Rimawi, MF

Abstract Background: Estrogen receptor (ER)-negative tumors and human epidermal growth factor 2-Neu (HER2) positive breast cancers are known to be more clinically aggressive subtypes of breast cancer and account for 30% of all breast cancers. Women with HER2 + breast cancers, whether ER+ or ER -, require cytotoxic chemotherapy with a HER2-targeting agent, and often have adverse outcomes. Thus, preventive agents are needed to reduce the incidence of these subtypes of aggressive breast cancer. Lapatinib, a dual tyrosine kinase inhibitor, inhibits epidermal growth factor receptors (EGFR) and HER2 kinases and has shown to decrease breast cell proliferation in invasive breast cancer and adjacent premalignant lesions. Therefore, we conducted a multi-institutional randomized Phase II clinical trial to study the effects of the signal transduction inhibitor lapatinib in women with HER2-positive or EGFR-positive ductal carcinoma in situ (DCIS). Methods: Randomized participants received either lapatinib (750mg, 1000mg, or 1500mg) or placebo daily for 2-6 weeks prior to their surgery. After minimal accrual, the trial was later amended to lapatinib 1000mg or placebo. Pre-treatment breast tissue was obtained from initial diagnostic core biopsy and post-treatment breast tissue was obtained from surgical excision specimen. Blood was obtained prior to surgery to assess serum lapatinib level. Participants kept a daily symptom assessment log and had a cardiac assessment at baseline and prior to surgery. Patients were instructed to take drug up to and including the day before surgery. The dual primary endpoint for this study was change in proliferation in pre- versus post-treatment biopsies between the two treatment arms, as measured by Ki67 as well as toxicity assessment. Secondary endpoints included incidence of DCIS at surgery and modulation of tissue biomarker expression in growth factor receptors (EGFR, ErbB2); phosphorylated growth factor receptor (phospho-ErbB2); signal transduction markers (MAPK, phospho-MAPK); hormone receptors (ER, PR); and p27. Results:Twenty-two women (mean age: 51; range: 32-66) with HER2+ or EGFR+ DCIS were treated with lapatinib (1,000 or 1,500 mg) or placebo for 2–6 weeks prior to surgical excision. Ki67 expression was significantly decreased in the lapatinib treatment arms compared to placebo (p=0.0122). Diarrhea, fatigue, and skin reactions were notable adverse events that occurred predominately in the lapatinib arm compared to placebo. No grade 3 or 4 events related to the study drug were noted during the study. No changes were noted in cardiac function. DCIS was present in all surgical specimens in both arms. Invasive breast cancer was noted in 1 patient on lapatinib 1000mg and 3 patients on placebo. No statistically significant changes were noted in signal transduction biomarkers Conclusion:These results demonstrate the effectiveness of lapatinib in reducing proliferation in women with EGFR+ or HER2+ DCIS. Even low-grade toxicities can deter use of an agent in the prevention setting. This and the lack of a risk model for HER2+ and triple negative breast cancer make the development of larger scale clinical prevention trials of lapatinib for the prevention a challenge. Citation Format: Thomas PS, Contreras A, Pruthi S, Krontiras H, Rimawi M, Garber J, Wang T, Hilsenbeck SG, Vornik LA, Gilmer T, Friedman R, Heckman-Stoddard BM, Dunn B, Kuerer H, Brown PH. A phase II pre-surgical trial of lapatinib for the treatment of women with HER2 positive or EGFR positive ductal carcinoma in situ [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD3-07.

Abstract We have recently reported that in patients with HER2-positive breast cancer, neoadjuvant targeted therapy with lapatinib and trastuzumab to more completely block the HER receptor layer, combined with endocrine therapy (in ER-positive tumors) and without chemotherapy led to a substantial 27% pathologic complete response (pCR) rate in the breast. Activation of downstream signaling pathways may lead to resistance to therapies targeting the HER pathway receptors. Aberrant activation of the PI3K pathway via decreased levels of PTEN and/or the presence of activating PIK3CA mutations has been implicated in resistance to targeted anti-HER2 therapy, but results of clinical trials are all confounded by the co-administration of chemotherapy and are inconsistent. We sought to clarify the role of these variables in predicting pCR, a surrogate for long-term outcome, in patients treated with potent targeted therapy alone in a prospective Phase II neoadjuvant trial in patients with HER2-positive breast cancer. Patients with large tumors (median 6 cm) were given 12 weeks of lapatinib plus trastuzumab followed by surgery (Rimawi et al. JCO, 2013). Serial tissue biopsies were obtained from study participants. For this study, we focused on baseline pre-treatment characteristics. PTEN protein levels were measured by IHC and scored using the H-score. PIK3CA mutations were identified on extracted DNA using multiplex PCR with targeted next generation sequencing (the Ion Torrent 50-gene cancer mutation panel). Of 64 evaluable patients, tissue was available on 59 for PTEN IHC, and sufficient DNA was available on 33 for the mutation panel. PTEN median H-score was 100 (range 0-300). PTEN status when dichotomized by the median was correlated with pCR (32% in high PTEN vs. 9% in low PTEN, p = 0.04). Activating PIK3CA mutations were identified in 12 out of 33 tumors (36%; 3 mutations in the helical and 9 in the catalytic domain) and were independent of ER status. None of the patients whose tumors harbored a PIK3CA mutation achieved pCR (p = 0.06). There was no association between PTEN status and PIK3CA mutation suggesting they are independent variables (p = 0.44). When PIK3CA mutations were considered together with PTEN status, there were 31 cases with data on both. The overall pCR rate in this cohort was 16% (lower than pCR rate observed in the overall trial). However, 0/17 cases (0%) with a mutation and/or PTEN low expression (<100 H score) had a pCR compared to 5/14 cases (36%) with PI3KCA wild type and high PTEN levels (p = 0.01). We conclude that PI3K pathway activation downstream of HER2 as a result of either low PTEN or activating PIK3CA mutation results in resistance to the combination of lapatinib and trastuzumab. This is the first report on patient tissue samples from a neoadjuvant trial using the combination of lapatinib and trastuzumab without chemotherapy. If validated in a larger cohort, our findings suggest that patients with HER2 positive tumors and who also harbor aberrant downstream PI3K pathway activation may benefit from the addition of PI3K/Akt/mTOR inhibitors to potent HER2 blockade. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD1-2.

Abstract Background: Imaging biomarkers of cellular division offer promise as non-invasive measures of tumor response. 3’-deoxy-3’[18F]-fluorothymidine ([18F]-FLT) positron emission tomography (PET) imaging generally correlates with pathology-based measurements of cancer proliferation, especially the Ki67 score. Though clinical studies have associated changes in [18F]-FLT uptake with therapeutic response, clinical studies validating its ability to assess cell proliferation are comparatively lacking. The goal of this study was to determine quantitative relationships between [18F]-FLT compared with molecular and cellular metrics of proliferation during treatment for locally advanced breast cancer (LABC). Methods: Baseline [18F]−FLT-PET scans were obtained prior to the initiation of chemotherapy for LABC from patients enrolled at several academic oncology study sites. MRI scans, and transmission CT scans were obtained. Core needle biopsies were obtained to determine Ki-67 indices using immuno-histochemistry and to assess an mRNA signature based measurement of proliferation. Prospectively specified quantitative relationships between PET, Ki67 immunohistochemistry and the mRNA signature were evaluated using image-matched tumor specimens. Correlations between volumetric MRI changes and pathologic responses were evaluated in a post-hoc exploratory analysis. Results: Motivated by the hypothesis that effective chemotherapies should decrease tumor cell proliferation, FLT-PET was compared with biomarkers of proliferation including Ki67 and the mRNA signature during neoadjuvant treatment for LABC. [18F]-FLT correlated both with the Ki67 labeling index (SUVmean r = 0.53) and with the proliferation signature (SUVmean r = 0.7), validating the principle of thymidine analogue imaging. However, variability in the [18F]-FLT PET and tumor cell proliferation measures likely contributed to correlations less than pre-specified target values considered appropriate for clinical use (r > 0.78). Moreover, none of the proliferation biomarkers predicted pathologic complete responses at the end of neoadjuvant therapy ∼16 weeks after the 3 week response scan. In contrast, an evaluation of change in tumor volume measured by MRI after 3 weeks of therapy confirmed its superior ability to predict pCR and tumor re-staging. Conclusion: With large numbers of cancer drugs entering therapeutic pipelines, early efficacy measures remain critical for drug development. The 3-4 month neoadjuvant treatment paradigm for LABC offers unique opportunities for drug evaluation. Functional imaging using [18F]-FLT has been advanced as an assessor of cellular proliferation, potentially offering a non-invasive approach to response evaluation. While [18F]-FLT generally correlated with proliferation, its lack of association with patient responses likely limit its clinical utility. On the other hand, the predictive value of MRI offers unique opportunities for future trial designs and confirms previous reports (1). 1. N. M. Hylton et al., Locally advanced breast cancer: MR imaging for prediction of response to neoadjuvant chemotherapy. Radiology 263, 663 (2012). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-01-11.

Abstract Background We evaluated the safety and efficacy of L+T in pts with 0–2 prior lines of chemotherapy (CT) for HER2+ MBC. In the context of this phase II trial, we evaluated metabolic response by FDG-PET and explored the relationship between metabolic response and clinical outcomes. Methods: Pts with measurable, HER2+ MBC were eligible. Cohort 1: No prior T, L, or CT +T for MBC, and >1 yr from adjuvant T, if received. Cohort 2: 1–2 prior lines of CT for MBC, including T, or relapse within 1 yr of adjuvant T. Pts received L 1,000 mg QD + T (2 mg/kg weekly or 6 mg/kg Q3W). Staging studies were done with CT or MRI at baseline (BL) and every 2 cycles (1 cycle=4 weeks [wks]). Objective response was assessed by local investigator according to RECIST 1.0. FDG-PET/CT was performed at BL, Wk 1, and Wk 8 per NCI guidelines. Central quality assurance, review, and analysis were performed on FDG-PET studies. Up to 5 target lesions were identified on BL FDG-PET images based on hypermetabolic uptake. Percent change in the summed maximum standardized uptake value (SUVmax) of target lesions was calculated at Wk 1 or Wk 8, compared to BL. Metabolic response was assessed according to EORTC criteria for % change in SUVmax (progressive disease [PD]: ≥25% increase; partial response [PR]: ≥25% decrease; stable disease [SD]: <25% change). Metabolic response at Wk 1 was compared to Wk 8 as well as to clinical outcome, including objective response, clinical benefit, and progression-free survival (PFS). Results: 87 pts were registered to the study. Of these, one pt did not begin protocol therapy and one pt did not have MBC on further testing, and are not included. 81/85 pts had FDG-PET data at Wk 1; 75/85 had data at Wk 8. Metabolic PR at Wk 1 was observed in 28/39 (72%) pts in Cohort 1 and 20/42 (48%) pts in Cohort 2. Metabolic PR at Wk 8 was observed in 27/34 (79%) pts in Cohort 1 and 18/41 (44%) pts in Cohort 2. Wk 1 and Wk 8 metabolic responses were similar. In cohort 1, 18/28 (64%) pts who achieved Wk 1 metabolic PR had clinical benefit by RECIST. Of pts with Wk 1 metabolic SD, 2/9 (22%) had clinical benefit. In cohort 2, 9/20 (45%) pts who achieved Wk 1 metabolic PR had clinical benefit; 5/22 (23%) who achieved Week 1 metabolic SD had clinical benefit. Exploratory analysis of progression-free survival (PFS) showed that pts in Cohort 1 who achieved Wk 1 metabolic PR experienced a median PFS of 9.3 months ([mos]; 95% CI 5.6−22.3); for pts with metabolic SD, median PFS was 1.9 mos (95% CI 0.8−5.5). For pts in Cohort 2, Wk 1 metabolic PR was associated with median PFS of 5.6 mos (95% CI 3.7−7.8), whereas for pts with metabolic SD, median PFS was 3.7 mos (95% CI 1.8−5.5). Conclusions: L+T is associated with a high rate of early and sustained metabolic response by FDG-PET. Exploratory analyses suggest that metabolic PR may be associated with clinical benefit and longer PFS. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-09-07.