (HER2) status, chemotherapy regimen, and under-treatment showed that obese patients (BMI 30.0 to 34.9) had similar prognoses to that of patients with a BMI < 25 (reference group) in terms of recurrence (Hazard Ratio [HR] = 1.08, 95% Confidence Interval [CI] = 0.90 to 1.30), BCM (HR = 1.02, 0.81 to 1.29), and OM (HR = 0.97, 0.78 to 1.19). Patients with severe obesity (BMI ≥ 35) had a significantly increased risk of recurrence (HR = 1.26, 1.00 to 1.59, P = 0.048), BCM (HR = 1.32, 1.00 to 1.74, P = 0.050), and OM (HR = 1.35, 1.06 to 1.71, P = 0.016) compared to our reference group. The prognostic effect of severe obesity did not vary by subtype. CONCLUSIONS: Severely obese patients treated with anthracyclines and taxanes present a worse prognosis regarding recurrence, BCM, and OM than patients with BMI < 25. The magnitude of the harmful effect of BMI on survival-related outcomes was similar across subtypes.

Health-related quality of life with adjuvant docetaxel- and trastuzumab-based regimens in patients with node-positive and high-risk node-negative, HER2-positive early breast cancer: results from the BCIRG 006 Study.

BACKGROUND: This study aims to describe and compare health-related quality of life (HRQL) in patients with node-positive and high-risk node-negative HER2-positive early breast cancer receiving adjuvant docetaxel and trastuzumab-based or docetaxel-based regimens alone. METHODS: Eligible patients (n = 3,222) were randomly assigned to either four cycles of adjuvant doxorubicin and cyclophosphamide followed by four cycles of docetaxel (AC→T) or one of two trastuzumab-containing regimens: adjuvant doxorubicin and cyclophosphamide followed by docetaxel plus trastuzumab administered for 1 year (AC→TH) or six cycles of docetaxel plus carboplatin combined with trastuzumab administered for 1 year (TCH). The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 and BR-23 were administered at baseline, the start of cycle 4 (mid), and the end of chemotherapy (EOC), as well as at 6, 12, and 24 months after chemotherapy. RESULTS: Compliance rates for the EORTC questionnaires were acceptable at 72%-93% of eligible patients out to the 12-month assessment. Systemic side effect (SE) change scores were significantly improved for TCH-treated patients compared with AC→TH and AC→T at EOC, suggesting improved tolerability. Physical functioning (PF) was only slightly worse at midpoint for those receiving TCH, compared with patients who were just starting on taxane in an AC→TH regimen, but was otherwise similar between arms. All treatment arms recovered from the deterioration in SE, PF, and Global Health Scale scores by 1 year and median future perspective change scores continued to improve throughout treatment and follow-up. CONCLUSION: HRQL outcomes for adjuvant docetaxel and trastuzumab-based regimens are favorable and support TCH as a more tolerable treatment option.

Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial.

BACKGROUND: A subcutaneous formulation of trastuzumab has been developed, offering potential improvements in patient convenience and resource use compared with the standard intravenous infusion of the drug. We compared the pharmacokinetic profile, efficacy, and safety of the subcutaneous and intravenous formulations in patients with HER2-positive early breast cancer. METHODS: The HannaH study was a phase 3, randomised, international, open-label, trial in the (neo)adjuvant setting. Patients with HER2-positive, operable, locally advanced or inflammatory breast cancer were randomly assigned to eight cycles of neoadjuvant chemotherapy administered concurrently with trastuzumab every 3 weeks either intravenously (8 mg/kg loading dose, 6 mg/kg maintenance dose) or subcutaneously (fixed dose of 600 mg); 1:1 ratio. Chemotherapy consisted of four cycles of docetaxel (75 mg/m(2)) followed by four cycles of fluorouracil (500 mg/m(2)), epirubicin (75 mg/m(2)), and cyclophosphamide (500 mg/m(2)), every 3 weeks. After surgery, patients continued trastuzumab to complete 1 year of treatment. Coprimary endpoints were serum trough concentration (C(trough)) at pre-dose cycle 8 before surgery (non-inferiority margin for the ratio between groups of 0·80) and pathological complete response (pCR; non-inferiority margin for the difference between groups of -12·5%), analysed in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT00950300. FINDINGS: 299 patients were randomly assigned to receive intravenous trastuzumab and 297 to receive subcutaneous trastuzumab. The geometric mean presurgery C(trough) was 51·8 µg/mL (coefficient of variation 52·5%) in the intravenous group and 69·0 µg/mL (55·8%) in the subcutaneous group. The geometric mean ratio of C(trough) subcutaneous to C(trough) intravenous was 1·33 (90% CI 1·24-1·44). 107 (40·7%) of 263 patients in the intravenous group and 118 (45·4%) of 260 in the subcutaneous group achieved a pCR. The difference between groups in pCR was 4·7% (95% CI -4·0 to 13·4). Thus subcutaneous trastuzumab was non-inferior to intravenous trastuzumab for both coprimary endpoints. The incidence of grade 3-5 adverse events was similar between groups. The most common of these adverse events were neutropenia (99 [33·2%] of 298 patients in the intravenous group vs 86 [29·0%] of 297 in the subcutaneous group), leucopenia (17 [5·7%] vs 12 [4·0%]), and febrile neutropenia (10 [3·4%] vs 17 [5·7%]). However, more patients had serious adverse events in the subcutaneous group (62 [21%] of 297 patients) than in the intravenous group (37 [12%] of 298); the difference was mainly attributable to infections and infestations (24 [8·1%] in the subcutaneous group vs 13 [4·4%] in the intravenous group). Four adverse events led to death (one in the intravenous group and three in the subcutaneous group), all of which occurred during the neoadjuvant phase. Of these, two--both in the subcutaneous group--were deemed to be treatment related. INTERPRETATION: Subcutaneous trastuzumab, administered over about 5 min, has a pharmacokinetic profile and efficacy non-inferior to standard intravenous administration, with a similar safety profile to intravenous trastuzumab, and therefore offers a valid treatment alternative. FUNDING: F Hoffmann-La Roche.

Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial.

BACKGROUND: Studies with pertuzumab, a novel anti-HER2 antibody, show improved efficacy when combined with the established HER2-directed antibody trastuzumab in breast cancer therapy. We investigated the combination of pertuzumab or trastuzumab, or both, with docetaxel and the combination of pertuzumab and trastuzumab without chemotherapy in the neoadjuvant setting. METHODS: In this multicentre, open-label, phase 2 study, treatment-naive women with HER2-positive breast cancer were randomly assigned (1:1:1:1) centrally and stratified by operable, locally advanced, and inflammatory breast cancer, and by hormone receptor expression 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), escalating, if tolerated, to 100 mg/m(2) every 3 weeks; group A) or pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks) and trastuzumab plus docetaxel (group B) or pertuzumab and trastuzumab (group C) or pertuzumab plus docetaxel (group D). The primary endpoint, examined in the intention-to-treat population, was pathological complete response in the breast. Neither patients nor investigators were masked to treatment. This study is registered with ClinicalTrials.gov, number NCT00545688. FINDINGS: Of 417 eligible patients, 107 were randomly assigned to group A, 107 to group B, 107 to group C, and 96 to group D. Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate (49 of 107 patients; 45·8% [95% CI 36·1-55·7]) compared with those given trastuzumab plus docetaxel (group A; 31 of 107; 29·0% [20·6-38·5]; p=0·0141). 23 of 96 (24·0% [15·8-33·7]) women given pertuzumab plus docetaxel (group D) had a pathological complete response, as did 18 of 107 (16·8% [10·3-25·3]) given pertuzumab and trastuzumab (group C). The most common adverse events of grade 3 or higher were neutropenia (61 of 107 women in group A, 48 of 107 in group B, one of 108 in group C, and 52 of 94 in group D), febrile neutropenia (eight, nine, none, and seven, respectively), and leucopenia (13, five, none, and seven, respectively). The number of serious adverse events was similar in groups A, B, and D (15-20 serious adverse events per group in 10-17% of patients) but lower in group C (four serious adverse events in 4% of patients). INTERPRETATION: Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate compared with those given trastuzumab plus docetaxel, without substantial differences in tolerability. Pertuzumab and trastuzumab without chemotherapy eradicated tumours in a proportion of women and showed a favourable safety profile. These findings justify further exploration in adjuvant trials and support the neoadjuvant approach for accelerating drug assessment in early breast cancer. FUNDING: F Hoffmann-La Roche.

The cancer-risk variant frequency among Polish population reported by the first national whole-genome sequencing study.

Introduction: Population-based cancer screening has raised many controversies in recent years, not only regarding the costs but also regarding the ethical nature and issues related to variant interpretation. Nowadays, genetic cancer screening standards are different in every country and usually encompass only individuals with a personal or family history of relevant cancer. Methods: Here we performed a broad genetic screening for cancer-related rare germline variants on population data from the Thousand Polish Genomes database based on 1076 Polish unrelated individuals that underwent whole genome sequencing (WGS). Results: We identified 19 551 rare variants in 806 genes related to oncological diseases, among them 89% have been located in non-coding regions. The combined BRCA1/BRCA2 pathogenic/likely pathogenic according to ClinVar allele frequency in the unselected population of 1076 Poles was 0.42%, corresponding to nine carriers. Discussion: Altogether, on the population level, we found especially problematic the assessment of the pathogenicity of variants and the relation of ACMG guidelines to the population frequency. Some of the variants may be overinterpreted as disease-causing due to their rarity or lack of annotation in the databases. On the other hand, some relevant variants may have been overseen given that there is little pooled population whole genome data on oncology. Before population WGS screening will become a standard, further studies are needed to assess the frequency of the variants suspected to be pathogenic on the population level and with reporting of likely benign variants.