HER2 gene amplifications and activating mutations in the HER2 receptor tyrosine kinase are present in 4% of metastatic colorectal cancers (mCRCs). HER2-targeted therapy is not standard of care, although preclinical and clinical data suggest that patients with HER2 amplifications and/or HER2-activating mutations may benefit from HER2-directed therapy. HER2 amplifications and activating mutations have also been implicated in resistance to anti-epidermal growth factor receptor-based therapy. This report describes a patient with KRAS, NRAS, and BRAF wild-type mCRC who experienced disease progression on first-line treatment with FOLFIRI and cetuximab after only 5 months, and subsequently experienced progression on second-line treatment with capecitabine and oxaliplatin plus bevacizumab after 2 months with significant functional decline. Next-generation sequencing of the primary tumor identified HER2 amplification, and we were able to obtain trastuzumab-DM1 for off-label use. The patient had symptomatic clinical benefit from trastuzumab-DM1 and had radiographic disease control for 7 months. On progression, therapy was changed to trastuzumab and pertuzumab, but the patient's disease progressed 3 months later. Treatment with the trastuzumab-DM1 resulted in a sustained response that was longer than his prior responses in the first and second lines of treatment, with a dramatic improvement in the patient's functional status. This case represents the first report, to our knowledge, of successful single-agent treatment of HER2-amplifed CRC with trastuzumab-DM1. Clinical trials targeting patients with HER2-mutated and -amplified metastatic colon cancer are currently underway. Molecular insights from investigating HER2 activation and the impact of HER2-directed therapies in a wide variety of solid tumors will create the needed evidence base to more broadly inform patient care.

While not itself life-threatening, ductal carcinoma in situ (DCIS) can progress to invasive disease if untreated, and confers an increased risk of future breast cancer. We investigated knowledge of DCIS among a cohort of English- and Spanish-speaking Latina and English-speaking non-Latina white women previously treated for DCIS. We examined knowledge of DCIS with four true/false statements about risk of invasive disease, breast cancer recurrence, and prognosis. For each knowledge statement, we modeled the odds of a correct answer by language-ethnicity (English-speaking Latinas, Spanish-speaking Latinas, and English-speaking whites) adjusting for demographics, health history, and treatment factors. Of 710 participants, 52 % were English-speaking whites, 21 % English-speaking Latinas, and 27 % Spanish-speaking Latinas. Less than half (41 %) of participants were aware that DCIS is not life-threatening and only 32 % knew that surgical treatment choice does not impact mortality; whereas two-thirds (67 %) understood that DCIS confers increased risk of future breast cancer, and almost all (92 %) knew that DCIS, if untreated, could become invasive. Only three Spanish-speakers used professional interpreters during discussions with their physicians. In adjusted analyses, compared to English-speaking whites, both English- and Spanish-speaking Latinas had significantly lower odds of knowing that DCIS was not life-threatening (OR, 95 % CI 0.6, 0.4-0.9 and 0.5, 0.3-0.9, respectively). In contrast, Spanish-speaking Latinas had a twofold higher odds of knowing that DCIS increases risk of future breast cancer (OR, 95 % CI 2.6, 1.6-4.4), but English-speaking Latinas were no different from English-speaking whites. Our data suggest that physicians are more successful at conveying the risks conferred by DCIS than the nuances of DCIS as a non-life-threatening diagnosis. This uneven communication is most marked for Spanish-speaking Latinas. In addition to the use of professional interpreters, efforts to create culturally and linguistically standardized information could improve knowledge and engagement in informed decision making for all DCIS patients.

Purpose

Little is known about the roles of genetic and molecular testing and Lynch syndrome screening in the formulation of predictive and prognostic assessments for patients with stage II colorectal cancer (CRC).

Methods

From 2012 to 2013, we surveyed medical oncologists in the Cancer Care Outcomes Research and Surveillance Consortium and evaluated oncologists' selection of microsatellite instability (MSI) and/or immunohistochemistry (IHC) for mismatch repair (MMR) proteins, germline testing for MMR genes, BRAF and KRAS mutation analysis, and Oncotype DX in stage II CRC. Physicians were randomly assigned to receive one of three vignettes that varied by strength of CRC family history. We used multivariable logistic regression to identify physician and practice characteristics associated with test selection.

Results

Among 327 oncologists, MSI and/or IHC for MMR proteins were most frequently selected (n = 205; 64%), with 82% versus 53% choosing MSI/IHC testing in patients with strong versus no CRC family history, respectively (adjusted odds ratio [OR], 3.87; 95% CI, 2.07 to 7.22). KRAS and Oncotype DX testing were chosen by 24% and 38% of oncologists, respectively. Graduates of non-US and Canadian medical schools and physicians compensated by fee-for-service or on the basis of productivity were more likely to choose KRAS testing versus those receiving salaries not on the basis of productivity (OR, 2.16; 95% CI, 1.17 to 3.99; and OR, 1.94; 95% CI, 1.02 to 3.66, respectively). Fee-for-service or productivity-based salaries were also associated with increased odds of Oncotype DX testing (OR, 2.04; 95% CI, 1.17 to 3.55).

Conclusion

Among surveyed oncologists, we found undertesting and overtesting related to genetic and molecular testing and Lynch syndrome screening for patients with stage II CRC,highlighting the need for improved implementation, targeted education, and evaluation of organizational and financial arrangements to promote the appropriate use of such tests.

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.

PURPOSE: Minimal residual disease (MRD) detection can identify the recurrence in patients with colorectal cancer (CRC) following definitive treatment. We evaluated a plasma-only MRD assay to predict recurrence and survival in patients with metastatic CRC who underwent curative intent procedures (surgery and/or radiotherapy), with or without (neo)adjuvant chemotherapy. The primary objective of this study was to assess the correlation of postprocedure tumor cell-free DNA detection status with radiographic disease recurrence. EXPERIMENTAL DESIGN: Preprocedure and postprocedure longitudinal samples were collected from 53 patients and analyzed with a multiomic MRD assay detecting circulating tumor DNA (ctDNA) from genomic and epigenomic signals. Preprocedure and postprocedure ctDNA detection correlated with recurrence-free and overall survival (OS). RESULTS: From 52 patients, 230/233 samples were successfully analyzed. At the time of data cutoff, 36 (69.2%) patients recurred with median follow-up of 31 months. Detectable ctDNA was observed in 19/42 patients (45.2%) with ctDNA analyzed 3 weeks postprocedure. ctDNA detection 3 weeks postprocedure was associated with shorter median recurrence-free survival (RFS; HR, 5.27; 95% CI, 2.31-12.0; P < 0.0001) and OS (HR, 12.83; 95% CI, 3.6-45.9; P < 0.0001). Preprocedure ctDNA detection status was not associated with RFS but was associated with improved OS (HR, 4.65; 95% CI, 1.4-15.2; P = 0.0111). Undetectable ctDNA preprocedure had notable long-term OS, >90% 3 years postprocedure. CONCLUSIONS: In this cohort of oligometastatic CRC, detection of ctDNA preprocedure or postprocedure was associated with inferior outcomes even after accounting for known prognostic clinicopathologic variables. This suggests ctDNA may enhance current risk stratification methods helping the evaluation of novel treatments and surveillance strategies toward improving patient outcomes.

"Liquid biopsy" approaches analyzing cell-free DNA (cfDNA) from the blood of patients with cancer are increasingly utilized in clinical practice. However, it is not yet known whether cfDNA sequencing from large cohorts of patients with cancer can detect genomic alterations at frequencies similar to those observed by direct tumor sequencing, and whether this approach can generate novel insights. Here, we report next-generation sequencing data from cfDNA of 1,397 patients with colorectal cancer. Overall, frequencies of genomic alterations detected in cfDNA were comparable to those observed in three independent tissue-based colorectal cancer sequencing compendia. Our analysis also identified a novel cluster of extracellular domain (ECD) mutations in EGFR, mediating resistance by blocking binding of anti-EGFR antibodies. Patients with EGFR ECD mutations displayed striking tumor heterogeneity, with 91% harboring multiple distinct resistance alterations (range, 1-13; median, 4). These results suggest that cfDNA profiling can effectively define the genomic landscape of cancer and yield important biological insights.Significance: This study provides one of the first examples of how large-scale genomic profiling of cfDNA from patients with colorectal cancer can detect genomic alterations at frequencies comparable to those observed by direct tumor sequencing. Sequencing of cfDNA also generated insights into tumor heterogeneity and therapeutic resistance and identified novel EGFR ectodomain mutations. Cancer Discov; 8(2); 164-73. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 127.