Trastuzumab versus observation for HER2 nonamplified early breast cancer with circulating tumor cells (EORTC 90091-10093, BIG 1-12, Treat CTC): a randomized phase II trial

BackgroundTrastuzumab improves the outcome of women with HER2 positive breast cancer. We aimed to assess whether trastuzumab decreases the detection rate of circulating tumor cells (CTCs) in women with high risk, HER2 nonamplified, early breast cancer.Patients and methodsThe EORTC 90091-10093 BIG 1–12 Treat CTC is a phase II trial, conducted in 70 hospitals and 6 CTC laboratories across 5 European countries. Patients with centrally confirmed HER2 nonamplified breast cancer and ≥1 centrally confirmed CTC per 15 ml of blood by CellSearch® following surgery and (neo)adjuvant chemotherapy were randomized (1 : 1) to 6 cycles of trastuzumab intravenously versus 18 weeks of observation. Randomization was stratified for center, locally confirmed estrogen receptor status and adjuvant versus neoadjuvant chemotherapy. The primary end point was rate of detection of ≥1 CTC per 15 ml of blood at week 18. Secondary end points were invasive disease-free survival (iDFS) and cardiac safety.ResultsBetween 30 April 2013 and 17 October 2016, 1317 patients were screened; 95 (7.2%) had detectable CTC(s), and 63 (4.8%) were randomized to trastuzumab (n = 31) or observation (n = 32). Fifty-eight patients were assessable for the primary end point, 29 in each arm. In 9 of the 58 patients, CTC(s) were still detected at week 18 : 5 in the trastuzumab and 4 in the observation arm (one-sided Fisher’s exact test, P = 0.765). An Independent Data Monitoring Committee recommended stopping further accrual for futility for the primary end point. Median follow-up at database lock was 13 months (IQR 4–16.5). The 1-year iDFS was 93.8% (95% CI 77.3–98.4) in the observation versus 84.8% (95% CI 63.4–94.2) in the trastuzumab arm. No grade 2–4 cardiac events were observed in the trastuzumab arm.ConclusionTrastuzumab does not decrease the detection rate of CTCs in HER2 nonamplified, nonmetastatic breast cancer.     

Trastuzumab in gastric cancer

Trastuzumab is a fully humanised monoclonal antibody directed at the human epidermal growth factor receptor-2 (HER-2) which has been a component of standard therapy for advanced and resected HER-2-positive breast cancers for almost a decade.HER-2 over-expression, defined as HER-2 protein over-expression using immunohistochemistry scored as 3+ and/or erbB-2 amplification detected by fluorescent in situ hybridisation, was detected in 22.1% of 3807 patients with advanced gastric and oesophagogastric junction (OGJ) adenocarcinoma screened for eligibility for the phase III ToGA study. The validated scoring system for HER-2 positivity in gastric cancers differs from that recommended for breast cancer due to an increased frequency of incomplete membranous immunoreactivity and heterogeneity of HER-2 expression in gastric cancers. The highest rates of HER-2 over-expression are observed in patients with OGJ rather than gastric tumours and intestinal-type rather than diffuse or mixed histology.The international multicentre randomised phase III ToGA study assessed the addition of trastuzumab to a cisplatin plus fluoropyrimidine (FP) chemotherapy doublet for patients with HER-2-positive advanced gastric or OGJ adenocarcinoma. The investigators reported a clinically and statistically significant benefit in terms of response rate (47.3% versus 34.5%, p = 0.0017), median progression-free survival (6.7 versus 5.5 months, p = 0.0002) and median overall survival (13.8 versus 11.1 months, p = 0.0046). Trastuzumab plus FP chemotherapy is now the standard of care for patients with advanced gastric and OGJ cancers which over-express HER-2.Further research to evaluate trastuzumab delivered beyond progression, in combination with alternative first-line chemotherapy regimens, and in the perioperative and adjuvant setting is urgently needed. Additionally, research into mechanisms of resistance and strategies to overcome primary or acquired resistance to trastuzumab must now be expedited, using lessons learnt over the past decade in HER-2-positive breast cancer to maximise the benefit from this agent.     

Very high quantitative tumor HER2 content and outcome in early breast cancer

BackgroundIt is unknown how a very high tumor total HER2 (human epidermal growth factor receptor-2) content (H2T) influences outcome in early breast cancer treated with adjuvant trastuzumab plus chemotherapy.Patients and methodsH2T was measured using a novel quantitative assay (HERmark®) from formalin-fixed tumor tissue of 899 women who participated in the FinHer trial (ISRCTN76560285). In a chromogenic in situ hybridization (CISH) test, 197 (21.9%) patients had HER2-positive cancer and were randomly assigned to receive trastuzumab or control.ResultsCancer H2T levels varied 1808-fold. High H2T levels were correlated with a positive HER2 status by CISH (P < 0.0001). A nonlinear association was present between H2T and the hazard of distant recurrence in a subpopulation treatment effect pattern plot analysis in CISH-positive disease. Patients with very high H2T (defined by ≥22-fold the median of HER2-negative cancers; 13% of CISH-positive cancers) did not benefit from adjuvant trastuzumab [hazard ratio (HR) 1.23; 95% confidence interval (CI) 0.33–4.62; P = 0.75], whereas the rest of the patients with HER2-positive disease by CISH (87%) did benefit (HR 0.52; 95% CI 0.28–1.00; P = 0.050).ConclusionPatients with HER2-positive breast cancer with very high tumor HER2 content may benefit less from adjuvant trastuzumab compared with those whose cancer has more moderate HER2 content.     

Tumor-infiltrating lymphocytes in patients with HER2-positive breast cancer treated with neoadjuvant chemotherapy plus trastuzumab,lapatinib or their combination: A meta-analysis of randomized controlled trials

BackgroundA relationship between baseline tumor-infiltrating lymphocytes (TIL) and outcomes has been described in HER2-positive breast cancer. Nevertheless, the magnitude of this association and whether this effect differs based on the type of anti-HER2 agent remain controversial. This meta-analysis investigated the association between baseline TIL and pathologic complete response (pCR) rates in HER2-positive breast cancer patients treated with neoadjuvant chemotherapy plus trastuzumab and lapatinib either alone or in combination.MethodsA literature search covering PubMed, Embase and the Cochrane library up to October 31, 2016 identified randomized, controlled trials investigating neoadjuvant chemotherapy plus trastuzumab and lapatinib either alone or in combination where published data for pCR based on pre-treatment TIL scores were available. Two subgroups were considered: high baseline TIL vs. non-high TIL, according to each study definition. Summary risk estimates (odds ratio) and 95% confidence intervals (CI) were calculated for pCR using pre-treatment TIL levels for each trial. Pooled analyses were conducted using random and fixed effects models. Interaction P-values were computed using a Monte Carlo permutation test.ResultsA total of 5 studies (N = 1256 patients) were included. Overall, high TIL subgroup was associated with a significantly increased pCR rate (OR 2.46; 95% CI 1.36–4.43; P = 0.003). No interaction was observed between TIL subgroup (high vs. non-high TIL) and response to anti-HER2 agent(s) (trastuzumab vs. lapatinib vs. their combination; P = 0.747) and chemotherapy (anthracycline and taxanes vs. taxanes only; P = 0.201). A stronger association between high TIL subgroup and pCR rates was observed when examining only the 4 studies using anthracycline- and taxane- based neoadjuvant chemotherapy and the 60% cut-off for high TIL (N = 869, NeoALTTO excluded) with an OR of 2.88 (95% CI 2.03–4.08; P < 0.001).ConclusionsIn HER2-positive breast cancer, high baseline TIL are associated with increased pCR probability irrespective of neoadjuvant anti-HER2 agent(s) and chemotherapy regimens used.     

Multicenter phase II study of trastuzumab in combination with capecitabine and oxaliplatin for advanced gastric cancer

BackgroundTrastuzumab has been approved for use in combination with fluoropyrimidine plus cisplatin for the treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC). Although capecitabine plus oxaliplatin (XELOX) is a standard first-line regimen for AGC, combination trastuzumab plus XELOX has not been studied.MethodsPatients with metastatic or unresectable HER2-positive AGC were diagnosed by either HER2 immunohistochemistry (IHC) 3+ or IHC 2+/fluorescence in-situ hybridisation (FISH)+ received intravenous trastuzumab (8 mg/kg for first cycle and 6 mg/kg for subsequent cycles on day 1) plus oral capecitabine (1000 mg/m² twice daily on days 1–14) and intravenous oxaliplatin (130 mg/m² on day 1), every 3 weeks. The primary end-point was the objective response rate, and secondary end-points included progression-free survival (PFS), overall survival (OS) and toxicity profiles.ResultsFifty-five HER2-positive AGC patients were enrolled between August 2011 and February 2013. The median age was 57 years (range = 29–74). The confirmed objective response rate was 67% (95% confidence interval (CI) = 54–80%). After a median follow-up period of 13.8 months (range = 6.1–23.9), the median PFS and OS were 9.8 months (95% CI = 7.0–12.6) and 21.0 months (95% CI = 6.4–35.7), respectively. Frequently encountered grade 3–4 toxicities included neutropenia (18%), anaemia (11%), and peripheral neuropathy (11%). There was a treatment-related death caused by severe diarrhoea and complicated sepsis.ConclusionCombination of trastuzumab and XELOX is well tolerated and highly effective in patients with HER2-positive AGC.     

A combinatorial biomarker predicts pathologic complete response to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2+ breast cancer

BackgroundHER2-positive (+) breast cancers, defined by HER2 overexpression and/or amplification, are often addicted to HER2 to maintain their malignant phenotype. Yet, some HER2+ tumors do not benefit from anti-HER2 therapy. We hypothesize that HER2 amplification levels and PI3K pathway activation are key determinants of response to HER2-targeted treatments without chemotherapy.Patients and methodsBaseline HER2+ tumors from patients treated with neoadjuvant lapatinib plus trastuzumab [with endocrine therapy for estrogen receptor (ER)+ tumors] in TBCRC006 (NCT00548184) were evaluated in a central laboratory for HER2 amplification by fluorescence in situ hybridization (FISH) (n = 56). HER2 copy number (CN) and FISH ratios, and PI3K pathway status, defined by PIK3CA mutations or PTEN levels by immunohistochemistry were available for 41 tumors. Results were correlated with pathologic complete response (pCR; no residual invasive tumor in breast).ResultsThirteen of the 56 patients (23%) achieved pCR. None of the 11 patients with HER2 ratio <4 and/or CN <10 achieved pCR, whereas 13/45 patients (29%) with HER2 ratio ≥4 and/or CN ≥10 attained pCR (P = 0.0513). Of the 18 patients with tumors expressing high PTEN or wild-type (WT) PIK3CA (intact PI3K pathway), 7 (39%) achieved pCR, compared with 1/23 (4%) with PI3K pathway alterations (P = 0.0133). Seven of the 16 patients (44%) with HER2 ratio ≥4 and intact PI3K pathway achieved pCR, whereas only 1/25 (4%) patients not meeting these criteria achieved pCR (P = 0.0031).ConclusionsOur findings suggest that there is a clinical subtype in breast cancer with high HER2 amplification and intact PI3K pathway that is especially sensitive to HER2-targeted therapies without chemotherapy. A combination of HER2 FISH ratio and PI3K pathway status warrants validation to identify patients who may be treated with HER2-targeted therapy without chemotherapy.     

Effect of docetaxel duration on clinical outcomes: exploratory analysis of CLEOPATRA,a phase III randomized controlled trial

BackgroundCombination pertuzumab, trastuzumab, and docetaxel (D) is considered standard first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. This post hoc, exploratory analysis of CLEOPATRA study data evaluated the clinical effects of D treatment duration within this regimen. The clinical benefits of pertuzumab and trastuzumab by different durations of D treatment were also evaluated.Patients and methodsPatients with HER2-positive metastatic breast cancer received trastuzumab and D plus pertuzumab or placebo. Clinical outcomes were analyzed by the number of D cycles that patients received (<6D, 6D, or >6D). Progression-free survival (PFS) and overall survival (OS) for each treatment arm within each D cycle group were estimated using the Kaplan–Meier approach. Time-dependent, multivariate Cox regression was applied to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for HER2-targeted therapy and D cycle groups.ResultsOverall, 804 patients received <6D (n = 119), 6D (n = 210), or >6D (n = 475) cycles. After adjusting for pertuzumab benefits versus placebo (PFS HR = 0.61, 95% CI 0.51–0.74, P < 0.0001; OS HR = 0.60, 95% CI, 0.49–0.74, P < 0.0001), >6D versus 6D cycles was not associated with statistically significant improvements in PFS (HR = 0.80, 95% CI 0.63–1.01, P = 0.0640) or OS (HR = 0.88, 95% CI 0.69–1.12, P = 0.3073). Consistent improvements in PFS and OS were observed with pertuzumab versus placebo, irrespective of D duration. The HRs for PFS were 0.395, 0.615, and 0.633 for <6D, 6D, and >6D cycles, respectively (P < 0.05 for all D cycle groups). Corresponding HRs for OS were 0.577, 0.700, and 0.612, respectively (P < 0.05 for <6D and >6D).ConclusionsAfter accounting for pertuzumab benefits, more than six cycles of D treatment was not associated with significant improvements in either PFS or OS compared with six cycles. The addition of pertuzumab to trastuzumab improved clinical outcomes versus trastuzumab plus placebo, regardless of D treatment duration.ClinicalTrials.gov identifierNCT00567190.     

Low-scale phosphoproteome analyses identify the mTOR effector p70 S6 kinase 1 as a specific biomarker of the dual-HER1/HER2 tyrosine kinase inhibitor lapatinib (Tykerb®) in human breast carcinoma cells

BackgroundDiscovery of key proliferative and/or survival cascades closely linked to the biological effects of human epidermal growth factor receptor (HER) 1 (erbB-1) and/or HER2 (erbB-2) inhibitors may identify a priori mechanisms responsible for the development of acquired resistance in breast cancer disease. Here, we took advantage of a semiquantitative protein array technology to identify intracellular oncogenic kinases that distinctively correlate with breast cancer cell sensitivity/resistance to the dual-HER1/HER2 tyrosine kinase inhibitor lapatinib (Tykerb®).Materials and methodsMCF-7 cells were forced to overexpress HER2 following stable transduction with pBABE-HER2 retroviruses. The Human Phospho-MAPK Array Proteome Profiler™ (R&D Systems) was used to molecularly assess the effects of both the mono-HER2 inhibitor trastuzumab (Herceptin™) and the dual-HER1/HER2 inhibitor lapatinib on 21 different oncogenic kinases. A model of acquired resistance to lapatinib (MCF-7/HER2-Lap10 cells) was established by chronically exposing MCF-7/HER2 cells to increasing concentrations of lapatinib for >10 months.ResultsTreatment of MCF-7/HER2 cells with either trastuzumab or lapatinib similarly impaired HER2-enhanced activation status (i.e. phosphorylation) of the mitogen-activated protein kinases, c-Jun N-terminal kinases 1–3 and p38α/β/γ/δ and of the serine/threonine kinases AKT, glycogen synthase kinase-3, p90 ribosomal s6 kinase1/2, and mitogen- and stress-activated protein kinase1/2. Trastuzumab was less effective than lapatinib at blocking extracellular-signal regulated kinase (ERK) 1/2 and, notably, it failed to deactivate the mammalian target of rapamycin (mTOR) effector p70S6K1. Conversely, lapatinib treatment caused a drastic decrease in the phosphorylation of p70S6K1 at ERK1/2-regulated sites (Thr⁴²¹/Ser⁴²⁴) and, as a consequence, p70S6K1 activity measured by its phospho-Thr³⁸⁹ levels was abolished. The mTOR inhibitor rapamycin was found to supraadditively increase lapatinib efficacy in MCF-7/HER2 cells [∼10-fold enhancement; combination index (CI₅₀) = 0.243 < 1.0 = additivity, P < 0.001] but not in p70S6K1 gene-amplified MCF-7 parental cells (∼1.3-fold enhancement; CI₅₀ = 0.920 ≅ 1.0 = additivity). Lapatinib-resistant MCF-7/HER2-Lap10 cells, which are capable of growing in the continuous presence of 10 μm lapatinib without significant effects on cell viability, notably exhibited a lapatinib-insensitive hyperphosphorylation of p70S6K1. Rapamycin cotreatment suppressed p70S6K1 hyperactivation and synergistically resensitized MCF-7/HER2-Lap10 cells to lapatinib (>20-fold increase in lapatinib-induced cytotoxicity; CI₅₀ = 0.175 < 1.0 = additivity).ConclusionsSerine–threonine kinase p70S6K1, a marker for mTOR activity that regulates protein translation, constitutes a specific biomarker for the biological effects of the dual-HER1/HER2 inhibitor lapatinib. The clinical implications of our data are that the efficacy of lapatinib might be enhanced with therapies that target the mTOR pathway. Rapamycin analogues such as CCI-779 (Temsirolimus) and RAD001 (Everolimus) may warrant further clinical evaluation to effectively delay or prevent the development of acquired resistance to lapatinib in HER2-positive breast cancer patients.     

Association between gain-of-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines

BackgroundThe mechanism of resistance to human epidermal growth factor receptor 2 (HER2)-targeted agents has not been fully understood. We investigated the influence of PIK3CA mutations on sensitivity to HER2-targeted agents in naturally derived breast cancer cells.Materials and methodsWe examined the effects of Calbiochem (CL)-387,785, HER2 tyrosine kinase inhibitor, and trastuzumab on cell growth and HER2 signaling in eight breast cancer cell lines showing HER2 amplification and trastuzumab-conditioned BT474 (BT474-TR).ResultsFour cell lines with PIK3CA mutations (E545K and H1047R) were more resistant to trastuzumab than the remaining four without mutations (mean percentage of control with 10 μg/ml trastuzumab: 58% versus 92%; P = 0.010). While PIK3CA-mutant cells were more resistant to CL-387,785 than PIK3CA-wild-type cells (mean percentage of control with 1 μm CL-387,785: 21% versus 77%; P = 0.001), CL-387,785 retained activity against BT474-TR. Growth inhibition by trastuzumab and CL-387,785 was more closely correlated with changes in phosphorylation of S6K (correlation coefficient, 0.811) than those of HER2, Akt, or ERK1/2. Growth of most HER2-amplified cells was inhibited by LY294002, regardless of PIK3CA genotype.Conclusions:PIK3CA mutations are associated with resistance to HER2-targeted agents. PI3K inhibitors are potentially effective in overcoming trastuzumab resistance caused by PIK3CA mutations. S6K phosphorylation is a possibly useful pharmacodynamic marker in HER2-targeted therapy.     

A phase two randomised trial of neratinib monotherapy versus lapatinib plus capecitabine combination therapy in patients with HER2+ advanced breast cancer

BackgroundThe safety and efficacy of neratinib monotherapy were compared with that of lapatinib plus capecitabine in patients with human epidermal growth factor receptor-2-positive (HER2+), locally advanced/metastatic breast cancer and prior trastuzumab treatment.MethodsPatients received neratinib 240 mg/d continuously (n = 117) or lapatinib 1250 mg/d continuously plus capecitabine 2000 mg/m² per day on days 1–14 of each 21-d cycle (n = 116). The primary aim was to demonstrate non-inferiority of neratinib for progression-free survival (PFS).FindingsThe non-inferiority of neratinib was not demonstrated when compared with lapatinib plus capecitabine (hazard ratio, 1.19; 95% confidence interval, 0.89–1.60; non-inferiority margin, 1.15). Median PFS for neratinib was 4.5 months versus 6.8 months for lapatinib plus capecitabine and median overall survival was 19.7 months versus 23.6 months. Objective response rate (neratinib, 29% versus lapatinib plus capecitabine, 41%; P = 0.067) and clinical benefit rate (44% versus 64%; P = 0.003) were lower for the neratinib arm but consistent with previously reported results. In both treatment arms, diarrhoea was the most frequently reported treatment-related adverse event of any grade (neratinib, 85% versus lapatinib plus capecitabine, 68%; P = 0.002) and of grade 3/4 (28% versus 10%; P < 0.001), but was typically managed with concomitant anti-diarrhoeal medication and/or study treatment modification. Importantly, neratinib had no significant skin toxicity.InterpretationThe results are considered as inconclusive since neither inferiority nor non-inferiority of treatment with neratinib versus lapatinib plus capecitabine could be demonstrated. The study confirmed relevant single-agent clinical activity and acceptable overall tolerability of neratinib in patients with recurrent HER2+ advanced breast cancer.     

Multicentre randomised phase II trial of gemcitabine + platinum,with or without trastuzumab,in advanced or metastatic urothelial carcinoma overexpressing Her2

AimTo investigate the efficacy and safety of gemcitabine and platinum salt, with or without trastuzumab, in patients with locally advanced or metastatic urothelial carcinoma overexpressing Her2.MethodsThe main eligibility criterion was Her2 overexpression on immunohistochemistry (IHC 2+ or 3+) of primary tumour tissue confirmed by fluorescence in situ hybridisation (FISH). Patients were randomised to Arm A: gemcitabine 1000 mg/m² (days 1 and 8) plus either cisplatin (70 mg/m²) or carboplatin (AUC = 5) (day 1 every 3 weeks) or Arm B: added trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 21 days until progression). The primary end-point was progression-free survival (PFS).ResultsAmong 563 screened patients, 75 (13.3%) were Her2 positive (IHC 2+/3+ and FISH+) and 61 met all eligibility criteria (median age, 64 years; 54/61 males; 50/61 baseline ECOG-PS 0-1; 11 locally advanced and 50 metastatic). There was no significant difference between Arms A and B in median PFS (10.2 versus 8.2 months, respectively, p = 0.689), objective response rate (65.5% versus 53.2%, p = 0.39), and median overall survival (15.7 versus 14.1 months, respectively, p = 0.684). In an exploratory analysis, trastuzumab-treated patients receiving cisplatin rather than carboplatin-based chemotherapy fared better (PFS: 10.6 versus 8.0; OS: 33.1 versus 9.5 months). Myelosuppression was the main grade 3/4 toxicity. A case of grade 3 cardiotoxicity and one death from febrile neutropenia occurred in arm B.ConclusionThe unexpectedly low incidence of Her2 overexpression precluded the detection of a significant difference in efficacy on addition of trastuzumab to platinum-based chemotherapy with gemcitabine. However, the satisfactory tolerance of the combination warrants further studies, especially of the cisplatin-based combination, in well-defined patient subsets.     

A phase II study of lapatinib monotherapy in chemotherapy-refractory HER2-positive and HER2-negative advanced or metastatic breast cancer

BackgroundThe efficacy and tolerability of the epidermal growth factor receptor/human epidermal growth factor receptor type 2 (HER2) tyrosine kinase inhibitor lapatinib in refractory metastatic breast cancer were assessed.Patients and methodsIn a phase II, open-label study, patients with previously treated HER2-positive (n = 140) or HER2-negative (n = 89) metastatic breast cancer received once-daily oral lapatinib 1500 mg/day.ResultsMost (76%) patients had received four or more lines of prior therapy. The response rate in the HER2-positive cohort was 4.3% by investigator assessment and 1.4% by independent assessment. Both assessments established that ∼6% of HER2-positive patients derived clinical benefit from lapatinib, being progression free for ≥6 months. No objective tumor responses occurred in the HER2-negative cohort. Independent review assessments of median time to progression and median progression-free survival were similar in the HER2-positive and HER2-negative cohorts (9.1 and 7.6 weeks, respectively). All responders exhibited HER2 overexpression (3+ by immunohistochemistry), and five of six responders were HER2 amplified by FISH. Lapatinib-related adverse events, including diarrhea (54%), rash (30%), and nausea (24%), were primarily mild to moderate in severity.ConclusionsLapatinib monotherapy had modest clinical activity in HER2-positive metastatic breast cancer that progressed on prior trastuzumab regimens. No apparent clinical activity was observed in chemotherapy-refractory, HER2-negative disease.     

Phase III,randomised trial of avelumab versus physician’s choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300

BackgroundThere currently are no internationally recognised treatment guidelines for patients with advanced gastric cancer/gastro-oesophageal junction cancer (GC/GEJC) in whom two prior lines of therapy have failed. The randomised, phase III JAVELIN Gastric 300 trial compared avelumab versus physician’s choice of chemotherapy as third-line therapy in patients with advanced GC/GEJC.Patients and methodsPatients with unresectable, recurrent, locally advanced, or metastatic GC/GEJC were recruited at 147 sites globally. All patients were randomised to receive either avelumab 10 mg/kg by intravenous infusion every 2 weeks or physician’s choice of chemotherapy (paclitaxel 80 mg/m² on days 1, 8, and 15 or irinotecan 150 mg/m² on days 1 and 15, each of a 4-week treatment cycle); patients ineligible for chemotherapy received best supportive care. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.ResultsA total of 371 patients were randomised. The trial did not meet its primary end point of improving OS {median, 4.6 versus 5.0 months; hazard ratio (HR)=1.1 [95% confidence interval (CI) 0.9–1.4]; P = 0.81} or the secondary end points of PFS [median, 1.4 versus 2.7 months; HR=1.73 (95% CI 1.4–2.2); P > 0.99] or ORR (2.2% versus 4.3%) in the avelumab versus chemotherapy arms, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 90 patients (48.9%) and 131 patients (74.0%) in the avelumab and chemotherapy arms, respectively. Grade ≥3 TRAEs occurred in 17 patients (9.2%) in the avelumab arm and in 56 patients (31.6%) in the chemotherapy arm.ConclusionsTreatment of patients with GC/GEJC with single-agent avelumab in the third-line setting did not result in an improvement in OS or PFS compared with chemotherapy. Avelumab showed a more manageable safety profile than chemotherapy.Trial registrationClinicalTrials.gov: NCT02625623.     

Left ventricular systolic function in HER2/neu negative breast cancer patients treated with anthracycline chemotherapy: A comparative analysis of left ventricular ejection fraction and myocardial strain imaging over 12 months

AimAnthracycline agents are undermined by their cardiotoxicity. As life expectancy following treatment is greatly improved, techniques that ensure early detection and timely management of cardiotoxicity are essential. The aim of the present study was to evaluate left ventricular (LV) systolic function with LV ejection fraction (LVEF) and two-dimensional myocardial strain up to 12 months after anthracycline chemotherapy, specifically in HER2/neu negative breast cancer patients.MethodsSeventy-eight consecutive anthracycline naïve breast cancer patients were studied before and immediately after anthracycline chemotherapy. Fifty HER2/neu negative patients were studied over 12 months with serial echocardiograms at four time points. All patients were treated with standard regimens containing anthracyclines.ResultsGlobal systolic strain was significantly reduced immediately after, and 6 months after anthracyclines (?19.0 ± 2.3% to ?17.5 ± 2.3% (P < 0.001) and ?18.2 ± 2.2% (P = 0.01) respectively). A non-uniform reduction in strain was observed each time with relative sparing of the LV apex. LVEF remained largely unchanged at both time points. Global strain normalised by 12 months in the majority of patients. Persistently reduced strain was observed in 16% (n = 8); these patients had a greater reduction in strain at 6 months (??17.2%), and had received higher cumulative anthracycline doses.ConclusionMyocardial strain imaging is more sensitive than LVEF for the early detection and intermediate term monitoring of LV systolic function following anthracycline chemotherapy in HER2/neu negative breast cancer patients, and may aid in the development of improved monitoring protocols.     

HER3 expression in patients with primary colorectal cancer and corresponding lymph node metastases related to clinical outcome

AimTo evaluate the expression and prognostic value of the epidermal growth factor receptor HER3 in patients with primary colorectal cancer (CRC) and corresponding lymph node metastases.Patient and methodsHER3 expression was analysed immunohistochemically (IHC) in primary tumours and in corresponding lymph node metastases from 236 patients with stage II and III CRC. In 58 primary tumours, fluorescence in situ hybridisation (FISH) detection was performed.ResultsHER3 was detected at high frequency in the cell membrane. Seventy percent of the primary tumours had a high HER3 expression compared to 75% in the lymph node metastases. HER3 expression in the primary tumour was an independent prognostic factor for overall survival in the entire group of patients (p = 0.026) and in the subgroup of patients with colon cancer stage II (p = 0.030). A high HER3 expression in the primary tumour was associated with worse clinical outcome. The expression of HER3 was homogenous within the primary tumour (r = 0.9, p < 0.0001) and correlated with the HER3 expression in corresponding lymph node metastases (r = 0.6, p < 0.0001). No gene amplification with respect to HER3 was seen in primary tumours using FISH analysis.ConclusionA high HER3 expression was found in 70% of the primary CRC tumours and in 75% of the corresponding lymph node metastases. HER3 expression in the tumour was an independent prognostic factor, where a high HER3 expression was associated with worse clinical outcome. There was a correlation in HER3 expression between primary tumour and corresponding lymph node metastases.     

Duration of adjuvant trastuzumab in HER2 positive breast cancer: Overall and disease free survival results from meta-analyses of randomized controlled trials

BackgroundOne year of trastuzumab, chosen empirically, improves survival of women with early-stage, HER2-positive breast cancer but also adds substantially to cost, toxicity, and inconvenience. Longer treatment does not improve outcomes, but potentiates toxicities.MethodsMedline, Embase, and major conference proceedings were searched systematically in June 2017 to identify Randomized Controlled Trials (RCTs) comparing one year versus shorter durations of trastuzumab in adjuvant treatment of breast cancer. Reported Hazard-Ratios (HR) for Overall Survival (OS) and Disease-Free Survival (DFS), and Odds-Ratio for cardiac events, with respective 95% Confidence Intervals (CI) from each study was weighted using generic inverse-variance, and pooled in a meta-analysis. Inter-study heterogeneity and sub-group difference (based on hormone-receptors and node-positivity) were assessed using I², and chi² statistics, respectively.ResultsFour studies (n = 7614) satisfied inclusion criteria. Individual RCTs had diverse pre-specified upper-limits of 95% CI for declaring non-inferiority (range: <1.15 to <1.53). Pooled results demonstrated significant improvements in OS (HR 1.28, p = 0.04), and DFS (HR 1.24, p = 0.005) with 1 year of trastuzumab compared to shorter durations. Absence of multiplicity argument allowed for declaring superiority of 1 year of trastuzumab based on our results despite non-inferiority designs of individual trials. No influence on overall effect by duration of trastuzumab in experimental arm (9 weeks versus 6 months) was noted. No statistical interaction by hormone-receptor status and node-positivity on overall results was noticed [p(sub-group difference) 0.73, and 0.52, respectively]. Odds-Ratio for cardiac events was 2.65 (p < 0.001) favoring shorter duration.ConclusionOne year of trastuzumab prolongs overall, and disease-free survivals in women with early-stage HER2 positive breast cancer compared to shorter durations and this should remain as the standard of care. Cardiotoxicity increased significantly with the 1-year treatment.     

Escalating and de-escalating treatment in HER2-positive early breast cancer

The current standard adjuvant systemic treatment of early HER2-positive breast cancer consists of chemotherapy plus 12 months of trastuzumab, with or without endocrine therapy. Several trials have investigated modifications of the standard treatment that are shorter and less resource-demanding (de-escalation) or regimens that aim at dual HER2 inhibition or include longer than 12 months of HER2-targeted treatment (escalation). Seven randomized trials investigate shorter than 12 months of trastuzumab treatment duration. The shorter durations were not statistically inferior to the 1-year duration in the 3 trials with survival results available, but 2 of the trials were small and 1 had a relatively short follow-up time of the patients at the time of reporting. The pathological complete response (pCR) rates were numerically higher in all 9 randomized trials that compared chemotherapy plus dual HER2 inhibition consisting of trastuzumab plus either lapatinib, neratinib, or pertuzumab with chemotherapy plus trastuzumab as neoadjuvant treatments, but the superiority of chemotherapy plus dual HER2-inhibition over chemotherapy plus trastuzumab remains to be demonstrated in the adjuvant setting. One year of adjuvant trastuzumab was as effective as 2 years of trastuzumab in the HERA trial, and was associated with fewer side-effects. Extending 1-year adjuvant trastuzumab treatment with 1 year of neratinib improved disease-free survival in the ExteNET trial, but the patient follow-up times are still short, and no overall survival benefit was reported. Several important trials are expected to report results in the near future and may modify the current standard.     

Extra-gain of HER2-positive cases through HER2 reassessment in primary and metastatic sites in advanced gastric cancer with initially HER2-negative primary tumours: Results of GASTric cancer HER2 reassessment study 1 (GASTHER1)

PurposeThe intratumoural heterogeneity of human epidermal growth factor receptor 2 (HER2) expression in gastric cancer is a major challenge when identifying patients who might benefit from HER2-targeting therapy. We investigated the significance of re-evaluation of HER2 status in primary sites and metastatic or recurrent sites in advanced gastric cancer patients whose primary tumours were initially HER2-negative.Patients and methodsIn part I of this study, we evaluated the significance of repeat endoscopic biopsy in unresectable or metastatic gastric cancer patients whose tumours were initially HER2-negative. In part II, we examined the HER2 positivity rate in metastatic or recurrent sites in patients whose primary tumours were HER2-negative in biopsy or surgical specimens.ResultsIn part I (n = 183), we identified patients with HER2-positive tumours for a rescued HER2 positivity rate of 8.7% (95% confidence interval [CI], 4.6–12.8%) that was associated with tumour location (diffuse stomach versus other = 0% versus 11.7%, P = 0.013), Bormann type (IV versus others = 0% versus 11.7%, P = 0.013), and initial biopsy HER2 immunohistochemistry score (0 versus 1 versus 2 = 6.7% versus 15.4% versus 25.0%, P = 0.028). Part II (n = 175) resulted in HER2 positivity of 5.7% (95% CI 2.3–9.1%) that was significantly associated with metastatic site (liver versus others = 17.2% versus 3.4%, P = 0.012). When compared with a historical control that showed HER2 positivity on initial assessment, patients who had rescued HER2 positivity had similar treatment benefits from trastuzumab-containing first-line chemotherapy.ConclusionRepeat HER2 assessment in primary and metastatic or recurrent sites is recommended in patients with advanced gastric cancer whose primary tumour is initially HER2-negative.     

Defining prognosis for women with breast cancer and CNS metastases by HER2 status

BackgroundThe purpose of this retrospective study was to determine, in a cohort of patients with breast cancer and central nervous system (CNS) metastases, the effect of trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive disease and to compare this with that of patients with HER2-negative disease.MethodsFive hundred and ninety-eight patients with invasive breast cancer, CNS metastases and known HER2 status were identified. Time to CNS metastases and survival after CNS metastases were estimated by the Kaplan–Meier method, and Cox models were fitted to determine the association between HER2 status, trastuzumab treatment and outcomes after adjustment for other patient characteristics.ResultsIn the multivariable model, patients with HER2-negative disease [Hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.15–1.95, P = 0.003] and patients with HER2-positive disease who did not receive trastuzumab (HR 2.13, 95% CI 1.51–3.00, P < 0.0001) had shorter times to CNS metastases compared with patients with HER2-positive disease who had received trastuzumab as first-line therapy for metastases. Furthermore, patients with HER2-negative disease (HR 1.66, 95% CI 1.31–2.12, P < 0.0001) and patients with HER2-positive disease who had never received trastuzumab (HR 1.34, 95% CI 0.78–2.30, P = 0.28) had an increased hazard of death compared with patients with HER2-positive disease who had received trastuzumab before or at the time of CNS metastases diagnosis.ConclusionIn our cohort of patients with breast cancer and CNS metastases, patients with HER2-positive disease treated with trastuzumab had longer times to development of and better survival from CNS metastases compared with patients with HER2-positive disease who had never received trastuzumab and patients with HER2-negative breast cancer.