Plasma Exosome Gene Signature Differentiates Colon Cancer from Healthy Controls.

BACKGROUND: Liquid biopsies have become an integral part of cancer management as minimally invasive options to detect molecular and genetic changes. However, current options show poor sensitivity in peritoneal carcinomatosis (PC). Novel exosome-based liquid biopsies may provide critical information on these challenging tumors. In this initial feasibility analysis, we identified an exosome gene signature of 445 genes (ExoSig445) from colon cancer patients, including those with PC, that is distinct from healthy controls. METHODS: Plasma exosomes from 42 patients with metastatic and non-metastatic colon cancer and 10 healthy controls were isolated and verified. RNAseq analysis of exosomal RNA was performed and differentially expressed genes (DEGs) were identified by the DESeq2 algorithm. The ability of RNA transcripts to discriminate control and cancer cases was assessed by principal component analysis (PCA) and Bayesian compound covariate predictor classification. An exosomal gene signature was compared with tumor expression profiles of The Cancer Genome Atlas. RESULTS: Unsupervised PCA using exosomal genes with greatest expression variance showed stark separation between controls and patient samples. Using separate training and test sets, gene classifiers were constructed capable of discriminating control and patient samples with 100% accuracy. Using a stringent statistical threshold, 445 DEGs fully delineated control from cancer samples. Furthermore, 58 of these exosomal DEGs were found to be overexpressed in colon tumors. CONCLUSIONS: Plasma exosomal RNAs can robustly discriminate colon cancer patients, including patients with PC, from healthy controls. ExoSig445 can potentially be developed as a highly sensitive liquid biopsy test in colon cancer.

Exosomal proteins as a source of biomarkers in colon cancer-derived peritoneal carcinomatosis - A pilot study.

PURPOSE: Peritoneal carcinomatosis (PC), metastasized from colorectal cancer (CRC), remains a highly lethal disease. Outcomes of PC is significantly influenced by the amount of intra-abdominal tumor burden and therefore diagnostic tests that facilitate earlier diagnosis could improve PC treatment and patient outcomes. EXPERIMENTAL DESIGN: Using mass-spectrometry-based proteomics, we characterized the protein features of circulating exosomes in the context of CRC PC, CRC with liver metastasis, and primary CRC limited to the colon. We profiled exosomes isolated from patient plasma to identify exosome-associated protein cargoes released by these cancer types. RESULTS: Analysis of the resulting data identified metastasis-specific exosome protein signatures. Bioinformatic analyses confirmed enrichment of proteins annotated to vesicle-associated processes and intracellular compartments, as well as representation of cancer hallmark functions and processes. CONCLUSION AND CLINICAL RELEVANCE: This research yielded distinct protein profiles for the CRC patient groups and suggests the utility of plasma exosome proteomic analysis for a better understanding of PC development and metastasis.

Redistribution of Outpatient Oncologic Surgical Specialty Referrals During COVID-19.

BACKGROUND: Initial reports of significantly worse outcomes for cancer patients with COVID-19 led to guidelines for triaging surgical cancer treatment. We sought to evaluate the effects of the COVID-19 pandemic on oncologic surgical specialty referrals. METHODS: We compared referrals to oncologic surgical specialty clinics at an academic tertiary care institution following implementation of stay-at-home orders in California (3/19/20-7/31/20, "COVID") to the same time period the year prior (3/19/19-7/31/19, "Pre-COVID"). The number of appointments, consulted surgical services, insurance types, acuity of diagnoses, and times from referral to first appointment (TRFA) were assessed. RESULTS: The overall number of patients seen in matched time periods decreased by 21.6% from 900 (pre-COVID) to 705 (COVID). Proportions of patients with malignant and suspicious diagnoses, surgical and thoracic oncology visits, and Medicaid insurance differed from comparison groups during the COVID period (P < .05). Overall median (interquartile range) TRFA decreased from 14 (20) to 12 (19) days (P = .001) during COVID. CONCLUSION: After implementation of stay-at-home orders, higher acuity and vulnerable patients were appropriately seen in oncologic surgical specialty clinics. While the long-term effects of decreased clinic visits during COVID remain uncertain, further examination of scheduling practices that led to shorter referral times may identify methods to improve timeliness of care and surgical oncologic outcomes in non-pandemic settings.

Treatment Factors Associated With Overall Survival in Retroperitoneal Sarcoma: An Institutional Review.

INTRODUCTION: Retroperitoneal sarcoma (RPS) is a rare malignancy, and curative resection is considered the main therapy. Use of chemotherapy and/or radiation in addition to surgery (multimodality therapy) is controversial. OBJECTIVE: To determine treatment factors that influence overall survival in RPS. METHODS: This retrospective Institutional Review Board-approved study identified patients with RPS treated at a single institution between 2000 and 2017. Patient, tumor, and treatment modalities were collected. Prism (v.8.2.1) was used to calculate Kaplan-Meier survival curves. RESULTS: There were 695 patients with sarcoma between 2000 and 2017, and 61 adults had RPS. The mean age was 59 (range 31-86) years, with 57.4% females (n = 35). Patients were 68.9% Caucasian (n = 42), 21.3% Hispanic (n = 13), 8.2% black (n = 5), and 1.6% Asian (n = 1). There were 4 patients who had neoadjuvant therapy (chemotherapy, n = 3; radiation, n = 2) and 17 who had adjuvant therapy (chemotherapy, n = 6; radiation, n = 14). There was no significant difference in survival between the groups who received multimodality therapy compared to surgery alone. There was a significant improvement in the median overall survival for patients who underwent one or multiple surgeries (P < .05). CONCLUSIONS: These institutional data suggest that treatment factors associated with overall survival included multiple resections. Use of multimodality therapy was low and did not influence overall survival in patients with RPS compared to surgery alone.

Peritoneal carcinomatosis in gastric cancer: Are Hispanics at higher risk?

BACKGROUND: A recent study from our group identified Hispanic race/ethnicity as an independent predictor of peritoneal carcinomatosis (PC) in gastric cancer. We sought to identify the tumor factors that might contribute to this strong association in Hispanics. METHODS: California Cancer Registry data were used to identify patients diagnosed with gastric adenocarcinoma from 2004 to 2014. Logistic regression analyses were performed to determine odds ratios for cancer stage, tumor location, grade, histology, and PC. RESULTS: Of 16,275 patients with gastric adenocarcinoma who met inclusion criteria, 6463 (39.7%) were non-Hispanic White (NHW), 4953 (30.4%) were Hispanic, 1020 (6.3%) were non-Hispanic Black (NHB), and 3915 (23.6%) were Asian/other. Compared to NHW, Hispanics were more likely to have a poorly differentiated grade (65.9% vs. 57.6%; p < .001), signet ring adenocarcinoma (28.1% vs. 17.6%; p < .001) and stage IV (51.9% vs. 45.0%; p < .001) gastric cancer. The proportion of stage IV patients with PC was also significantly higher in Hispanics compared to NHW, NHB, and Asian/other (28.5% vs. 16.6%, 20.5%, and 25.2%, respectively; p < .001). CONCLUSIONS: Hispanic ethnicity is an independent predictor of aggressive tumor phenotype and PC. Disproportionate incidence of signet ring adenocarcinoma and PC highlight the need to explore the genomic differences in Hispanic gastric cancer.

Rate of Peritoneal Carcinomatosis in Resected Stage II and III Colon Cancer.

INTRODUCTION: Incidence of peritoneal carcinomatosis (PC) after curative resection of stage II and III colon cancer varies widely. Although certain features are considered high risk for PC, the impact of these features on PC incidence is unclear. METHODS: A retrospective analysis was performed on patients ≥ 18 years old with resected stage II and III colonic adenocarcinoma treated at two academic institutions from 2007 to 2018. Clinicopathologic features, treatment and outcomes data were recorded. Patients with reported high-risk features (pT3N0-2 with mucinous/signet ring components, pT4, pN1c, perforation) were identified. The remaining stage II and III patients were used for comparison. RESULTS: Of 219 eligible patients, 93/219 (42.5%) were stage II and 126/219 (57.5%) were stage III. Median follow-up time was 25 (1-146) months. Adjuvant systemic treatment was administered to 133/219 (60.7%) patients. Overall incidence of PC was 14/219 (6.4%) and the median time to PC was 18 (1-37) months. The high-risk and comparison groups contained 113 and 106 patients, respectively. Incidence of PC was significantly different between groups (high-risk 9.7% vs comparison 2.8%, p = 0.04). Median time to PC was not significantly different between the groups [high-risk 17 (1-37) months vs comparison 20 (7-36) months, p = 0.88]. CONCLUSION: Overall PC incidence in patients with resected stage II and III colon cancer was 6.4%. Although the high-risk group developed PC at a significantly higher rate, the rate of PC in this group was still below 10%. The results of this study represent real-world rates of PC and should be taken into account when designing future studies.

Gastric Cancer Peritoneal Carcinomatosis Risk Score.

BACKGROUND: Gastric cancer (GC) peritoneal carcinomatosis (PC) is associated with a poor prognosis. Although grade, histology, and stage are associated with PC, the cumulative risk of PC when multiple risk factors are present is unknown. This study aimed to develop a cumulative GCPC risk score based on individual demographic/tumor characteristics. METHODS: Patient-level data (2004-2014) from the California Cancer Registry were reviewed by creating a keyword search algorithm to identify patients with gastric PC. Multivariable logistic regression was used to assess demographic/tumor characteristics associated with PC in a randomly selected testing cohort. Scores were assigned to risk factors based on beta coefficients from the logistic regression result, and these scores were applied to the remainder of the subjects (validation cohort). The summed scores of each risk factor formed the total risk score. These were grouped, showing the percentages of patients with PC. RESULTS: The study identified 4285 patients with gastric adenocarcinoma (2757 males, 64.3%). The median age of the patients was 67 years (interquartile range [IQR], 20 years). Most of the patients were non-Hispanic white (n = 1748, 40.8%), with proximal (n = 1675, 39.1%) and poorly differentiated (n = 2908, 67.9%) tumors. The characteristics most highly associated with PC were T4 (odds ratio [OR], 3.12; 95% confidence interval [CI], 2.19-4.44), overlapping location (OR 2.27; 95% CI 1.52-3.39), age of 20-40 years (OR 3.42; 95% CI 2.24-5.21), and Hispanic ethnicity (OR 1.86; 95% CI 1.36-2.54). The demographic/tumor characteristics used in the risk score included age, race/ethnicity, T stage, histology, tumor grade, and location. Increasing GCPC score was associated with increasing percentage of patients with PC. CONCLUSION: Based on demographic/tumor characteristics in GC, it is possible to distinguish groups with varying odds for PC. Understanding the risk for PC based on the cumulative effect of high-risk features can help clinicians to customize surveillance strategies and can aid in early identification of PC.

Response to Neoadjuvant Treatment Is Influenced by Grade in Gastric Cancer.

Neoadjuvant therapy is commonly used in the management of gastric cancer. Primary tumor response to treatment correlates with prognosis. Published studies have compared efficacy of neoadjuvant therapy based on stage but not grade. The objective of this study was to determine the change in staging of gastric cancer after neoadjuvant therapy and resection based on grade. A retrospective analysis of gastric cancer patients treated at our institution between 2005 and 2017 was performed. Patient demographics, tumor characteristics, clinical and pathological stage, and microscopic treatment response were analyzed based on grade. Of the 269 patients identified during this period, 82 patients underwent definitive surgical resection, of which 38 patients received neoadjuvant therapy (low grade (grades 1 and 2), n = 17; high grade (grade 3), n = 18; and unknown grade, n = 3). Pathologic downstaging was observed in 52.9 per cent (9/17) of low-grade tumors compared with 22.2 per cent (4/18) of high-grade tumors. Majority of high-grade tumors (77.8%, 14/18) had either upstaging or unchanged stage. High-grade gastric cancers often lack response to neoadjuvant therapy. Novel targeted therapies based on biologic behavior should be evaluated and incorporated into neoadjuvant treatment. Neoadjuvant studies should stratify patients based on grade and report response by grade.

From Evidence to Practice: Are Low-Risk Breast Cancer Patients still Enduring Unnecessary Costs of Radiation?

Radiation is routinely recommended after conservative surgery for breast cancer, despite long-standing Level I evidence showing no survival benefit for elderly patients with favorable disease using endocrine therapy. We sought to evaluate radiation use and costs in patients eligible for omission of radiation. A retrospective single-institution review from 2005 to 2017 was performed of women aged ≥70 years, with cT1N0M0, who were ER/PR positive and HER-2 negative, and receiving breast-conserving surgery. Patient, tumor, and treatment characteristics were compared by use of radiation. Cost estimates used Medicare's 2019 fee schedule. Of 84 patients meeting the study criteria, 72.6 per cent received radiation and 56 per cent received endocrine therapy, with four recurrences (4.9% radiated and 4.4% not radiated, P = 0.9). Early and late grade I radiation toxicities occurred in 67.2 per cent and 26.2 per cent of radiated patients, respectively. Younger age (P = 0.01), receipt of endocrine therapy (P < 0.0001), and axillary surgery (P < 0.0001) were significantly associated with radiation use. There were no significant differences in radiation use based on race/ethnicity, language, comorbidities, BMI, or pathologic tumor size. Estimated total radiation cost was $646,426. Radiation remains overused and endocrine therapy, underused in breast cancer patients eligible to avoid radiation. As gatekeepers for radiation oncology referrals, surgeons can diminish both physical and financial costs of radiation in eligible patients.

Sexual and urinary outcomes in robotic rectal surgery: review of the literature and technical considerations.

Several studies have reported high rates of urogenital dysfunction after open and laparoscopic surgery for rectal cancer. Robotic surgery has several features that could facilitate identification and preservation of autonomic nerves. This manuscript aims to summarize the literature regarding urogenital function after robotic rectal cancer surgery and focus on technical aspects of nerve-sparing total mesorectal excision. Comprehensive searches were conducted through online databases. Selection criteria included: original articles assessing urinary and sexual function after robotic surgery of males and/or females with standardized questionnaires. A total of 16 articles were included in the review. Seven of the nine cohort studies evaluating male sexual function showed earlier recovery or better outcomes in patients operated with robotic techniques. Two studies did not find any statistically significant difference. Three out of four case series found no difference in sexual function scores measured preoperatively and after 1 year. Female sexual function was assessed in seven studies: two case series show no deterioration of at 1 year. Three comparative studies showed no difference between robotic and laparoscopic groups. Two randomized control trials showed different results in terms of male and female sexual functions with better preservation at 1 year in the robotic group in one and no difference in another. Urinary functions assessed in males and/or females in the 16 studies showed no statistically significant differences at long-term follow-up. At present, there is no evidence of superiority of robotic surgery for performing nerve-sparing rectal cancer surgery.

Role of lymph node ratio in selection of adjuvant treatment (chemotherapy vs. chemoradiation) in patients with resected gastric cancer.

BACKGROUND: Recent randomized controlled trials have failed to show a survival difference between adjuvant chemotherapy (CT) and adjuvant chemoradiotherapy (CRT) in patients with resected gastric cancer (GC). However, a subset of patients with lymph node (LN) positive disease may still benefit from CRT. Additional evidence is needed to help guide physicians in identifying patients in whom CRT should be considered. Our objective was then to compare survival outcomes based on lymph node ratio (LNR) (ratio of metastatic to harvested LNs) for patients with gastric and gastroesophageal junction (GEJ) adenocarcinoma treated with surgery and either CT or CRT. METHODS: This retrospective population-based study used California Cancer Registry (CCR) data from 2004 to 2013. It included 1,493 patients diagnosed with stage IB-III gastric/GEJ adenocarcinoma and treated with CT or CRT following total or partial gastrectomy. Overall survival (OS) was the primary outcome and GC-specific survival was secondary. Mortality hazards ratios (HR) for these outcomes were computed using propensity score weighted Cox regression models, stratified by LNR strata categories as 0%, 1-9%, 10-25% and >25%. RESULTS: Out of 1,493 patients that met inclusion criteria, 462 were treated with CT while 1,031 received CRT. Median follow-up for all subjects was 76 months and median survival was 54 months for CRT and 35 for the CT cohort, P<0.001. Compared to CT, CRT was associated with improved survival among patients with LNR of 10-25% [HR =0.62 (95% CI, 0.46-0.83)] and >25% [HR =0.67 (95% CI, 0.56-0.80)]. Similar findings were observed for GC-specific survival and for analyses limited to patients that had at least 15 LNs evaluated. CONCLUSIONS: LNR appears to be a simple and readily available measure that could be used in treatment planning for resected GC. CRT offers significant survival advantage over CT among patients with high LN disease burden (LNR of ≥10%).

Impact of Breast Reconstruction on Time to Definitive Surgical Treatment, Adjuvant Therapy, and Breast Cancer Outcomes.

BACKGROUND: Delays in surgery and adjuvant treatment for breast cancer are associated with decreased survival. However, the time between diagnosis and surgery is rising, partly attributed to the added complexity of immediate breast reconstruction (IBR). We sought to investigate time to treatment and survival outcomes in breast cancer patients undergoing IBR. METHODS: We performed a retrospective review of 2004-2014 California Cancer Registry data for stage 0-III breast cancer patients undergoing mastectomy. Time to surgery, adjuvant systemic therapy and radiation therapy, propensity score, and covariate-adjusted overall mortality hazard ratios (HRs) were assessed by IBR status. RESULTS: Of 56,782 patients, 13,738 (24.2%) underwent IBR, with a median follow-up of 68.8 months. Median time between diagnosis and surgery was increased for patients undergoing IBR compared with those without {49 days (interquartile range [IQR] 34-73) vs. 35 days (IQR 21-56), p < 0.001}. IBR did not affect the interval from surgery to adjuvant chemotherapy or radiation, but prolonged time to endocrine therapy by 5 days (p = 0.014). Significantly lower survival was observed when time to surgery exceeded 120 days (vs. 0-30 days; HR 1.14 [1.02-1.28], p = 0.023), and improved survival with IBR (vs. without; HR 0.67 [0.61-0.74], p < 0.001). The benefit associated with reconstruction persisted for all age groups except age 80 + years, while surgical delay > 120 days demonstrated significantly lower survival in women < 60 years of age. CONCLUSIONS: While IBR delays time to definitive surgery, its use did not substantially affect time to adjuvant treatment or survival outcomes. Further research is ongoing to mitigate the effects of potential selection bias in favor of IBR.

High-Risk Stage II Colon Cancer: Not All Risks Are Created Equal.

INTRODUCTION: Adjuvant chemotherapy is recommended in patients with stage II colon cancer with high-risk features (HRF). However, there is no quantification of the amount of risk conferred by each HRF or the overall survival (OS) benefit gained by chemotherapy based on the risk factor. OBJECTIVE: To assess survival benefits associated with adjuvant chemotherapy among stage II colon cancer patients having one or more HRF [T4 tumors, less than 12 lymph nodes examined (< 12LN), positive margins, high-grade tumor, perineural invasion (PNI), and lymphovascular invasion (LVI)]. METHODS: Patients diagnosed with stage II colon cancer between 2010 and 2013 were identified from California Cancer Registry. Propensity score weighted all-cause mortality hazard ratios (HR) were calculated for combinations of HRF. RESULTS: A total of 5160 stage II colon cancer patients were identified, of which 2398 had at least one HRF and 510 of 2398 (21%) received adjuvant chemotherapy. Compared with patients with a single HRF, presence of any 2 or ≥ 3 HRF showed increasingly poorer survival [HR 1.42, 95% confidence interval (CI) 1.16-1.73 and HR 2.50, 95% CI 1.96-3.20, respectively]. Chemotherapy was associated with improved overall survival only among patients with T4 as the single HRF (HR 0.51, 95% CI 0.34-0.78) or combinations involving T4 as T4/< 12 LN (HR 0.31, 95% CI 0.11-0.90), T4/high grade (HR 0.26, 95% CI 0.11-0.61), and T4/LVI (HR 0.16, 95% CI 0.04-0.61). CONCLUSIONS: Not all high-risk features have similar adverse effects on OS. T4 tumors and their combination with other HRF achieve the most survival benefit with adjuvant therapy. Type and number of high-risk features should be taken into consideration when recommending adjuvant chemotherapy in stage II colon cancer.

Comparison of perioperative chemotherapy with adjuvant chemoradiotherapy for resectable gastric cancer: findings from a population-based study.

BACKGROUND: Both perioperative chemotherapy (PC) and adjuvant chemoradiotherapy (CRT) improve survival in resectable gastric cancer; however, these treatments have never been formally compared. Our objective was to evaluate treatment trends and compare survival outcomes for gastric cancer patients treated with surgery and either PC or CRT. METHODS: We performed a retrospective population-based cohort study between 2007 through 2013 using California Cancer Registry data. Patients diagnosed with stage IB-III gastric adenocarcinoma and treated with total or partial gastrectomy were eligible for this study. Based on the type of treatment received, patients were grouped into surgery-only, PC, or CRT. Primary and secondary outcomes were overall survival (OS) and gastric cancer-specific survival (GCCS) respectively. Mortality hazards ratios (HRs) for each of these outcomes were computed using propensity score weighted and covariate-adjusted Cox regression models, stratified by clinical node status. RESULTS: Of 2,146 patients who underwent surgical resection, 1,067 had surgery-only, while 771 and 308 received PC or CRT, respectively. Median OS was 25, 33, and 52 months for surgery-only, PC, and CRT, respectively; P<0.001. Overall, patients treated with PC had significantly poorer survival compared to CRT (HR =1.45; 95% CI: 1.22-1.73). PC was also associated with higher mortality in patients with signet ring histology (HR =1.66; 95% CI: 1.21-2.28) and clinical node negative cancer (HR =1.85; 95% CI: 1.32-2.60). Survival was not different between PC vs. CRT in clinical node positive patients (HR =1.29; 95% CI: 0.84-2.08). Of note, the percentage of patients receiving PC increased from 17.5% in 2007-2008, to 41.5% in 2013-2014; P<0.001. CONCLUSIONS: Despite the rapid adoption of PC, overall, CRT is associated with better survival than PC. Specifically, clinical node negative and signet ring histology patients had better survival when treated with CRT compared to PC. Based on these findings, we recommend against indiscriminate adoption of PC and consideration for CRT over PC in clinical node negative patients.

Factors Predictive of Outcomes after Cytoreductive Surgery and Heated Intraperitoneal Chemotherapy for Colon and Appendiceal Carcinomatosis: A Single-Institution Experience.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC), although considered an acceptable treatment option in the management of selected patients with colon and appendiceal peritoneal carcinomatosis (PC), concerns about morbidity have limited its acceptance. Our objective was to evaluate the short- and long-term outcomes of CRS/HIPEC for appendix and colon PC performed at our institution and to elucidate factors predictive of patient outcomes. All patients who underwent CRS/HIPEC for appendix or colon PC from 2011 to 2017 were identified from our institution's prospective database. Postoperative outcomes, overall survival, and recurrence-free survival were assessed. Of 125 patients who underwent CRS/HIPEC during the study period, 45 patients were eligible (appendix n = 26; colon n = 19). The median postoperative length of stay was nine days (5-28 days). Grade III/IV complications occurred in 4/45 (8.8%) patients. There were no postoperative mortalities. Median DFS and overall survival have not yet been reached, in both the colon and appendix groups. As of the study conclusion date, 37/45 (82.2%) patients were alive with or without disease. Lymph node status was predictive of recurrence in appendix PC. In our experience, CRS/HIPEC can be safely performed with acceptable short- and long-term outcomes. Lymph node status is an important predictor of recurrence.

Association of Primary Tumor Site With Mortality in Patients Receiving Bevacizumab and Cetuximab for Metastatic Colorectal Cancer.

Importance: Biologic therapy (BT) (eg, bevacizumab or cetuximab) is increasingly used to treat metastatic colorectal cancer (mCRC). Recent investigations have suggested that right- or left-sided primary tumor origin affects survival and response to BT. Objective: To evaluate the association of tumor origin with mortality in a diverse population-based data set of patients receiving systemic chemotherapy (SC) and bevacizumab or cetuximab for mCRC. Design, Setting, and Participants: This population-based nonconcurrent cohort study of statewide California Cancer Registry data included all patients aged 40 to 85 years diagnosed with mCRC and treated with SC only or SC plus bevacizumab or cetuximab from January 1, 2004, through December 31, 2014. Patients were stratified by tumor origin in the left vs right sides. Interventions: Treatment with SC or SC plus bevacizumab or cetuximab. Main Outcomes and Measures: Mortality hazards by tumor origin (right vs left sides) were assessed for patients receiving SC alone or SC plus bevacizumab or cetuximab. Subgroup analysis for patients with wild-type KRAS tumors was also performed. Results: A total of 11 905 patients with mCRC (6713 men [56.4%] and 5192 women [43.6%]; mean [SD] age, 60.0 [10.9] years) were eligible for the study. Among these, 4632 patients received SC and BT. Compared with SC alone, SC plus bevacizumab reduced mortality among patients with right- and left-sided mCRC, whereas SC plus cetuximab reduced mortality only among patients with left-sided tumors and was associated with significantly higher mortality for right-sided tumors (hazard ratio [HR], 1.31; 95% CI, 1.14-1.51; P < .001). Among patients treated with SC plus BT, right-sided tumor origin was associated with higher mortality among patients receiving bevacizumab (HR, 1.31; 95% CI, 1.25-1.36; P < .001) and cetuximab (HR, 1.88; 95% CI, 1.68-2.12; P < .001) BT, compared with left-sided tumor origin. In patients with wild-type KRAS tumors (n = 668), cetuximab was associated with reduced mortality among only patients with left-sided mCRC compared with bevacizumab (HR, 0.75; 95% CI, 0.63-0.90; P = .002), whereas patients with right-sided mCRC had more than double the mortality compared with those with left-sided mCRC (HR, 2.44; 95% CI, 1.83-3.25, P < .001). Conclusions and Relevance: Primary tumor site is associated with response to BT in mCRC. Right-sided primary tumor location is associated with higher mortality regardless of BT type. In patients with wild-type KRAS tumors, treatment with cetuximab benefited only those with left-sided mCRC and was associated with significantly poorer survival among those with right-sided mCRC. Our results underscore the importance of stratification by tumor site for current treatment guidelines and future clinical trials.

Making Meaningful Clinical Use of Biomarkers.

This review discusses the current state of biomarker discovery for the purposes of diagnostics and therapeutic monitoring. We underscore relevant challenges that have defined the gap between biomarker discovery and meaningful clinical use. We highlight recent advancements in and propose a way to think about future biomarker development.