Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: The optimal chemotherapy backbone for dual HER2 blockade in the neoadjuvant setting for early breast cancer is unknown. We investigated whether the addition of anthracyclines would improve pathological complete response compared with a carboplatin-taxane regimen, when given in combination with the HER2-targeted agents trastuzumab and pertuzumab. METHODS: The TRAIN-2 study is an open-label, randomised, controlled, phase 3 trial being done in 37 hospitals in the Netherlands. We recruited patients aged 18 years or older with previously untreated, histologically confirmed stage II-III HER2-positive breast cancer. Patients were randomly allocated using central randomisation software (1:1 ratio) with minimisation without a random component, stratified by tumour stage, nodal stage, oestrogen receptor status, and age, to receive 5-fluorouracil (500 mg/m2), epirubicin (90 mg/m2), and cyclophosphamide (500 mg/m2) every 3 weeks for three cycles followed by paclitaxel (80 mg/m2 on days 1 and 8) and carboplatin (area under the concentration-time curve [AUC] 6 mg/mL per min on day 1 or optionally, as per hospital preference, AUC 3 mg/mL per min on days 1 and 8) every 3 weeks for six cycles, or to receive nine cycles of paclitaxel and carboplatin at the same dose and schedule as in the anthracycline group. Patients in both study groups received trastuzumab (6 mg/kg, loading dose 8 mg/kg) and pertuzumab (420 mg, loading dose 840 mg) concurrently with all chemotherapy cycles. The primary endpoint was the proportion of patients who achieved a pathological complete response in breast and axilla (ypT0/is ypN0) in the intention-to-treat population. Safety was analysed in patients who received at least one treatment cycle according to actual treatment received. This trial is registered with ClinicalTrials.gov, number NCT01996267, and follow-up for long-term outcome is ongoing. FINDINGS: Between Dec 9, 2013, and Jan 14, 2016, 438 patients were enrolled and randomly assigned to the two treatment groups (219 patients to each group), of whom 418 were evaluable for the primary endpoint (212 in the anthracycline group and 206 in the non-anthracycline group). The median follow-up for all patients was 19 months (IQR 16-23 months). A pathological complete response was recorded in 141 (67%, 95% CI 60-73) of 212 patients in the anthracycline group and in 140 (68%, 61-74) of 206 in the non-anthracycline group (p=0·95). One patient randomly allocated to the non-anthracycline group did receive anthracyclines and was thus included in the anthracycline group for safety analyses; therefore, for the safety analyses there were 220 patients in the anthracycline group and 218 in the non-anthracycline group. Serious adverse events were reported in 61 (28%) of 220 patients in the anthracycline group and in 49 (22%) of 218 in the non-anthracycline group. The most common adverse events of any cause were grade 3 or worse neutropenia (in 131 [60%] of 220 patients in the anthracycline group vs 118 [54%] of 218 in the non-anthracycline group), grade 3 or worse diarrhoea (26 [12%] vs 37 [18%]), and grade 2 or worse peripheral neuropathy (66 [30%] vs 68 [31%]), with no substantial differences between the groups. Grade 3 or worse febrile neutropenia was more common in the anthracycline group than in the non-anthracycline group (23 [10%] vs three [1%], p<0·0001). Symptomatic left ventricular systolic dysfunction was rare in both groups (two [1%] of 220 vs 0 of 218). One patient in the anthracycline group died because of a pulmonary embolism, which was possibly treatment related. INTERPRETATION: In view of the high proportion of pathological complete responses recorded in both groups and the fact that febrile neutropenia was more frequent in the anthracycline group, omitting anthracyclines from neoadjuvant treatment regimens might be a preferred approach in the presence of dual HER2 blockade in patients with early HER2-positive breast cancer. Long-term follow-up is required to confirm these results. FUNDING: Roche Netherlands.

Early On-treatment Circulating Tumor DNA Measurements and Response to Immune Checkpoint Inhibitors in Advanced Urothelial Cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) can induce durable disease control in metastatic urothelial cancer (mUC), but only 20-25% of patients respond. Early identification of a nondurable response will improve management strategies. OBJECTIVE: To investigate whether on-treatment circulating tumor DNA (ctDNA) measurements can predict ICI responsiveness in mUC patients. DESIGN, SETTING, AND PARTICIPANTS: This study consists of a discovery cohort of 40 mUC patients and a prospective multicenter validation cohort of 16 mUC patients. Plasma cell-free DNA was collected at baseline and after 3 and 6 wk on ICIs. The ctDNA levels were calculated from targeted sequencing. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcome measurements were progression-free survival (PFS), overall survival (OS), and nondurable response (PFS ≤6 mo). Relationships with ctDNA were assessed using Cox regression. Changes in ctDNA level at 3 and 6 wk were categorized by an increase or decrease relative to baseline. RESULTS AND LIMITATIONS: In the discovery cohort, ctDNA was detected in 37/40 (93%) of patients at baseline. A ctDNA increase was observed in 12/15 (80%) and ten of 12 (83%) patients with a nondurable response at 3 and 6 wk, respectively. Of patients with a durable response (PFS >6 mo), 94% showed a decrease. A ctDNA increase at 3 wk was associated with shorter PFS (hazard ratio [HR] 7.8, 95% confidence interval [CI] 3.1-19.5) and OS (HR 8.0, 95% CI 3.0-21.0), independent of clinical prognostic variables. Similar results were observed at 6 wk. The 3-wk association with PFS was validated in a prospective cohort (HR 7.5, 95% CI 1.3-42.6). Limitations include the limited number of patients. CONCLUSIONS: Early changes in ctDNA levels are strongly linked to the duration of ICI benefit in mUC and may contribute to timely therapy modifications. PATIENT SUMMARY: Benefit from immunotherapy can be predicted after only 3 wk of treatment by investigating cancer DNA in blood. This could help in timely therapy changes for urothelial cancer patients with limited benefit from immunotherapy.

The Impact of Baseline PSMA PET/CT Versus CT on Outcomes of 223Ra Therapy in Metastatic Castration-Resistant Prostate Cancer Patients.

Imaging before 223Ra-dichloride (223Ra) therapy is crucial for selecting metastatic castration-resistant prostate cancer (mCRPC) patients with bone-only disease. The purpose of this study was to evaluate if baseline prostate-specific membrane antigen (PSMA) PET/CT (bPSMA) versus CT is associated with outcomes of 223Ra therapy. Methods: A secondary analysis of the data of a prospective observational study (NCT04995614) was performed. Patients received a maximum of 6 223Ra cycles and were retrospectively divided into the bPSMA or baseline CT (bCT) groups. All patients received baseline bone scintigraphy. Primary endpoints were alkaline phosphatase and prostate-specific antigen response. Secondary endpoints were overall survival (OS) and radiologic response. Results: Between 2017 and 2020, 122 mCRPC patients were included: 18 (14.8%) in the bPSMA group and 104 (85.2%) in the bCT group. All baseline characteristics were comparable. No significant differences in alkaline phosphatase or prostate-specific antigen response were found. The bCT group showed an OS significantly shorter than that of the bPSMA group (12.4 vs. 19.9 mo, P = 0.038). In 31 of 76 patients (40.1%) in the bCT group who also received posttherapy CT, lymph node or visceral metastases (soft-tissue involvement [STI]) were detected after 223Ra therapy, compared with 0 of 15 patients in the bPSMA group who received posttherapy PSMA PET/CT or CT. No significant difference in OS was found between patients in the bCT or posttherapy CT subgroup without STI (46/76) and the bPSMA group. Conclusion: bPSMA versus CT does not seem to impact biochemical response during 223Ra therapy in mCRPC patients. Nevertheless, patients in the bCT group had a significantly shorter OS, most likely due to underdetection of STI in this group. Therefore, replacing bCT with PSMA PET/CT appears to be a valuable screening method for identifying patients who will benefit most from 223Ra therapy.

Comparing treatment and outcomes in advanced esophageal, gastroesophageal junction, and gastric adenocarcinomas: a population-based study.

Background: Treatment of advanced or metastatic esophageal adenocarcinoma (EAC) follows the guidelines for gastroesophageal junction adenocarcinoma (GEJC) and gastric adenocarcinoma (GAC), but patients with EAC are often excluded from clinical studies of GEJC/GAC. Objectives: Here we describe treatment and survival of patients with advanced EAC, GEJC, and GAC to provide population-based evidence on distinctions and similarities between these populations. Design: Retrospective cohort study of patients with unresectable advanced (cT4b) or metastatic (cM1) EAC, GEJC, or GAC (2015-2020) were selected from the Netherlands Cancer Registry. Methods: Overall survival (OS) was assessed using Kaplan-Meier methods, log-rank tests, and multivariable Cox regression. Results: In all, 7391 patients were included (EAC: n = 3346, GEJC: n = 1246, and GAC: n = 2798). Patients with EAC were more often males and more often had ⩾2 metastatic locations. First-line systemic therapy was received by 42%, 47%, and 36% of patients with EAC, GEJC, and GAC, respectively. Median OS was 5.0, 5.1, and 4.0 months for all patients with EAC, GEJC, and GAC, respectively (p < 0.001). Median OS from start of first-line therapy of patients with human epidermal growth factor receptor 2 (HER2)-negative adenocarcinomas was 7.6, 7.8, and 7.5 months (p = 0.12) and of patients with HER2-positive carcinoma receiving first-line trastuzumab-containing therapy was 11.0, 13.3, and 9.5 months (p = 0.37) in EAC, GEJC, and GAC, respectively. After multivariable adjustment, no difference in OS for patients with EAC, GEJC, and GAC was observed. Conclusion: Despite differences in clinical characteristics and treatment strategies, survival between patients with advanced EAC, GEJC, and GAC was similar. We advocate that EAC patients should not be excluded from clinical trials for patients with molecularly similar GEJC/GAC.

Health-related quality of life, psychological distress, and fatigue in metastatic castration-resistant prostate cancer patients treated with radium-223 therapy.

BACKGROUND: Radium-223 is a registered treatment option for symptomatic bone metastatic castration-resistant prostate cancer (mCRPC). Aim of this multicenter, prospective observational cohort study was to evaluate health-related quality of life (HR-QoL), psychological distress and fatigue in mCRPC patients treated with radium-223. METHODS: Primary endpoint was cancer-specific and bone metastases-related HR-QoL, as measured by the EORTC QLQ-C30 and BM-22 questionnaires. Secondary endpoints were psychological distress and fatigue, evaluated by the HADS and CIS-Fatigue questionnaires. Outcomes were analyzed for the total cohort and between subgroups (1-3 versus 4-5 versus 6 radium-223 injections). A trajectory analysis was performed to explore HR-QoL patterns over time. RESULTS: In total, 122 patients were included for analysis. Baseline HR-QoL, pain intensity, psychological distress and fatigue were worse in patients who did not complete radium-223 therapy. In patients who completed therapy, stabilization of HR-QoL was perceived and psychological distress and fatigue remained stable, whereas clinically meaningful and statistically significant deterioration of HR-QoL, psychological distress and fatigue over time was observed in patients who discontinued radium-223 therapy. Trajectory analysis revealed that HR-QoL deterioration over time was more likely in patients with baseline opioid use, low hemoglobin and high alkaline phosphatase levels. CONCLUSIONS: Patients who discontinued radium-223 therapy showed worse HR-QoL, psychological distress and fatigue at baseline and more frequent deterioration of HR-QoL, psychological distress and fatigue over time when compared to patients who completed therapy. Specific attention with regard to HR-QoL during follow-up is indicated in patients with opioid use, low hemoglobin and high alkaline phosphatase levels before radium-223 therapy initiation. CLINICAL TRIAL REGISTRATION NUMBER: NCT04995614.

Liquid biopsy reveals KLK3 mRNA as a prognostic marker for progression free survival in patients with metastatic castration-resistant prostate cancer undergoing first-line abiraterone acetate and prednisone treatment.

Circulating RNAs extracted from liquid biopsies represent a promising source of cancer- and therapy-related biomarkers. We screened whole blood from patients with metastatic castration-resistant prostate cancer (mCRPC) following their first-line treatment with abiraterone acetate and prednisone (AA-P) to identify circulating RNAs that may correlate with progression-free survival (PFS). In a prospective multicenter observational study, 53 patients with mCRPC were included after they started first-line AA-P treatment. Blood was drawn at baseline, 1, 3, and 6 months after treatment initiation. The levels of predefined circulating RNAs earlier identified as being upregulated in patients with mCRPC (e.g., microRNAs, long noncoding RNAs, and mRNAs), were analyzed. Uni- and multivariable Cox regression and Kaplan-Meier analyses were used to analyze the prognostic value of the various circulating RNAs for PFS along treatment. Detectable levels of kallikrein-related peptidase 3 (KLK3) mRNA at baseline were demonstrated to be an independent prognostic marker for PFS (201 vs 501 days, P = 0.00054). Three months after AA-P treatment initiation, KLK3 could not be detected in the blood of responding patients, but was still detectable in 56% of the patients with early progression. Our study confirmed that KLK3 mRNA detection in whole blood is an independent prognostic marker in mCRPC patients receiving AA-P treatment. Furthermore, the levels of circulating KLK3 mRNA in patients receiving AA-P treatment might reflect treatment response or early signs of progression.

Three-Year Follow-up of Neoadjuvant Chemotherapy With or Without Anthracyclines in the Presence of Dual ERBB2 Blockade in Patients With ERBB2-Positive Breast Cancer: A Secondary Analysis of the TRAIN-2 Randomized, Phase 3 Trial.

IMPORTANCE: Primary analysis of the TRAIN-2 study showed high pathologic complete response rates after neoadjuvant chemotherapy with or without anthracyclines plus dual ERBB2 (formerly HER2) blockade. OBJECTIVE: To evaluate 3-year event-free survival (EFS) and overall survival (OS) of an anthracycline-free and anthracycline-containing regimen with dual ERBB2 blockade in patients with stage II and III ERBB2-positive breast cancer. DESIGN, SETTING, AND PARTICIPANTS: A total of 438 patients with stage II and III ERBB2-positive breast cancer were enrolled in this randomized, clinical, open-label phase 3 trial across 37 hospitals in the Netherlands from December 9, 2013, until January 14, 2016. Follow-up analyses were performed after a median follow-up of 48.8 months (interquartile range, 44.1-55.2 months). Analysis was performed on an intention-to-treat basis. INTERVENTIONS: Participants were randomly assigned on a 1:1 basis, stratified by age, tumor stage, nodal stage, and estrogen receptor status, to receive 3 cycles of fluorouracil (500 mg/m2), epirubicin (90 mg/m2), and cyclophosphamide (500 mg/m2), followed by 6 cycles of paclitaxel and carboplatin or 9 cycles of paclitaxel (80 mg/m2 days 1 and 8) and carboplatin (area under the concentration-time curve, 6 mg/mL/min). Both groups received trastuzumab (6 mg/kg; loading dose 8 mg/kg) and pertuzumab (420 mg intravenously; loading dose 840 mg) every 3 weeks. MAIN OUTCOMES AND MEASURES: Three-year EFS, OS, and safety. RESULTS: A total of 438 women were randomized, with 219 per group (anthracycline group, median age, 49 years [interquartile range, 43-55 years]; and nonanthracycline group, median age, 48 years [interquartile range, 43-56 years]). A total of 23 EFS events (10.5%) occurred in the anthracycline group and 21 EFS events (9.6%) occurred in the nonanthracycline group (hazard ratio, 0.90; 95% CI, 0.50-1.63; favoring nonanthracyclines). Three-year EFS estimates were 92.7% (95% CI, 89.3%-96.2%) in the anthracycline group and 93.6% (95% CI, 90.4%-96.9%) in the nonanthracycline group and 3-year OS estimates were 97.7% (95% CI, 95.7%-99.7%) in the anthracycline group and 98.2% (95% CI, 96.4%-100%) in the nonanthracycline group. The results were irrespective of hormone receptor and nodal status. A decline in left ventricular ejection fraction of 10% or more from baseline to less than 50% was more common in patients who received anthracyclines than those who did not (17 of 220 [7.7%] vs 7 of 218 [3.2%]; P = .04). Two patients treated with anthracyclines developed acute leukemia. CONCLUSIONS AND RELEVANCE: This follow-up analysis of the TRAIN-2 study shows similar 3-year EFS and OS estimates with or without anthracyclines in patients with stage II and III ERBB2-positive breast cancer. Anthracycline use is associated with increased risk of febrile neutropenia, cardiotoxic effects, and secondary malignant neoplasms. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01996267.

RNA Biomarkers as a Response Measure for Survival in Patients with Metastatic Castration-Resistant Prostate Cancer.

Treatment evaluation in metastatic castration-resistant prostate cancer is challenging. There is an urgent need for biomarkers to discriminate short-term survivors from long-term survivors, shortly after treatment initiation. Thereto, the added value of early RNA biomarkers on predicting progression-free survival (PFS) and overall survival (OS) were explored. The RNA biomarkers: KLK3 mRNA, miR-375, miR-3687, and NAALADL2-AS2 were measured in 93 patients with mCRPC, before and 1 month after start of first-line abiraterone acetate or enzalutamide treatment, in two prospective clinical trials. The added value of the biomarkers to standard clinical parameters in predicting PFS and OS was tested by Harell's C-index. To test whether the biomarkers were independent markers of PFS and OS, multivariate Cox regression was used. The best prediction model for PFS and OS was formed by adding miR-375 and KLK3 (at baseline and 1 month) to standard clinical parameters. Baseline miR-375 and detectable KLK3 after 1 month of therapy were independently related to shorter PFS, which was not observed for OS. In conclusion, the addition of KLK3 and miR-375 (at baseline and 1 month) to standard clinical parameters resulted in the best prediction model for survival assessment.

Toxicity of dual HER2-blockade with pertuzumab added to anthracycline versus non-anthracycline containing chemotherapy as neoadjuvant treatment in HER2-positive breast cancer: The TRAIN-2 study.

BACKGROUND: The addition of pertuzumab to neoadjuvant trastuzumab-based chemotherapy improves pathologic complete response rates in HER2-positive breast cancer. However, increased toxicity has been reported with the addition of pertuzumab, and this may differ between various chemotherapy backbone regimens. We evaluated toxicities of pertuzumab when added to either FEC-T (5-fluorouracil, epirubicin, cyclophosphamide, trastuzumab) or weekly paclitaxel, trastuzumab, carboplatin (PTC). METHODS: The TRAIN-2 study is a neoadjuvant randomized controlled trial in stage II and III HER2-positive breast cancer (NCT01996267). Patients are randomly assigned to receive either three cycles of FEC-T plus pertuzumab or three cycles of PTC plus pertuzumab, followed by six cycles of PTC plus pertuzumab in both arms. Toxicities are described per treatment arm according to the Common Toxicity Criteria for Adverse Events version 4.03. RESULTS: This analysis includes 110 patients balanced over both treatment arms. Neutropenia was the most common hematologic toxicity, with grade 3-4 occurring in 53% in the FEC-T-arm and in 51% in the PTC-arm. Febrile neutropenia occurred in 9% in the FEC-T arm and did not occur in the PTC-arm. Secondary G-CSF prophylaxis was used in 35-40% of patients. Asymptomatic ejection fraction decrease grade 2 was observed in 24% in the FEC-T-arm and 11% in the PTC-arm. The most common grade 3-4 non-hematologic toxicity was diarrhea (5% in the FEC-T-arm and 18% in the PTC-arm). CONCLUSIONS: Pertuzumab in combination with FEC-T mostly causes neutropenia, and when added to PTC mostly causes diarrhea. Significant cardiac toxicity is rare with both regimens, and toxicity is overall well manageable.

Molecular causes of colon cancer.

Cells in a developing embryo communicate with each other through a limited number of intercellular signalling pathways, of which the Wnt signalling pathway is one. Little is known about the function of Wnt signalling beyond that in embryogenesis. However, recent insights into the molecular etiology of colon cancer have implied a central role for the Wnt signalling pathway. The malignant transformation of colorectal epithelium is well defined, leading to adenoma and sequentially carcinoma formation. Several genes that regulate the Wnt pathway are mutated in cancer of the human colon and other organs. All of these mutations lead to the inappropriate activation of the pathway, which instructs the cell to divide unrestrictedly. These insights now allow the Wnt pathway to be exploited as a new target for drug development in colon cancer.