An aCGH classifier derived from BRCA1-mutated breast cancer and benefit of high-dose platinum-based chemotherapy in HER2-negative breast cancer patients

BackgroundBreast cancer cells deficient for BRCA1 are hypersensitive to agents inducing DNA double-strand breaks (DSB), such as bifunctional alkylators and platinum agents. Earlier, we had developed a comparative genomic hybridisation (CGH) classifier based on BRCA1-mutated breast cancers. We hypothesised that this BRCA1-like^CGH classifier could also detect loss of function of BRCA1 due to other causes besides mutations and, consequently, might predict sensitivity to DSB-inducing agents.Patients and methodsWe evaluated this classifier in stage III breast cancer patients, who had been randomly assigned between adjuvant high-dose platinum-based (HD-PB) chemotherapy, a DSB-inducing regimen, and conventional anthracycline-based chemotherapy. Additionally, we assessed BRCA1 loss through mutation or promoter methylation and immunohistochemical basal-like status in the triple-negative subgroup (TN subgroup).ResultsWe observed greater benefit from HD-PB chemotherapy versus conventional chemotherapy among patients with BRCA1-like^CGH tumours [41/230 = 18%, multivariate hazard ratio (HR) = 0.12, 95% confidence interval (CI) 0.04–0.43] compared with patients with non-BRCA1-like^CGH tumours (189/230 = 82%, HR = 0.78, 95% CI 0.50–1.20), with a significant difference (test for interaction P = 0.006). Similar results were obtained for overall survival (P interaction = 0.04) and when analyses were restricted to the TN subgroup. Sixty-three percent (20/32) of assessable BRCA1-like^CGH tumours harboured either a BRCA1 mutation (n = 8) or BRCA1 methylation (n = 12).ConclusionBRCA1 loss as assessed by CGH analysis can identify patients with substantially improved outcome after adjuvant DSB-inducing chemotherapy when compared with standard anthracycline-based chemotherapy in our series.     

A Randomized Parallel Controlled Phase II Trial of Recombinant Human Endostatin Added to Neoadjuvant Chemotherapy for Stage III Breast Cancer

BackgroundTo explore the potential advantage of preoperative anti-angiogenosis therapy, we implemented a study to evaluate the efficacy of recombinant human endostatin (EN) in combination with neoadjuvant chemotherapy in the treatment of stage III breast cancer.Patients and MethodsEighty-seven patients were randomized to neoadjuvant TEC (docetaxel, epirubicin, and cyclophosphamide) or to EN+TEC, followed by surgery. The primary endpoint was the objective response rate (ORR). Secondary endpoints included pathologic complete response (pCR), relapse-free survival (RFS), overall survival (OS), and safety.ResultsPatients receiving EN+TEC achieved significantly higher ORR (81.82%; 36/44) compared with those receiving TEC (58.14%; 25/43; P=0.016). There was a non-significant trend of increased pCR with EN treatment (15.91% vs. 6.98%). The median follow-up was 54 months and revealed a significantly higher RFS with EN+TEC (median, 67.3 months; 95% confidence interval [CI], 61.0-73.7 months), compared with TEC (median, 55.0 months; 95% CI, 48.3-61.7 months; P =0.014). EN+TEC also significantly improved OS (74.2 months; 95% CI, 68.9-79.6 months), compared with TEC (59.1 months; 95% CI, 52.0-66.1 months; P =0 .006). The 3- and 5-year OS rates are estimated to be 88.5% and 82.8% with EN+TEC and 76.7% and 54.4% with TEC, respectively. Cox proportional regression analyses showed that EN+TEC was associated with improved OS (hazard ratio, 0.377; 95% CI, 0.418-0.959; P =0 .041). There was no significant difference in adverse events between EN+TEC and TEC.ConclusionThe combination of EN+TEC neoadjuvant chemotherapy significantly improved the ORR and OS, suggesting a benefit of adding anti-angiogenesis to standard chemotherapy in the treatment of locally advanced breast cancer.     

Cemiplimab Plus Chemotherapy Versus Chemotherapy Alone in Advanced NSCLC: 2-Year Follow-Up From the Phase 3 EMPOWER-Lung 3 Part 2 Trial

IntroductionEMPOWER-Lung 3 part 2 (NCT03409614), a double-blind, placebo-controlled phase 3 study, investigated cemiplimab (antiprogrammed cell death protein 1) plus chemotherapy versus placebo plus chemotherapy in patients with advanced NSCLC without EGFR, ALK, or ROS1 aberrations, with either squamous or nonsquamous histology, irrespective of programmed death-ligand 1 levels. At primary analysis, after 16.4 months of follow-up, cemiplimab plus chemotherapy improved median overall survival (OS) versus chemotherapy alone (21.9 versus 13.0 mo, hazard ratio [HR] = 0.71, 95% confidence interval [CI]: 0.53–0.93, p = 0.014). Here, we report protocol-specified final OS and 2-year follow-up results.MethodsPatients (N = 466) were randomized 2:1 to receive histology-specific platinum-doublet chemotherapy, with 350 mg cemiplimab (n = 312) or placebo (n = 154) every 3 weeks for up to 108 weeks. Primary end point was OS; secondary end points included progression-free survival and objective response rates.ResultsAfter 28.4 months of median follow-up, median OS was 21.1 months (95% CI: 15.9–23.5) for cemiplimab plus chemotherapy versus 12.9 months (95% CI: 10.6–15.7) for chemotherapy alone (HR = 0.65, 95% CI: 0.51–0.82, p = 0.0003); median progression-free survival was 8.2 months (95% CI: 6.4–9.0) versus 5.5 months (95% CI: 4.3–6.2) (HR = 0.55, 95% CI: 0.44–0.68, p < 0.0001), and objective response rates were 43.6% versus 22.1%, respectively. Safety was generally consistent with previously reported data. Incidence of treatment-emergent adverse events of grade 3 or higher was 48.7% with cemiplimab plus chemotherapy and 32.7% with chemotherapy alone.ConclusionsAt protocol-specified final OS analysis with 28.4 months of follow-up, the EMPOWER-Lung 3 study continued to reveal benefit of cemiplimab plus chemotherapy versus chemotherapy alone in patients with advanced squamous or nonsquamous NSCLC, across programmed death-ligand 1 levels.     

A phase III randomized trial of adding topical nitroglycerin to first-line chemotherapy for advanced nonsmall-cell lung cancer: the Australasian lung cancer trials group NITRO trial

BackgroundWe sought to determine whether the substantial benefits of topical nitroglycerin with first-line, platinum-based, doublet chemotherapy in advanced nonsmall-cell lung cancer (NSCLC) seen in a phase II trial could be corroborated in a rigorous, multicenter, phase III trial.Patients and methodsPatients starting one of five, prespecified, platinum-based doublets as first-line chemotherapy for advanced NSCLC were randomly allocated treatment with or without nitroglycerin 25 mg patches for 2 days before, the day of, and 2 days after, each chemotherapy infusion. Progression-free survival (PFS) was the primary end point.ResultsAccrual was stopped after the first interim analysis of 270 events. Chemotherapy was predominantly with carboplatin and gemcitabine (79%) or carboplatin and paclitaxel (18%). The final analysis included 345 events in 372 participants with a median follow-up of 33 months. Topical nitroglycerin had no demonstrable effect on PFS [median 5.0 versus 4.8 months, hazard ratio (HR) = 1.07, 95% confidence interval (CI) 0.86–1.32, P = 0.55], overall survival (median 11.0 versus 10.3 months, HR = 0.99, 95% CI 0.79–1.24, P = 0.94), or objective tumor response (31% versus 30%, relative risk = 1.03, 95% CI 0.82–1.29, P = 0.81). Headache, hypotension, syncope, diarrhea, dizziness, and anorexia were more frequent in those allocated nitroglycerin.ConclusionThe addition of topical nitroglycerin to carboplatin-based, doublet chemotherapy in NSCLC had no demonstrable benefit and should not be used or pursued further.Clinical Trials NumberAustralian New Zealand Clinical Trials Registry Number ACTRN12608000588392.     

Platinum-based neoadjuvant chemotherapy in triple-negative breast cancer: a systematic review and meta-analysis

BackgroundThe role of platinum-based neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) patients is highly controversial and it is not endorsed by current guidelines. Our meta-analysis aimed to better elucidate its activity, efficacy and safety.Material and methodsA systematic search of Medline, Web of Science and conferences proceedings up to 30 October 2017 was carried out to identify randomized controlled trials (RCTs) investigating platinum-based versus platinum-free neoadjuvant chemotherapy in TNBC patients. Using the fixed and random effects models, pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CI) were calculated for pathological complete response (pCR, defined as ypT0/is pN0), event-free survival (EFS), overall survival (OS) and grade 3 and 4 adverse events (AEs: neutropenia, anemia, thrombocytopenia and neuropathy).ResultsNine RCTs (N = 2109) were included. Overall, platinum-based neoadjuvant chemotherapy significantly increased pCR rate from 37.0% to 52.1% (OR 1.96, 95% CI 1.46–2.62, P < 0.001). Platinum-based neoadjuvant chemotherapy remained significantly associated with increased pCR rate also after restricting the analysis to the three RCTs (N = 611) that used the same standard regimen in both groups of weekly paclitaxel (with or without carboplatin) followed by anthracycline and cyclophosphamide (OR 2.53, 95% CI 1.37–4.66, P = 0.003). Conversely, among the 96 BRCA-mutated patients included in two RCTs, the addition of carboplatin was not associated with significantly increased pCR rate (OR 1.17, 95% CI 0.51–2.67, P = 0.711). Two RCTs (N = 748) reported survival outcomes: no significant difference in EFS (HR 0.72, 95% CI 0.49–1.06, P = 0.094) and OS (HR 0.86, 95% CI 0.46–1.63, P = 0.651) was observed.A significant higher risk of grade 3 and 4 hematological AEs, with no increased risk of grade 3 and 4 neuropathy was observed with platinum-based neoadjuvant chemotherapy.ConclusionIn TNBC patients, platinum-based neoadjuvant chemotherapy is associated with significantly increased pCR rates at the cost of worse hematological toxicities. Platinum-based neoadjuvant chemotherapy may be considered an option in TNBC patients.PROSPERO registration numberCRD42018080042.     

Systematic review and meta-analysis of randomised,phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer

BackgroundPrevious studies have demonstrated the efficacy and safety of bevacizumab in the treatment of non-small-cell lung cancer (NSCLC).MethodsSummary data from randomised trials comparing first-line bevacizumab plus platinum-based chemotherapy with chemotherapy alone for inoperable locally advanced, recurrent or metastatic NSCLC were meta-analysed. Pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and pooled odds ratio (OR) for adverse events were calculated. The chi-squared tests evaluated interactions between treatment effects, and prognostic factors and patient characteristics.ResultsData of 2194 patients (1313 bevacizumab; 881 controls) from four phase II and III trials: AVF-0757g, JO19907, ECOG 4599 and AVAiL, were analysed. Compared with chemotherapy alone, bevacizumab significantly prolonged OS (HR 0.90; 95% confidence interval [CI] 0.81, 0.99; P = 0.03), and PFS (0.72; 95% CI 0.66, 0.79; P < 0.001). Bevacizumab showed a significantly greater effect on OS in patients with adenocarcinoma versus other histologies (P = 0.02), and patients with body weight loss ≤5% versus >5% (P = 0.03). Bevacizumab significantly increased the risk of grade ≥3 proteinuria, hypertension, haemorrhagic events, neutropenia, and febrile neutropenia.ConclusionsBevacizumab significantly prolonged OS and PFS when added to first-line platinum-based chemotherapy in patients with advanced NSCLC; no unexpected toxicity was evident.     

EGFR exon 20 Insertion NSCLC and Response to Platinum-Based Chemotherapy

IntroductionIn classical EGFR mutant non-small-cell lung cancer (NSCLC), EGFR tyrosine kinase inhibitor (TKI) therapy yields better outcomes than platinum-based chemotherapy. However, EGFR exon 20 insertion (ex20ins) NSCLC is relatively resistant to currently available EGFR TKIs. Though platinum-based chemotherapy is the frontline standard of care for EGFR ex20ins NSCLC, its efficacy is not fully described.Study DesignA retrospective, single-center, case seriesMethodsPatients were identified through an electronic research database at a single institution and included if they had advanced EGFR ex20ins NSCLC, received platinum-based chemotherapy for metastatic disease, and had scans evaluable for response. Each patient's demographics, tumor characteristics, and clinical course were recorded. Treatment response was evaluated using RECIST v1.1 criteria, and the PFS was calculated by the Kaplan-Meier method.ResultsAmong 27 patients identified with EGFR ex20ins NSCLC at our institution, 18 (67%) received platinum-based chemotherapy for metastatic disease and had scans evaluable for response. These patients received platinum-based chemotherapy in the first-line (N = 17, 94%) and second-line settings (N = 1, 6%). The objective response rate (ORR) to platinum-based chemotherapy was 39% (7 of 18 patients; 95% confidence interval [CI] 16-61). The median PFS with platinum-based chemotherapy was 7.1 months (95% CI, 6.3 -13.7), and the median overall survival was 3.2 years (95% CI, 1.92 – NR).ConclusionsThe efficacy of platinum-based chemotherapy in EGFR ex20ins NSCLC is similar to that expected for TKI sensitive EGFR mutant NSCLC. Novel agents designed to specifically target ex20ins mutant EGFR should additionally improve outcomes.     

Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomised trials

BackgroundTwo recent studies (ABC-02 [UK] and BT22 [Japan]) have demonstrated the superiority of cisplatin and gemcitabine (CisGem) chemotherapy over gemcitabine (Gem) alone for patients with pathologically proven advanced biliary tract cancer (BTC: cholangiocarcinoma, gallbladder and ampullary cancers). This pre-planned analysis evaluates the efficacy of CisGem with increased statistical power.Patients and methodsWe carried out a meta-analysis of individual patient-level data of these studies to establish the effect of CisGem versus Gem on progression-free survival (PFS), overall survival (OS) and carried out exploratory subgroup analyses.ResultsCisGem demonstrates a significant improvement in PFS [hazard ratio (HR) = 0.64, 95% confidence interval (CI) 0.53–0.76, P < 0.001] and OS (HR = 0.65, 95% CI 0.54–0.78, P < 0.001) over Gem. This effect is most marked among patients with good performance status (PS 0–1): HR for PFS is 0.61 (95% CI 0.51–0.74), P < 0.001 and OS HR = 0.64 (95% CI 0.53–0.77), P < 0.001. CisGem resulted in improved PFS and OS for intra- and extra-hepatic cholangiocarcinomas and gallbladder cancer. The treatment effect between UK and Japanese patients was consistent with respect to OS (HR = 0.65, 95% CI 0.53–0.79 and 0.65, 95% CI 0.42–1.03, respectively); with similar OS in the combination arms (median 11.7 and 11.1 months, respectively). Subgroups least likely to benefit included patients with ampullary tumours and poor performance status (PS2).ConclusionsCisGem is the standard of care for the first-line treatment of good-PS patients with advanced BTC regardless of ethnicity. Future studies should aim to enhance the effectiveness of this regimen in the first-line setting, establish the role of subsequent (second-line) therapy and assess the role of rationally developed molecular-targeted therapies.     

Pathologic complete response to neoadjuvant chemotherapy with trastuzumab predicts for improved survival in women with HER2-overexpressing breast cancer

BackgroundWe sought to determine the prognostic value of pathologic response to neoadjuvant chemotherapy with concurrent trastuzumab.Patients and methodsTwo hundred and twenty-nine women with HER2/neu (HER2)-overexpressing breast cancer were treated with neoadjuvant chemotherapy plus trastuzumab between 2001 and 2008. Patients were grouped based on pathologic complete response (pCR, n = 114) or less than pCR (<pCR, n = 115); as well as by pathologic stage. Locoregional recurrence-free (LRFS), distant metastasis-free (DMFS), recurrence-free (RFS), and overall survival (OS) rates were compared.ResultsThe median follow-up was 63 (range 53–77) months. There was no difference in clinical stage between patients with pCR or <pCR. Compared with patients achieving <pCR, those with the pCR had higher 5-year rates of LRFS (100% versus 95%, P = 0.011), DMFS (96% versus 80%, P < 0.001), RFS (96% versus 79%, P < 0.001), and OS (95% versus 84%, P = 0.006). Improvements in RFS and OS were seen with decreasing post-treatment stage. Failure to achieve a pCR was the strongest independent predictor of recurrence (hazard ratio [HR] = 4.09, 95% confidence interval [CI]: 1.67–10.04, P = 0.002) and death (HR = 4.15, 95% CI: 1.39–12.38, P = 0.011).ConclusionspCR and lower pathologic stage after neoadjuvant chemotherapy with trastuzumab are the strongest predictors of recurrence and survival and are surrogates of the long-term outcome in patients with HER2-overexpressing disease.     

DNA Repair Gene Polymorphisms Predict Favorable Clinical Outcome in Advanced Non–Small-Cell Lung Cancer

BackgroundGenetic polymorphisms of genes involved in DNA repair and glutathione metabolic pathways may affect patients' response to platinum-based chemotherapy. We retrospectively assessed whether single nucleotide polymorphisms (SNP) of DNA-repair genes ERCC1, XPD, XRCC1 and glutathione S-transferase genes GSTP1, GSTT1 and GSTM1 predict overall survival (OS), response and toxicity in 119 non–small-cell lung cancer (NSCLC) patients treated with platinum-based regimens as first- or second-line chemotherapy.Patients and MethodsPatients' genotypes were determined by PCR-RFLP and sequencing approaches.ResultsERCC1 (Asn118Asn) genotype was significantly associated with response to treatment. Patients with either one or two C alleles (C/C, C/T) at Asn118Asn were more likely to respond to platinum-based chemotherapy compared with those without the C allele (Odds ratio, 0.10; 95% CI, 0.013-0.828; P = .033, by binary logistic regression). There was a significant association between the ERCC1 C8092A polymorphism and OS (P = .009, by log-rank test), with median survival times of 9.8 (C/C) and 14.1 (C/A or A/A) months, respectively, suggesting that any copies of the A allele were associated with an improved outcome. Cox's multivariate analysis suggested that the joint effect of ERCC1 polymorphic variants (C8092A and N118N) (0 vs. 2, hazard ratio 2.5; 95% CI, 1.26–4.96; P = .009) as well as the XRCC1 N399Q polymorphism (AA vs. GA/GG, hazard ratio 3.1; 95% CI, 1.4–6.8; P = .005) were independent prognostic factors for OS in advanced NSCLC patients treated with platinum-based chemotherapy.ConclusionThese findings support the notion that assessment of genetic variations of ERCC1 and XRCC1 could facilitate therapeutic decisions for individualized therapy in advanced NSCLC.     

KRAS mutation does not predict the efficacy of neo-adjuvant chemoradiotherapy in rectal cancer: A systematic review and meta-analysis

IntroductionThe current management of locally advanced rectal cancer involves total mesorectal excision, which may be preceded by neo-adjuvant chemoradiotherapy (CRT). Individual patient response to CRT is variable and reproducible biomarkers of response are needed. The role of the V-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) in rectal cancer remains equivocal. The aim of the current study was to systematically appraise the effect of KRAS mutation on outcomes following CRT for rectal cancer.MethodsA comprehensive search for published studies examining the effect of KRAS mutation on outcome after neo-adjuvant CRT in rectal cancer was performed. Each study was reviewed and data extracted. Random-effects methods were used to combine data.ResultsData was retrieved from 8 series describing 696 patients. Neo-adjuvant treatment regimens varied in usage of chemotherapeutic agents and interval to surgery. KRAS mutation was present in an average of 33.2 ± 11.8% of patients with rectal cancer. KRAS mutation was not associated with decreased rates of pathological complete response (odds ratio (OR): 0.778, 95% confidence interval (CI): 0.424–1.428, P = 0.418), tumor down-staging (OR: 0.846, 95% CI: 0.331–2.162, P = 0.728) or an increase in cancer related mortality (OR: 1.239, 95% CI: 0.607–2.531, P = 0.555).ConclusionsBased on these data, the presence of KRAS mutation does not affect tumor down-staging or cancer specific survival following neo-adjuvant CRT and surgery for rectal cancer.     

Platinum versus platinum-combination chemotherapy in platinum-sensitive recurrent ovarian cancer: a meta-analysis using individual patient data

BackgroundThe majority of women with ovarian cancer develop recurrent disease. For patients with a platinum-free interval of >6 months, platinum-based chemotherapy is a treatment of choice. The benefit of platinum-based combination chemotherapy in randomized trials varies, and a meta-analysis was carried out to gain more secure information on the size of the benefit of this treatment.Materials and methodsWe initiated a systematic review and meta-analysis following a pre-specified protocol to determine whether combination chemotherapy is superior to single-agent platinum chemotherapy in women with relapsed platinum-sensitive ovarian cancer.ResultsA total of five potentially eligible randomized trials were identified that had used combination-platinum chemotherapy versus single-agent platinum chemotherapy in women with relapsed platinum-sensitive ovarian cancer. For one trial (190 patients), adequate contact with the investigators could not be established. Therefore, four trials that randomly assigned 1300 patients were included, with a median follow-up of 36.1 months. Overall survival (OS) analyses were based on 865 deaths and demonstrated evidence for the benefit of combination-platinum chemotherapy (HR = 0.80; 95% CI, 0.64–1.00; P = 0.05). Progression-free survival (PFS) analyses were based on 1167 events and demonstrated strong evidence for the benefit of combination-platinum chemotherapy (HR = 0.68; 95% CI, 0.57–0.81; P < 0.001). There was no evidence of a difference in the relative effect of combination-platinum chemotherapy on either OS or PFS in patient subgroups defined by previous paclitaxel (Taxol) treatment (OS, P = 0.49; PFS, P = 0.66), duration of treatment-free interval (OS, P = 0.86; PFS, P = 0.48) or the number of previous lines of chemotherapy (OS, P = 0.21; PFS, P = 0.27).ConclusionsIn this individual patient data (IPD) meta-analysis, we have demonstrated that combination-platinum chemotherapy improves OS and PFS across all subgroups. This provides the strongest evidence to date of the benefit of combination-platinum over single-agent platinum.     

Prognostic significance of preexisting interstitial lung disease in Japanese patients with small-cell lung cancer

BackgroundIn Japan, iatrogenic acute exacerbation of interstitial lung disease (ILD) is a serious complication in patients with lung cancer and simultaneous ILD. Results of some reports suggest that patients with ILD and small-cell lung cancer (SCLC) might benefit from chemotherapy, but the influence of ILD on prognosis is unclear.Patients and MethodsRetrospective study of patients with SCLC with or without ILD. Between April 2006 and March 2011, 122 patients with SCLC who were receiving platinum-based combination chemotherapy participated.ResultsTwenty-eight patients (23.0%) had ILD at diagnosis. Pneumonitis associated with chemotherapy, including acute exacerbation–ILD was significantly increased in patients with preexisting ILD (8/28 vs. 2/94; P = .0001). In patients receiving chemotherapy alone, response rates and median progression-free survival of first-line chemotherapy in patients with or without preexisting ILD was not significantly different (P = .26; 20/26 vs. 52/60 and P = .089; 4.4 months vs. 5.4 months, respectively). The median overall survival of all patients was 15.5 months, but those without preexisting ILD survived significantly longer (P = .0010; 17.8 months vs. 10.7 months). Multivariate analysis revealed that performance status of 0 or 1 (hazard ratio [HR] 0.19 [95% confidence interval {CI}, 0.10-0.37]; P < .0001) limited disease (HR 0.42 [95% CI, 0.23-0.73]; P = .0017), and no preexisting ILD (HR 0.36 [95% CI, 0.19-0.69]; P = .0027) were significantly associated with longer overall survival.ConclusionPatients with SCLC and ILD might benefit from chemotherapy, but preexisting ILD is an independent prognostic factor for poorer survival.     

Comparison of Chemotherapy Plus Pembrolizumab vs. Chemotherapy Alone in EGFR-Mutant Non–small-Cell Lung Cancer Patients

IntroductionPlatinum doublet chemotherapy is the standard of care in patients with non–small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation who had disease progression after tyrosine kinase inhibitor (TKI). We aimed to assess immune checkpoint inhibitors efficacy in EGFR-mutant advanced NSCLC.Materials and MethodsWe retrospectively reviewed the data of sensitive EGFR-mutant NSCLC patients who progressed after EGFR-TKIs and received platinum doublet chemotherapy plus immunotherapy between 2015 and 2021. Efficacy outcomes, including overall response rate, progression-free survival, and overall survival, were assessed and compared with those of patients who had received platinum-based doublet chemotherapy.ResultsOf the total 869 patients, 82 treated with pembrolizumab and chemotherapy and 82 with only chemotherapy were selected. The median progression-free survival in patients administered pembrolizumab was significantly longer than those not administered pembrolizumab (6.7 months; 95% confidence interval [CI] 5.0-8.5 vs. 4.2 months; 95% CI 3.3-5.0, hazard ratio [HR] 0.64, 95% CI 0.46-0.89, P = .0076). Improved median overall survival was also observed in patients receiving pembrolizumab plus chemotherapy (26.7 [95% CI 22.6-30.8] vs. 13.4 months [95% CI 10.4-16.4], HR, 0.49 [95% CI 0.31-0.75], P = .0052). In addition, the overall response rate was higher in patients treated with than patients treated without pembrolizumab (34.1% and 20.7%, respectively).ConclusionThe combination of pembrolizumab with chemotherapy is associated with improved efficacy and survival in patients with EGFR-mutant NSCLC after TKI resistance, but these findings need to be confirmed in further prospective studies.     

Tumour size is the only predictive factor of distant recurrence after pathological complete response to neoadjuvant chemotherapy in patients with large operable or locally advanced breast cancers: A sub-study of EORTC 10994/BIG 1-00 phase III trial

PurposeAlthough achieving a pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) in breast cancer predicts a better outcome, some patients still relapse. The objectives of this study were to describe the types of events in this group of patients and to identify predictive factors for relapse.MethodsPatients with large operable or locally advanced breast cancers (T4d tumours were excluded) were randomised to receive either six cycles of anthracycline-based chemotherapy or three cycles of docetaxel followed by three cycles of eprirubicin/docetaxel. pCR was defined as no evidence of residual invasive cancer (or very few scattered tumour cells) in the primary tumour and axillary lymph nodes at surgery. Two Cox regression analyses were performed to identify predictive factors of relapse: one for recurrence-free interval (RFI) and one for distant recurrence-free interval (DRFI).ResultsOut of 283 eligible patients who achieved a pCR, 40 (14.1%) and 28 (9.9%) presented an event of interest for the RFI and DRFI analyses, respectively. Five-year RFI, DRFI and overall survival (OS) were 85.3% (95% confidence interval (CI), 80.1–89.3), 89.6% (95% CI, 85.0–92.9) and 91.9% (95% CI, 87.2–94.9), respectively. No predictors for RFI after pCR were identified. For DRFI, tumour size was the only predictor: Hazard ratio (HR) T3 versus T1–2 = 3.62 (95% CI, 1.66–7.89); HR T4 versus T1–2: HR, 2.80 (95% CI, 0.62–12.64) p = 0.0048.ConclusionIn this study, clinical tumour size emerged as the only predictor for DRFI after pCR, with T3 and T4 tumours having an increased risk for distant recurrence compared to T1–2 tumours.     

In real life,one-quarter of patients with hormone receptor-positive metastatic breast cancer receive chemotherapy as initial palliative therapy: a study of the Southeast Netherlands Breast Cancer Consortium

BackgroundThe objective of this study was to present initial systemic treatment choices and the outcome of hormone receptor-positive (HR+) metastatic breast cancer.Patients and methodsAll the 815 consecutive patients diagnosed with metastatic breast cancer in 2007–2009 in eight participating hospitals were identified. From the 611 patients with HR+ disease, a total of 520 patients with HER2-negative (HER2-) breast cancer were included. Initial palliative systemic treatment was registered. Progression-free survival (PFS) and overall survival (OS) per initial palliative systemic therapy were obtained using the Kaplan–Meier method and compared using the log-rank test.ResultsFrom the total of 520 patients with HR+/HER2- metastatic breast cancer, 482 patients (93%) received any palliative systemic therapy. Patients that received initial chemotherapy (n = 116) were significantly younger, had less comorbidity, had received more prior adjuvant systemic therapy and were less likely to have bone metastasis only compared with patients that received initial endocrine therapy (n = 366). Median PFS of initial palliative chemotherapy was 5.3 months [95% confidence interval (CI) 4.2–6.2] and of initial endocrine therapy 13.3 months (95% CI 11.3–15.5), with a median OS of 16.1 and 36.9 months, respectively. Initial chemotherapy was also associated with worse outcome in terms of PFS and OS after adjustment for prognostic factors.ConclusionsA high percentage of patients with HR+ disease received initial palliative chemotherapy, which was associated with worse outcome, even after adjustment of relevant prognostic factors.     

Prognostic Value of the Pretreatment Neutrophil-to-Lymphocyte Ratio in Different Phenotypes of Locally Advanced Breast Cancer During Neoadjuvant Systemic Treatment

PurposeNeutrophils are among the key cellular players in the inflammatory milieu produced in patients with breast cancer (BC), and strong evidence exists in terms of the prognostic value of assessing the neutrophil-to-lymphocyte ratio (NLR) in patients with BC. In this study we sought to determine whether the baseline NLR correlates with pathological complete response (pCR), disease-free survival (DFS), and overall survival (OS) in patients with locally advanced BC in the neoadjuvant chemotherapy (NAC) setting.MethodsWe analyzed the pretreatment NLR from the first blood count of patients treated from 2007 to 2015 in terms of pCR, DFS, and OS in patients with locally advanced BC. Patients received standard medical care based on national guidelines.ResultsA total of 1519 patients were included in the study. Median age was 49 years (22-88). The cutoff point for NLR was 2.0. NLR was not associated with pCR or DFS. However, patients with high NLR had worse OS in the presence of triple-negative BC (105.9 months; 95% confidence interval [CI], 100.2-111.5] vs. 98.7 months; 95% CI, 91.1-106.3; P = .029), Her2 overexpression (114.0 months; 95% CI, 110.5-118.0 vs. 100.8 months; 95% CI 95.7-105.9; P = .019), and residual disease after NAC for both phenotypes. Multivariate analysis showed that NLR was independently associated with OS (hazard ratio, 1.4; 95% CI, 1.02-1.95; P = .037).ConclusionsPretreatment NLR in patients with locally advanced BC correlates with OS as an independent prognostic factor. This influence depends on phenotype and residual disease. Routine assessment of this parameter could be an easy and affordable tool for defining prognosis.     

Efficacy and safety of capecitabine-based first-line chemotherapy in advanced or metastatic breast cancer: a meta-analysis of randomised controlled trials

We sought to evaluate the efficacy and safety of capecitabine-based therapy as first-line chemotherapy in advanced breast cancer. Randomised controlled trials of capecitabine monotherapy or combined treatment were included in the meta-analysis. PubMed, EMBASE, the Cochrane Library database and important meeting summaries were searched systematically. Outcomes were progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and grades 3–4 drug-related adverse events.Nine trials with 1798 patients were included. The results indicated a significant improvement with capecitabine-based chemotherapy compared with capecitabine-free chemotherapy in ORR (relative risk [RR] 1.14, 95% confidence interval [CI] 1.03 to 1.26, P = 0.013) and PFS (hazard ratio [HR] 0.77, 95% CI 0.69 to 0.87, P < 0.0001). Overall survival favoured capecitabine-based chemotherapy, but this was not significant. There were more incidences of neutropenia and neutropenic fever in the capecitabine-free chemotherapy group and more vomiting, diarrhoea and hand–foot syndrome in the capecitabine-based chemotherapy group. There were no significant differences in nausea, fatigue, cardiotoxicity or mucositis/stomatitis between the two treatment regimens.Capecitabine-based chemotherapy significantly improves ORR and PFS in patients with advanced breast cancer, but has no demonstrable impact on OS. Capecitabine-based regimens are suitable as first-line treatment for patients with advanced breast cancer.     

Impact of timing of adjuvant chemotherapy for early breast cancer: the Royal Marsden Hospital experience

Background The optimal time to deliver adjuvant chemotherapy has not been defined.Methods A retrospective study of consecutive patients receiving adjuvant anthracycline and/or taxane 1993–2010. Primary endpoint included 5-year disease-free survival (DFS) in patients commencing chemotherapy <31 versus ≥31 days after surgery. Secondary endpoints included 5-year overall survival (OS) and sub-group analysis by receptor status.Results We identified 2003 eligible patients: 1102 commenced chemotherapy <31 days and 901 ≥31 days after surgery. After a median follow-up of 115 months, there was no difference in 5-year DFS rate with chemotherapy <31 compared to ≥31 days after surgery in the overall population (81 versus 82% hazard ratio (HR) 1.15, 95% confidence interval (95% CI) 0.92–1.43, p = 0.230). The 5-year OS rate was similar in patients who received chemotherapy <31 or ≥31 days after surgery (90 versus 91%, (HR 1.21, 95% CI 0.89–1.64, p = 0.228). For 250 patients with triple-negative breast cancer OS was significantly worse in patients who received chemotherapy ≥31 versus <31 days (HR = 2.18, 95% CI 1.11–4.30, p = 0.02).Discussion Although adjuvant chemotherapy ≥31 days after surgery did not affect DFS or OS in the whole study population, in TN patients, chemotherapy ≥31 days after surgery significantly reduced 5-year OS; therefore, delays beyond 30 days in this sub-group should be avoided.Subject terms: Chemotherapy, Breast cancer     

Final efficacy and updated safety results of the randomized phase III BEATRICE trial evaluating adjuvant bevacizumab-containing therapy in triple-negative early breast cancer

BackgroundThe purpose of this analysis was to assess the long-term impact of adding bevacizumab to adjuvant chemotherapy for early triple-negative breast cancer (TNBC).MethodsPatients eligible for the open-label randomized phase III BEATRICE trial had centrally confirmed triple-negative operable primary invasive breast cancer (pT1a–pT3). Investigators selected anthracycline- and/or taxane-based chemotherapy for each patient. After definitive surgery, patients were randomized 1:1 to receive ≥4 cycles of chemotherapy alone or with 1 year of bevacizumab (5 mg/kg/week equivalent). Stratification factors were nodal status, selected chemotherapy, hormone receptor status, and type of surgery. The primary end point was invasive disease-free survival (IDFS; previously reported). Secondary outcome measures included overall survival (OS) and safety.ResultsAfter 56 months’ median follow-up, 293 of 2591 randomized patients had died. There was no statistically significant difference in OS between treatment arms in either the total population (hazard ratio 0.93, 95% confidence interval [CI] 0.74–1.17; P = 0.52) or pre-specified subgroups. The 5-year OS rate was 88% (95% CI 86–90%) in both treatment arms. Updated IDFS results were consistent with the primary IDFS analysis. Five-year IDFS rates were 77% (95% CI 75–79%) with chemotherapy alone versus 80% (95% CI 77–82%) with bevacizumab. From 18 months after first study dose to study end, new grade ≥3 adverse events occurred in 4.6% and 4.5% of patients in the two arms, respectively.ConclusionFinal OS results showed no significant benefit from bevacizumab therapy for early TNBC. Late-onset toxicities were rare in both groups. Five-year OS and IDFS rates suggest that the prognosis for patients with TNBC is better than previously thought.ClinicalTrials.govNCT00528567