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Trastuzumab added to a nonanthracycline regimen to treat HER2-positive breast cancer resulted in rates of disease-free and overall survival that were similar to those for an anthracycline-containing regimen, with lower rates of cardiac toxicity and secondary leukemia. The HER2 gene encodes a tyrosine kinase receptor that mediates critical signaling functions in normal and malignant breast epithelial cells. 1 An acquired alteration consisting of amplification and overexpression of the gene product occurs in approximately 20 to 25% of human breast cancers. 2 , 3 HER2 overexpression is associated with an aggressive clinical phenotype that includes high-grade tumors, increased growth rates, early systemic metastasis, and decreased rates of disease-free and overall survival. 2 , 3 Preclinical data indicate that this adverse clinical picture results from fundamental changes in the biologic features of breast-cancer cells containing the alteration, including increased proliferation, suppression of apoptosis, increased . . .

PARTNER is a prospective, phase II–III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer 1 , 2 , who were germline  BRCA 1 and BRCA2 wild type 3 . Here we report the results of the trial. Patients ( n  = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin–paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR) 4 , and secondary end points included event-free survival (EFS) and overall survival (OS) 5 . pCR was achieved in 51% of patients in the research arm and 52% in the control arm ( P  = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P  > 0.9), respectively; OS was 90% and 87.2% (log-rank P  = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P  < 0.001), and OS was 96% and 83% (log-rank P  < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin–paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576 . A study details the results of the PARTNER trial, a prospective, randomized controlled trial of the use of neoadjuvant olaparib with carboplatin–paclitaxel chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2  wild type.

Anthracyclines can induce a type 1 interferon response in tumor cells that may predict clinical response to these drugs. Some of the anti-neoplastic effects of anthracyclines in mice originate from the induction of innate and T cell–mediated anticancer immune responses. Here we demonstrate that anthracyclines stimulate the rapid production of type I interferons (IFNs) by malignant cells after activation of the endosomal pattern recognition receptor Toll-like receptor 3 (TLR3). By binding to IFN-α and IFN-β receptors (IFNARs) on neoplastic cells, type I IFNs trigger autocrine and paracrine circuitries that result in the release of chemokine (C-X-C motif) ligand 10 (CXCL10). Tumors lacking Tlr3 or Ifnar failed to respond to chemotherapy unless type I IFN or Cxcl10, respectively, was artificially supplied. Moreover, a type I IFN–related signature predicted clinical responses to anthracycline-based chemotherapy in several independent cohorts of patients with breast carcinoma characterized by poor prognosis. Our data suggest that anthracycline-mediated immune responses mimic those induced by viral pathogens. We surmise that such 'viral mimicry' constitutes a hallmark of successful chemotherapy.

The MINDACT trial showed excellent 5-year distant metastasis-free survival of 94·7% (95% CI 92·5–96·2) in patients with breast cancer of high clinical and low genomic risk who did not receive chemotherapy. We present long-term follow-up results together with an exploratory analysis by age. MINDACT was a multicentre, randomised, phase 3 trial done in 112 academic and community hospitals in nine European countries. Patients aged 18–70 years, with histologically confirmed primary invasive breast cancer (stage T1, T2, or operable T3) with up to three positive lymph nodes, no distant metastases, and a WHO performance status of 0–1 were enrolled and their genomic risk (using the MammaPrint 70-gene signature) and clinical risk (using a modified version of Adjuvant! Online) were determined. Patients with low clinical and low genomic risk results did not receive chemotherapy, and patients with high clinical and high genomic risk did receive chemotherapy (mostly anthracycline-based or taxane-based, or a combination thereof). Patients with discordant risk results (ie, patients with high clinical risk but low genomic risk, and those with low clinical risk but high genomic risk) were randomly assigned (1:1) to receive chemotherapy or not based on either the clinical risk or the genomic risk. Randomisation was done centrally and used a minimisation technique that was stratified by institution, risk group, and clinical–pathological characteristics. Treatment allocation was not masked. The primary endpoint was to test whether the distant metastasis-free survival rate at 5 years in patients with high clinical risk and low genomic risk not receiving chemotherapy had a lower boundary of the 95% CI above the predefined non-inferiority boundary of 92%. In the primary test population of patients with high clinical risk and low genomic risk who adhered to the treatment allocation of no chemotherapy and had no change in risk post-enrolment. Here, we present updated follow-up as well as an exploratory analysis of a potential age effect (≤50 years vs >50 years) and an analysis by nodal status for patients with hormone receptor-positive and HER2-negative disease. These analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT00433589, and the European Clinical Trials database, EudraCT2005–002625–31. Recruitment is complete and further long-term follow-up is ongoing. Between Feb 8, 2007, and July 11, 2011, 6693 patients were enrolled. On Feb 26, 2020, median follow-up was 8·7 years (IQR 7·8–9·7). The updated 5-year distant metastasis-free survival rate for patients with high clinical risk and low genomic risk receiving no chemotherapy (primary test population, n=644) was 95·1% (95% CI 93·1–96·6), which is above the predefined non-inferiority boundary of 92%, supporting the previous analysis and proving MINDACT as a positive de-escalation trial. Patients with high clinical risk and low genomic risk were randomly assigned to receive chemotherapy (n=749) or not (n=748); this was the intention-to-treat population. The 8-year estimates for distant metastasis-free survival in the intention-to-treat population were 92·0% (95% CI 89·6–93·8) for chemotherapy versus 89·4% (86·8–91·5) for no chemotherapy (hazard ratio 0·66; 95% CI 0·48–0·92). An exploratory analysis confined to the subset of patients with hormone receptor-positive, HER2-negative disease (1358 [90.7%] of 1497 randomly assigned patients, of whom 676 received chemotherapy and 682 did not) shows different effects of chemotherapy administration on 8-year distant metastasis-free survival according to age: 93·6% (95% CI 89·3–96·3) with chemotherapy versus 88·6% (83·5–92·3) without chemotherapy in 464 women aged 50 years or younger (absolute difference 5·0 percentage points [SE 2·8, 95% CI −0·5 to 10·4]) and 90·2% (86·8–92·7) versus 90·0% (86·6–92·6) in 894 women older than 50 years (absolute difference 0·2 percentage points [2·1, −4·0 to 4·4]). The 8-year distant metastasis-free survival in the exploratory analysis by nodal status in these patients was 91·7% (95% CI 88·1–94·3) with chemotherapy and 89·2% (85·2–92·2) without chemotherapy in 699 node-negative patients (absolute difference 2·5 percentage points [SE 2·3, 95% CI −2·1 to 7·2]) and 91·2% (87·2–94·0) versus 89·9% (85·8–92·8) for 658 patients with one to three positive nodes (absolute difference 1·3 percentage points [2·4, −3·5 to 6·1]). With a more mature follow-up approaching 9 years, the 70-gene signature shows an intact ability of identifying among women with high clinical risk, a subgroup, namely patients with a low genomic risk, with an excellent distant metastasis-free survival when treated with endocrine therapy alone. For these women the magnitude of the benefit from adding chemotherapy to endocrine therapy remains small (2·6 percentage points) and is not enhanced by nodal positivity. However, in an underpowered exploratory analysis this benefit appears to be age-dependent, as it is only seen in women younger than 50 years where it reaches a clinically relevant threshold of 5 percentage points. Although, possibly due to chemotherapy-induced ovarian function suppression, it should be part of informed, shared decision making. Further study is needed in younger women, who might need reinforced endocrine therapy to forego chemotherapy. European Commission Sixth Framework Programme.

Background Anthracycline-based chemotherapy is associated with reduced cardiorespiratory fitness in breast cancer patients. High intensity interval training (HIIT) induces greater benefits on cardiorespiratory fitness than moderate continuous aerobic exercise in patients with heart failure. The study purpose was to determine whether a HIIT intervention is a feasible exercise strategy for breast cancer patients undergoing anthracycline-based chemotherapy. Methods Thirty women were randomized to either HIIT or non-exercise control group (CON). Participants performed a maximal cycling fitness test to measure peak power output during maximal oxygen uptake (VO 2 max). The HIIT group participated in an 8-week HIIT intervention occurring 3 times weekly. Feasibility was calculated by computing (1) the average weekly minutes of HIIT over 8 weeks and (2) the number of sessions attended and multiplied by 100 (percentage of sessions). The intervention was considered feasible if more than 50% of participants completed both an average of 70% of weekly minutes (63/90 min) and attended 70% exercise sessions (17/24 sessions). Results Participants were 46.9 ± 9.8 (mean ± SD) years old, diagnosed with clinical stage II (30%) or III (63%) breast cancer. The average weekly minutes of exercise completed was 78 ± 5.1 out of 90 min. Twelve of 15 participants met both feasibility criteria, attending 19.2 ± 2.1 out of 24 sessions (82.3%). VO 2 max was maintained (19.7 ± 8.7 to 19.4 ± 6.6 ml/kg/min) in HIIT group ( p  = 0.94) while there was a significant decrease in VO 2 max (18.7 ± 7.1 to 16.1 ± 6.0 ml/kg/min) in CON group from baseline to 8 weeks ( p  = 0.001). Conclusions HIIT is a feasible exercise intervention to maintain VO 2 max in breast cancer patients receiving anthracycline-based chemotherapy. Trial registration The protocol and informed consent were approved by the institutional IRB (HS-12-00227) and registered ( ClinicalTrials.gov NCT02454777; date of registration: May 272,015).

The addition of 10 mg olanzapine to the standard triplet antiemetic therapy has shown superiority in controlling chemotherapy-induced nausea and vomiting compared with triplet therapy alone for highly emetogenic chemotherapy, albeit with sedative side-effects. We aimed to investigate if administering 5 mg of olanzapine at home after anthracycline plus cyclophosphamide chemotherapy, rather than before chemotherapy, can maintain efficacy in controlling chemotherapy-induced nausea and vomiting while minimising sedative side-effects and associated risks. This was a phase 3, double-blind, randomised, placebo-controlled trial, done in 15 hospitals and cancer centres in Japan. Eligible patients were female adults aged 20 years or older with stage I–III breast cancer and an Eastern Cooperative Oncology Group performance status of 0–1, who were scheduled to receive intravenous anthracycline plus cyclophosphamide-based chemotherapy, and were naive to chemotherapy or had never received moderately to highly emetogenic chemotherapy. Eligible patients were randomly assigned 1:1 to oral olanzapine 5 mg or placebo via the central registration system. Randomisation was performed using blocked stratification, with age (≥55 years vs <55 years) and institution as stratification factors and a block size of two. Allocation was concealed and masking was achieved by using tablets with identical appearance. Treatment was administered at home within 5 h after the end of anthracycline plus cyclophosphamide administration and before the patient's evening meal on day 1 to minimise the risk of sedation during hospital visits and transportation, and on the next 3 days after their evening meal, both with pre-chemotherapeutical application of intravenous dexamethasone 9·9 mg, intravenous palonosetron 0·75 mg, and oral aprepitant 125 mg on day 1 followed by an additional dose of aprepitant 80 mg on days 2 and 3 or intravenous fosaprepitant 150 mg as a premedication on day 1. The primary endpoint was the proportion of patients with a complete response, defined as no vomiting and no rescue medication during the overall phase (0–120 h after the initiation of anthracycline plus cyclophosphamide) based on patient diary. The primary analysis was done by modified intention-to-treat, including all patients who received at least one dose of the study treatment and had at least one efficacy evaluation. Safety was analysed in all patients who received any treatment. This trial was registered with the Japan Registry of Clinical Trials, jRCT1031200134, and is complete. Between Oct 26, 2020 and Nov 2, 2022, 500 female patients from 15 medical institutions in Japan were randomly assigned to receive olanzapine (n=251) or placebo (n=249). Median age at enrolment was 52 years (IQR 45–60) in the olanzapine group and 51 years (46–60) in the placebo group. Data on gender and race or ethnicity were not collected. The median follow-up was 168 h (IQR 168–168). 480 participants (246 in the olanzapine group and 234 in the placebo group) received at least one dose of study medication and were eligible for the efficacy analysis. The complete response rate in the olanzapine group (58·1%, n=143) was significantly higher than in the placebo group (35·5%, n=83; difference 22·7%, 95% CI 14·0–31·4%; p<0·0001) during the overall phase. The most frequently reported severe or very severe symptoms based on the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) version 1.0 were anorexia (33 [13%] of 246 patients in the olanzapine group vs 89 [38%] of 235 in the placebo group) and constipation (30 [12%] vs 37 [16%]). Severe or very severe concentration impairment was reported in 25 (10%) of 246 patients in the olanzapine group and 34 (14%) of 235 patients in the placebo group. Experimental drug-related grade 3–4 adverse events according to the Common Terminology Criteria for Adverse Events version 5.0 included somnolence (four [2%] of 246 patients in the olanzapine group vs none of 235 in the placebo group), and concentration impairment (two [1%] vs none). There were no deaths. Post-chemotherapy administration of 5 mg olanzapine in combination with triplet antiemetic therapy before anthracycline plus cyclophosphamide-based chemotherapy significantly improved the complete response rate for chemotherapy-induced nausea and vomiting during the overall phase compared with placebo in female patients with breast cancer receiving outpatient chemotherapy, with an acceptable level of safety. The findings represent a substantial advancement in managing chemotherapy-induced nausea and vomiting and provide assurance that the safe and effective administration of olanzapine can be achieved at a dosage of 5 mg. The Capture of Outstanding Clinical Research and Evolution (CORE) project at Juntendo University.

Background Previous studies have shown that the addition of platinum to neoadjuvant chemotherapy (NAC) improved outcomes for patients with triple-negative breast cancer (TNBC). However, no studies have assessed the efficacy and safety of the combination of taxane and lobaplatin. In this study, we conducted a randomized controlled phase II clinical study to compare the efficacy and safety of taxane combined with lobaplatin or anthracycline. Methods We randomly allocated patients with stage I–III TNBC into Arm A and Arm B. Arm A received six cycles of taxane combined with lobaplatin (TL). Arm B received six cycles of taxane combined with anthracycline and cyclophosphamide (TEC) or eight cycles of anthracycline combined with cyclophosphamide and sequential use of taxane (EC-T). Both Arms underwent surgery after NAC. The primary endpoint was the pathologic complete response (pCR). Secondary endpoints were event-free survival (EFS), overall survival (OS), and safety. Results A total of 103 patients (51 in Arm A and 52 in Arm B) were assessed. The pCR rate of Arm A was significantly higher than that of Arm B (41.2% vs . 21.2%, P  = 0.028). Patients with positive lymph nodes and low neutrophil-to-lymphocyte ratio (NLR) benefited significantly more from Arm A than those with negative lymph nodes and high NLR ( P interaction  = 0.001, P interaction  = 0.012, respectively). There was no significant difference in EFS ( P  = 0.895) or OS ( P  = 0.633) between the two arms. The prevalence of grade-3/4 anemia was higher in Arm A ( P  = 0.015), and the prevalence of grade-3/4 neutropenia was higher in Arm B ( P  = 0.044). Conclusions Neoadjuvant taxane plus lobaplatin has shown better efficacy than taxane plus anthracycline, and both regimens have similar toxicity profiles. This trial may provide a reference for a better combination strategy of immunotherapy in NAC for TNBC in the future.

To test if statin administration attenuated renal sinus fat (RSF) accumulation and if RSF was associated with renal function in women with breast cancer (BC) receiving anthracycline-based chemotherapy. This was a secondary analysis in a subgroup of women with stage I-III BC randomized to placebo (n = 35) or statin (40 mg/day atorvastatin, n = 44) therapy. At baseline and 24-months after randomization, RSF and intraabdominal fat were measured from magnetic resonance images, and estimated glomerular filtration rate (eGFR) was calculated from serum creatinine. Participants in this study averaged 51 years of age (SD 11), 87% reported White race, and had a mean BMI (±SD) of 30.2 kg/m2 (±6.1). Most participants (60%) were diagnosed with stage II BC. At 24-months, RSF was higher in the placebo group relative to the statin group (β [95% CI], p-value: 0.17 [0.009, 0.34], p = 0.04). After adjusting for baseline RSF, this signal remained but was attenuated (β [95% CI], p-value: 0.12 [-0.06, 0.29], p = 0.18). In all participants at baseline and prior to beginning chemotherapy for BC or study drug, higher RSF was associated with lower eGFR values in all participants (r = -0.23, p = 0.03). At 24-months by study group, greater RSF was associated with decreased eGFR in the placebo group (-0.51, p = 0.01) but not in the statin group (-0.25, p = 0.19). Statin administration may lower RSF during anthracycline-based chemotherapy. These findings merit further investigation to determine if statins protect renal function during BC treatment.

Background We have previously demonstrated S-1 is non-inferior to taxane with respect to overall survival as first-line chemotherapy for HER2-negative metastatic breast cancer. We aimed to confirm whether S-1 is also non-inferior to anthracycline-containing regimens in the same setting. Methods We conducted an open-label, non-inferiority, Phase 3 study. Individuals who had HER2-negative metastatic breast cancer, had received no chemotherapy for advanced disease and had endocrine therapy resistance, were randomly assigned to the anthracycline-containing regimens or S-1. The primary endpoint was overall survival. A pre-planned combined analysis of our two Phase 3 studies was also carried out. Results We enrolled 230 patients (anthracycline, n  = 115; S-1, n  = 115). Median overall survival was 30.1 months (95% CI 24.9–35.8) with the S-1 group and 33.7 months (95% CI 25.5–36.9) with the anthracycline group. The HR for the anthracycline group was 1.09 (95% CI 0.80–1.48). The combined analysis constituted 814 patients (395 assigned to standard treatment (anthracycline or taxane); 419 assigned to S-1). Median overall survival was 36.3 months in the standard treatment group and 32.7 months in the S-1 group. S-1 was non-inferior to standard treatment in terms of overall survival (HR 1.06 (95% CI 0.90–1.25); P non-inferiority = 0.0062). Conclusions S-1 could be considered a new treatment option for first-line chemotherapy for patients with HER2-negative metastatic breast cancer. Clinical trial registration The University Hospital Medical Information Network, Japan: UMIN000005449. This trial was registered on 15 April, 2011.