Purpose Patients with HER2-positive metastatic breast cancer (MBC) usually receive many years of trastuzumab treatment. It is unknown whether these patients require continuous left ventricular ejection fraction (LVEF) monitoring. We studied a real-world cohort to identify risk factors for cardiotoxicity to select patients in whom LVEF monitoring could be omitted. Methods We included patients with HER2-positive MBC who received > 1 cycle of trastuzumab-based therapy in eight Dutch hospitals between 2000 and 2014. Cardiotoxicity was defined as LVEF < 50% that declined > 10%-points and was categorized into non-severe cardiotoxicity (LVEF 40–50%) and severe cardiotoxicity (LVEF < 40%). Multivariable Cox and mixed model analyses were performed to identify risk factors associated with cardiotoxicity. Additionally, we explored the reversibility of cardiotoxicity in patients who continued trastuzumab. Results In total, 429 patients were included. Median follow-up for cardiotoxicity was 15 months (interquartile range 8–31 months). The yearly incidence of non-severe + severe cardiotoxicity in the first and second year was 11.7% and 9.1%, respectively, which decreased thereafter. The yearly incidence of severe cardiotoxicity was low (2.8%) and stable over time. In non-smoking patients with baseline LVEF > 60% and no cardiotoxicity during prior neoadjuvant/adjuvant treatment, the cumulative incidence of severe cardiotoxicity was 3.1% after 4 years of trastuzumab. Despite continuing trastuzumab, LVEF decline was reversible in 56% of patients with non-severe cardiotoxicity and in 33% with severe cardiotoxicity. Conclusions Serial cardiac monitoring can be safely omitted in non-smoking patients with baseline LVEF > 60% and without cardiotoxicity during prior neoadjuvant/adjuvant treatment.

In this study, we explored the predictive value of serum microRNA (miRNA) expression for early tumor progression during FOLFIRINOX chemotherapy and its association with overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC). A total of 132 PDAC patients of all disease stages were included in this study, of whom 25% showed progressive disease during FOLFIRINOX according to the RECIST criteria. MiRNA expression was analyzed in serum collected before the start and after one cycle of chemotherapy. In the discovery cohort (n = 12), a 352-miRNA RT-qPCR panel was used. In the validation cohorts (total n = 120), miRNA expression was detected using individual RT-qPCR miRNA primers. Before the start of FOLFIRINOX, serum miR-373-3p expression was higher in patients with progressive disease compared to patients with disease control after FOLFIRINOX (Log2 fold difference (FD) 0.88, p = 0.006). MiR-194-5p expression after one cycle of FOLFIRINOX was lower in patients with progressive disease (Log2 FD −0.29, p = 0.044). Both miRNAs were predictors of early tumor progression in a multivariable model including disease stage and baseline CA19-9 level (miR-373-3p odds ratio (OR) 3.99, 95% CI 1.10–14.49; miR-194-5p OR 0.91, 95% CI 0.83–0.99). MiR-373-3p and miR-194-5p did not show an association with OS after adjustment for disease stage, baseline CA19-9, and chemotherapy response. In conclusion, high serum miR-373-3p before the start and low serum miR-194-5p after one cycle are associated with early tumor progression during FOLFIRINOX.

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Background pCR rates in stage II – III HER2-positive breast cancer have greatly improved since the addition of HER2 targeted agents to neoadjuvant chemotherapy and are associated with excellent long-term survival. While longer treatment regimens increase pCR rate, early complete responses are also common. We evaluated an image-guided approach to tailor chemotherapy duration based on the identification of early complete responders. Methods 45 hospitals across the Netherlands participated in the phase 2 TRAIN-3 trial. Patients received neoadjuvant systemic treatment consisting of paclitaxel, trastuzumab, carboplatin and pertuzumab (PTC-Ptz). Response to treatment was monitored every three cycles and patients were referred for surgery in case of a radiologic complete response (rCR) or after a maximum of 9 cycles. RCR was defined as the absence of pathological enhancement on MRI breast plus negative vacuum assisted core biopsies in case of hormone-receptor positive (HR+) tumors. In addition, negative fine needle aspiration or lymph node biopsy was required in patients with nodal involvement at baseline. The primary endpoint was 3-year event-free survival (EFS). Here, we report locally assessed rCR and pCR rates after 3, 6 and 9 cycles, the negative predictive value of rCR assessment and the incidence of adverse events (AEs). Analyses are stratified by HR-status. Results We included 467 patients between April 2019 and May 2021. Median age was 51 years, 69% had stage II disease and 232 had HR+ tumors. 33.6% of HR- patients and 15.5% of HR+ patients achieved pCR after 3 cycles of PTC-Ptz (see table). The NPV was higher in HR- patients and independent of the number of cycles. AE evaluation is currently ongoing. Conclusion Three cycles of PTC-Ptz induce an early pCR in one in three HR- and one in six HR+ tumors in patients with stage II-III HER2+ breast cancer. Dynamic contrast enhanced MRI-based response evaluation identifies these patients with ±87% certainty in HR- disease and ±58% in HR+ disease. Continuation of PTC-Ptz after 6 cycles further improves pCR rates and can be considered to reduce the need for adjuvant T-DM1. Efficacy and safety of this image-guided approach to tailor treatment duration need to be confirmed with follow-up in EFS and OS analyses. Table 1: Cumulative rCR & pCR according to HR-status *Including patients who underwent surgery for other reasons than rCR Citation Format: Anna van der Voort, Mette S. van Ramshorst, Rob Kessels, Ingrid A. Mandjes, Inge Kemper, Mariëtte J. Agterof, Wim A. van der Steeg, Joan B. Heijns, Marlies L. van Bekkum, Ester J. Siemerink, Philomeen M. Kuijer, Astrid Scholten, Jelle Wesseling, Marie-Jeanne T.F.D. Vrancken Peeters, Ritse M. Mann, Gabe S. Sonke. Image-guided optimization of neoadjuvant chemotherapy duration in stage II and III HER2-positive breast cancer: radiologic and pathologic complete response (pCR) rates in the multicenter phase 2 TRAIN-3 study (BOOG 2018-01) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-06.

We investigated the effect of trastuzumab on cardiac function in a real-world historic cohort of patients with HER2-positive metastatic breast cancer (MBC) with reduced baseline left ventricular ejection fraction (LVEF). Thirty-seven patients with HER2-positive MBC and baseline LVEF of 40% to 49% were included. Median LVEF was 46% (interquartile range [IQR] 44%-48%) and median follow-up was 18 months (IQR 9-34 months). During this period, the LVEF did not worsen in 24/37 (65%) patients, while 13/37 (35%) patients developed severe cardiotoxicity defined as LVEF <40% with median time to severe cardiotoxicity of 7 months (IQR 4-10 months) after beginning trastuzumab. Severe cardiotoxicity was reversible (defined as LVEF increase to a value <5%-points below baseline value) in 7/13 (54%) patients, partly reversible (defined as absolute LVEF increase ≥10%-points from nadir to a value