Aparna Parikh

Convergent Therapeutic Strategies to Overcome the Heterogeneity of Acquired Resistance in BRAFV600E Colorectal Cancer

Clonal heterogeneity associated with acquired resistance presents a critical therapeutic challenge. Whole-exome sequencing of paired tumor biopsies and targeted sequencing of cell-free DNA (cfDNA) from patients with BRAFV600E colorectal cancer receiving BRAF inhibitor combinations identified 14 distinct alterations in MAPK pathway components driving acquired resistance, with as many as eight alterations in a single patient. We developed a pooled clone system to study clonal outgrowth during acquired resistance, in vitro and in vivoIn vitro, the dynamics of individual resistant clones could be monitored in real time in cfDNA isolated from culture media during therapy. Outgrowth of multiple resistant clones was observed during therapy with BRAF, EGFR, and MEK inhibitor combinations. However, ERK inhibition, particularly in combination with BRAF and EGFR inhibition, markedly abrogated clonal outgrowth in vitro and in vivo Thus, convergent, up-front therapy may suppress outgrowth of heterogeneous clones harboring clinically observed resistance alterations, which may improve clinical outcome.Significance: We observed heterogeneous, recurrent alterations in the MAPK pathway as key drivers of acquired resistance in BRAFV600E colorectal cancer, with multiple concurrent resistance alterations detectable in individual patients. Using a novel pooled clone system, we identify convergent up-front therapeutic strategies capable of intercepting multiple resistance mechanisms as potential approaches to suppress emergence of acquired resistance. Cancer Discov; 8(4); 417-27. ©2018 AACR.See related commentary by Janku, p. 389See related article by Corcoran et al., p. 428This article is highlighted in the In This Issue feature, p. 371.

Primary tumor sidedness is an independent prognostic marker for survival in metastatic colorectal cancer: Results from a large retrospective cohort with mutational analysis

Recent reports demonstrate inferior outcomes associated with primary right‐sided vs left‐sided colorectal tumors in patients with metastatic colorectal cancer (mCRC). We sought to describe our experience with mCRC patients on whom we have molecular data to determine whether primary tumor sidedness was an independent prognostic marker for overall survival (OS). mCRC patients with documented primary tumor sidedness who received mutational profiling between 2009 and 2014 were identified (n = 367, median follow‐up 30.4 months). Mutational profiling for >150 mutations across commonly mutated cancer genes including RAS, PIK3CA, BRAF, and PTEN as well as treatment data, including receipt of a biologic agent, were collected. Univariable/multivariable models were used to analyze relationships between collected data and OS. Among 367 patients, sidedness breakdown was as follows: 234 left (64%), 133 right (36%). 56% were male, with a median age at diagnosis of 57 (range 24‐89). A total of 143 patients had RAS mutations. Five‐year OS was 41%, median OS was 54 months (range 1‐149). Five‐year OS for left‐ vs right‐sided tumors was 46% vs 24% (P < .0001). On univariable analysis, among both RAS wildtype and mutant tumors, left‐sided tumors continued to have improved OS vs right‐sided tumors (HR: 0.49, 95% CI: 0.34‐0.69 RAS wildtype; HR: 0.61, 95% CI: 0.40‐0.95 RAS mutant). Left‐sidedness was an important prognostic factor for OS among RAS wildtype patients despite treatment with or without a biologic agent (P < .05). Left‐sidedness remained significant for improved OS on multivariable analysis (P < .0001). Left‐sided primary tumor remained most important prognostic factor for OS, even when adjusting for mutational status and receipt of biologic agent.

Liver reirradiation for patients with hepatocellular carcinoma and liver metastasis

PURPOSE This study aimed to assess the safety and efficacy of administering liver reirradiation to patients with primary liver tumors or liver metastasis. METHODS AND MATERIALS A total of 49 patients (with 64 individual tumors) who received liver reirradiation at our institution between June 2008 and December 2016 were identified for retrospective review. Patients were treated to the same, different, or a combination of previously treated liver tumors for recurrent primary (53%) or metastatic (47%) disease using photons or protons. Clinical and treatment-related factors were compiled and patients were monitored for toxicity and evidence of classic or nonclassic radiation-induced liver disease. Survival was estimated with the Kaplan-Meier method and cumulative incidence of local failure (LF) was used to estimate LF using the Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS The median age at the time of reirradiation was 72 years and the median interval between radiation courses was 9 months. At a median follow-up of 10.5 months, 36 patients (73%) had died, 9 patients (18%) were alive, and 4 patients (8%) were lost to follow-up. The median survival for the cohort was 14 months. The overall 1-year estimate of LF was 46.4%. The 1-year estimates of LF for liver metastases and hepatocellular carcinoma were 61.0% and 32.5%, respectively. The average prescription dose was similar between the reirradiation and initial courses (equivalent dose in 2 Gy fractions EQD2: 65.0 vs 64.3 Gyα/β = 10, respectively) but the average dose to the untreated liver was lower at the time of reirradiation (EQD2: 10.5 vs 13.9 Gyα/β = 3, respectively, P = .01). Among patients with hepatocellular carcinoma, the average normal liver dose was significantly larger for patients who exhibited a worsening of Child-Pugh score after reirradiation compared with those who did not (1210 cGy vs 759 cGy, P = .04). With regard to toxicity, 85.7% of patients experienced grade 1 to 2 toxicity, 4.1% developed grade 3, and only 2 patients (4.1%) met the criteria for radiation-induced liver disease after reirradiation. CONCLUSIONS Liver reirradiation may be an effective and safe option for select patients; however, further prospective study is necessary to establish treatment guidelines and recommended dosing.

MAVERICC, a randomized, biomarker-stratified, phase 2 study of mFOLFOX6-bevacizumab vs FOLFIRI-bevacizumab as first-line chemotherapy in metastatic colorectal cancer

Purpose: MAVERICC compared the efficacy and safety of modified leucovorin/5-fluorouracil/oxaliplatin plus bevacizumab (mFOLFOX6-BV) with leucovorin/5-fluorouracil/irinotecan plus bevacizumab (FOLFIRI-BV) in patients with previously untreated metastatic colorectal cancer (mCRC). Patients and Methods: MAVERICC was a global, randomized, open-label, phase II study. Primary objectives were to assess associations between (i) excision repair cross-complementing 1 (ERCC1) expression with progression-free survival (PFS), and (ii) plasma VEGF A (VEGF-A) with PFS in patients with previously untreated mCRC receiving mFOLFOX6-BV or FOLFIRI-BV. Before randomization, patients were stratified by tumoral ERCC1/β-actin mRNA expression level and region. Results: Of 376 enrolled patients, 188 each received mFOLFOX6-BV and FOLFIRI-BV. PFS and overall survival (OS) were comparable between FOLFIRI-BV and mFOLFOX6-BV, with numerically higher PFS [HR = 0.79; 95% CI (confidence interval): 0.61–1.01; P = 0.06] and OS (HR = 0.76; 95% CI: 0.56–1.04; P = 0.09) observed for FOLFIRI-BV. In the high ERCC1 subgroup, PFS and OS were comparable between treatment groups (PFS, HR = 0.84; 95% CI: 0.56–1.26; P = 0.40; OS, HR = 0.80; 95% CI: 0.51–1.26; P = 0.33). Across treatment groups, high plasma VEGF-A levels (>5.1 pg/mL) were observed with shorter PFS (HR = 1.19; 95% CI: 0.93–1.53; P = 0.17) and significantly shorter OS (HR = 1.64; 95% CI: 1.20–2.24; P < 0.01) versus low levels (≤5.1 pg/mL). Safety findings for FOLFIRI-BV or mFOLFOX6-BV were comparable with those reported previously. Conclusions: First-line FOLFIRI-BV and mFOLFOX6-BV had comparable PFS and OS, similar to results in patients with high baseline tumor ERCC1 levels. There were no new safety signals with these bevacizumab-containing regimens.

Tools for Communication: Novel Infrastructure to Address Patient-Perceived Gaps in Oncology Care

BACKGROUND: Healthcare providers (HCPs) and patient communication are integral to high‐quality oncology care. The patient and HCP perspectives are needed to identify gaps in care and develop communication tools. OBJECTIVES: This study aimed to understand patient‐ and HCP‐perceived elements of and gaps in high‐quality care to develop novel communication tools to improve care. METHODS: Qualitative interviews were conducted among 16 patients with cancer and 10 HCPs in the United States. Trained interviewers elicited patients’ and HCPs’ concerns, views, and perceived needs for communication tools. A thematic analysis was used to identify four quality of care domains, depicted in a conceptual model, and two draft communication tools were developed to address identified gaps. FINDINGS: No patients reported previously using a communication tool, and gaps in communication regarding treatment aims and education were evident. Two tools were developed to assess patients’ life and treatment goals and the importance of ongoing education.

Fast-TRKing Drug Development for Rare Molecular Targets

Drug development for rare molecular targets in oncology presents unique challenges. In this issue of Cancer Discovery, Drilon and colleagues report the accelerated development and innovative initial clinical trial strategy of a next-generation TRK inhibitor, LOXO-195, designed to overcome common secondary TRK resistance mutations. Cancer Discov; 7(9); 934-6. ©2017 AACR.See related article by Drilon et al., p. 963.

How is KRAS testing associated with treatment and supportive care for patients with metastatic colorectal cancer? VA national assist project.

64 Background: EGFR monoclonal antibody (mAb) therapies improve quality of life and outcomes for metastatic colorectal cancer (mCRC), but only wild-type KRAS benefit from treatment. We evaluated KRAS testing and pharmacogenetic-guided treatment and supportive and end of life (EOL) care. METHODS Among a national random sample of 265 veterans diagnosed with mCRC in 2008 we evaluated KRAS testing, EGFR mAb therapy, supportive care using the Cancer Quality ASSIST indicators, and healthcare use. Three oncology nurses abstracted charts for care received 2008-2011. We linked chart to VA and Medicare administrative data and compared care received by KRAS testing and results. RESULTS 227/265 (85%) veterans died within 3 years and received an average of 48% of recommended supportive care processes. 96 / 265 (36%) underwent KRAS testing, of whom 41, 42, and 13 had wild-type, mutant, and indeterminant/unknown KRAS. 27/41 (66%) wild-type KRAS patients received an EGFR mAb; 18/45 (40%) patients receiving an EGFR mAb had mutant, indeterminant/unknown, or untested KRAS. KRAS testing was associated with increased systemic therapy but not differences in supportive care or intensity of care at the EOL. KRAS tested vs. not tested received hospice or palliative care (67 vs. 73%, p=0.55); any systemic therapy (96 vs. 40%, p<0.001) including new regimen in last month (0 vs. 6%); any chemotherapy in last 14 days of life (9 vs. 7%); and any acute care in last month of life (28 vs. 32%, p=0.78). CONCLUSIONS KRAS testing was not performed for most veterans with mCRC in 2008, and EGFR mAb therapy was administered to many without wild-type KRAS. KRAS-tested patients were more likely to receive systemic treatments, and testing was not associated with greater intensity or inappropriate EOL care, and rates of such care were low among veterans.