Overall Survival, BRAF, RAS, and MSI Status in Patients Who Underwent Cetuximab After Refractory Chemotherapy for Metastatic Colorectal Cancer.

PURPOSE: Evaluate overall survival (OS), RAS, BRAF, and MSI frequencies in patients with metastatic colorectal cancer (mCRC), refractory to chemotherapy, and finally treated with cetuximab. METHODS: A retrospective cohort study to evaluate 211 mCRC patients with wild-type KRAS treated with cetuximab. BRAF V600E, KRAS, NRAS gene mutations, and MSI status were identified using PCR techniques in a population of pre-treated patients who were refractory to fluoropyrimidines, oxaliplatin, and irinotecan. In addition, we evaluated the mutation frequency of the BRAF and NRAS genes and the MSI status of this population. Uni- and multivariate analyses were performed for independent prognostic factors of OS. RESULTS: The median OS was 10.4 months, 6.6 months for patients with right and 11.5 months for left colon cancers (p = 0.02). The frequencies of mutations were BRAF at 3.9% (median OS of 4.9 months), NRAS at 3.38% (median OS of 6.9 months), and MSI-High status at 3.3% (median OS of 4.6 months). The OS, NRAS, and MSI frequencies were similar to those found in other studies that evaluated cetuximab in poly-treated patients and were associated with lower survival rates in univariate analyses. The frequency of BRAF mutations was lower than that found in previous studies. The only variable that remained significant for OS in the multivariate model was tumour laterality, with patients with right colon cancer presenting a worse prognosis (HR = 2.81). CONCLUSION: Although BRAF, NRAS mutations, and MSI-High status were associated with shorter OS in univariate analyses, only tumour laterality remained an independent prognostic factor in the multivariate analysis.

Systemic Therapy for Advanced Hepatocellular Carcinoma: Current Stand and Perspectives.

Hepatocellular carcinoma often develops in the context of chronic liver disease. It is the sixth most frequently diagnosed cancer and the third most common cause of cancer-related mortality worldwide. Although the mainstay of therapy is surgical resection, most patients are not eligible because of liver dysfunction or tumor extent. Sorafenib was the first tyrosine kinase inhibitor that improved the overall survival of patients who failed to respond to local therapies or had advanced disease, and for many years, it was the only treatment approved for the first-line setting. However, in recent years, trials have demonstrated an improvement in survival with treatments based on immunotherapy and new targeting agents, thereby extending the treatment options. A phase III trial showed that a combination of immunotherapy and targeted therapy, including atezolizumab plus bevacizumab, improved survival in the first-line setting, and is now considered the new standard of care. Other agents and combinations are being tested, including the combination of nivolumab plus ipilimumab and tremelimumab plus durvalumab, and they reportedly have clinical benefits. The aim of this manuscript is to review the latest approved therapeutic options in first- and second-line settings for advanced HCC and discuss future perspectives.

Medical Oncologists' Perspectives on How the Results of the IDEA Collaboration Impact the Adjuvant Treatment of Stage III Colon Cancer.

BACKGROUND: The International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration aimed to evaluate whether 3 months of adjuvant chemotherapy are noninferior to 6 months. Our study objectives were to characterize medical oncologists' perspectives toward the results of the IDEA collaboration and to evaluate how IDEA impacted prescribing patterns of adjuvant FOLFOX and CAPOX in colon cancer. MATERIALS AND METHODS: A list of questions developed by four medical oncologists regarding IDEA results were formulated and distributed online to gastrointestinal medical oncologists globally. Descriptive statistics and chi-square tests were used to summarize information. RESULTS: Of 174 responses, 145 were complete and analyzed. Responses were obtained globally from South America (53%); the U.S. and Canada (28%); Europe, Australia, and New Zealand (12%); and Asia (7%). Most clinicians (98%) were aware of the IDEA study. Prior to IDEA, clinicians preferred FOLFOX over CAPOX (81% vs. 19%). Subsequent to IDEA, 55% of clinicians preferred CAPOX over FOLFOX (odds ratio, 5.0; 95% confidence interval, 3.0-8.5; p < .01 compared with pre-IDEA). Two thirds (68%) of responders tailored duration of adjuvant therapy based on risk stratification. Most oncologists (76%) were more willing to discontinue oxaliplatin early if toxicities develop after the results of IDEA. Half of responders (50%) found that IDEA increased their confidence in decision making for adjuvant treatment; 36% were unchanged, and 15% indicated decreased confidence. Less than half (48%) were comfortable communicating the study results and the concept of a noninferiority trial with patients. CONCLUSION: IDEA appears to have shifted clinician preference from FOLFOX to CAPOX for adjuvant therapy, and most clinicians now use a risk-stratified approach in determining duration of adjuvant therapy. Patient education resources may facilitate better communication of IDEA results to patients. IMPLICATIONS FOR PRACTICE: This global survey illustrates that most gastrointestinal medical oncologists now use a risk-stratified approach for determining the duration of adjuvant chemotherapy for stage III colon cancer. Clinicians are five times more likely to choose CAPOX over FOLFOX after the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration results.

Immunotherapy and Targeted Therapy for Hepatocellular Carcinoma: A Literature Review and Treatment Perspectives.

Advanced hepatocellular carcinoma is a prevalent and potentially aggressive disease. For more than a decade, treatment with sorafenib has been the only approved therapeutic approach. Moreover, no agent has been proven to prolong survival following the progression of disease after sorafenib treatment. However, in recent years, this scenario has changed substantially with several trials being conducted to examine the effects of immunotherapy and novel targeting agents. Several immune checkpoint inhibitors have shown promising results in early-stage clinical trials. Moreover, phase III trials with large cohorts have demonstrated remarkable improvement in survival with the use of new targeted therapies in second-line treatment. Treatment regimens involving the combination of two immune checkpoint inhibitors as well as immune checkpoint inhibitors and anti-angiogenic targeted therapies have shown potential to act synergistically in clinical trials. Recently, the combination of atezolizumab and bevacizumab evaluated in a phase III clinical trial has demonstrated survival superiority in the first-line treatment; it is the new considered standard of care. In this manuscript, we aimed to review the latest advances in the systemic treatment of advanced hepatocellular carcinoma focusing on immunotherapy and targeted therapies.

Clinical and molecular characterization of early-onset colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) incidence is increasing in adults younger than 50 years. This study evaluated clinical and molecular features to identify those features unique to early-onset CRC that differentiate these patients from patients 50 years old or older. METHODS: Baseline characteristics were evaluated according to the CRC onset age with 3 independent cohorts. A fourth cohort was used to describe the impact of age on the consensus molecular subtype (CMS) prevalence. RESULTS: This retrospective review of more than 36,000 patients with CRC showed that early-onset patients were more likely to have microsatellite instability (P = .038), synchronous metastatic disease (P = .009), primary tumors in the distal colon or rectum (P < .0001), and fewer BRAF V600 mutations (P < .001) in comparison with patients 50 years old or older. Patients aged 18 to 29 years had fewer adenomatous polyposis coli (APC) mutations (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.35-0.90; P = .015) and an increased prevalence of signet ring histology (OR, 4.89; 95% CI, 3.23-7.39; P < .0001) in comparison with other patients younger than 50 years. In patients younger than 40 years, CMS1 was the most common subtype, whereas CMS3 and CMS4 were uncommon (P = .003). CMS2 was relatively stable across age groups. Early-onset patients with inflammatory bowel disease were more likely to have mucinous or signet ring histology (OR, 5.54; 95% CI, 2.24-13.74; P = .0004) and less likely to have APC mutations (OR, 0.24; 95% CI, 0.07-0.75; P = .019) in comparison with early-onset patients without predisposing conditions. CONCLUSIONS: Early-onset CRC is not only distinct from traditional CRC: special consideration should be given to and further investigations should be performed for both very young patients with CRC (18-29 years) and those with predisposing conditions. The etiology of the high rate of CMS1 in patients younger than 40 years deserves further exploration.

Prognostic Implications of Mucinous Differentiation in Metastatic Colorectal Carcinoma Can Be Explained by Distinct Molecular and Clinicopathologic Characteristics.

BACKGROUND: The mucinous histologic subtype accounts for 5% to 20% of colorectal cancer (CRC) cases but remains poorly characterized. The present study characterized the baseline characteristics, mutational profile, and clinical outcomes of patients diagnosed with mucinous CRC. MATERIALS AND METHODS: We identified 1877 patients with metastatic CRC with available histologic findings and molecular profiling and summarized the baseline clinical and pathologic characteristics and overall survival (OS) stratified by the histologic type. The data from separate cohorts with consensus molecular subtype (CMS) and CpG island methylator information were also summarized. RESULTS: The mucinous histologic type was found in 277 of the 1877 patients (14.8%) and was associated with an increased prevalence of microsatellite instability (P < .001) and a right-sided primary (P < .001). An increased frequency of CMS1 (microsatellite instability immune) and lower rates of CMS2 (canonical) were identified, with mucinous compared with nonmucinous adenocarcinoma (P < .0001). Mutations in SMAD4 (P < .001), GNAS (P < .001), ERBB2 (P = .02), BRAF (P < .001), and KRAS (P < .001) occurred at greater frequencies in the mucinous CRC cases, and TP53 (P < .001), APC (P < .001), and NRAS mutations (P = .03) were less common. Univariate (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.17-1.63; P < .001) and multivariate analysis (HR, 1.36; 95% CI, 1.12-1.64; P = .002) demonstrated that the mucinous histologic type is associated with worse OS. The features associated with the mucinous histologic subtype were independent predictors for shorter OS, including BRAF (HR, 1.74; 95% CI, 1.35-2.25; P < .001) and KRAS (HR, 1.42; 95% CI, 1.22-1.65; P < .001) mutations, right-sided location (HR, 1.20; 95% CI, 1.04-1.39; P = .01), and synchronous metastases (HR, 2.92; 95% CI, 2.49-3.42; P < .001). CONCLUSION: Compared with nonmucinous adenocarcinoma, the mucinous histologic type is associated with a worse prognosis, even when controlling for known prognostic features. This unique biologic behavior should be considered in the treatment and prognostic assessment of patients with CRC.

Classifying Colorectal Cancer by Tumor Location Rather than Sidedness Highlights a Continuum in Mutation Profiles and Consensus Molecular Subtypes.

Purpose: Colorectal cancers are classified as right/left-sided based on whether they occur before/after the splenic flexure, with established differences in molecular subtypes and outcomes. However, it is unclear if this division is optimal and whether precise tumor location provides further information.Experimental Design: In 1,876 patients with colorectal cancer, we compared mutation prevalence and overall survival (OS) according to side and location. Consensus molecular subtype (CMS) was compared in a separate cohort of 608 patients.Results: Mutation prevalence differed by side and location for TP53, KRAS, BRAFV600, PIK3CA, SMAD4, CTNNB1, GNAS, and PTEN Within left- and right-sided tumors, there remained substantial variations in mutation rates. For example, within right-sided tumors, RAS mutations decreased from 70% for cecal, to 43% for hepatic flexure location (P = 0.0001), while BRAFV600 mutations increased from 10% to 22% between the same locations (P < 0.0001). Within left-sided tumors, the sigmoid and rectal region had more TP53 mutations (P = 0.027), less PIK3CA (P = 0.0009), BRAF (P = 0.0033), or CTNNB1 mutations (P < 0.0001), and less MSI (P < 0.0001) than other left-sided locations. Despite this, a left/right division preceding the transverse colon maximized prognostic differences by side and transverse colon tumors had K-modes mutation clustering that appeared more left than right sided. CMS profiles showed a decline in CMS1 and CMS3 and rise in CMS2 prevalence moving distally.Conclusions: Current right/left classifications may not fully recapitulate regional variations in tumor biology. Specifically, the sigmoid-rectal region appears unique and the transverse colon is distinct from other right-sided locations. Clin Cancer Res; 24(5); 1062-72. ©2017 AACRSee related commentary by Dienstmann, p. 989.

Gonadotropin-Releasing Hormone Agonists for Ovarian Function Preservation in Premenopausal Women Undergoing Chemotherapy for Early-Stage Breast Cancer: A Systematic Review and Meta-analysis.

IMPORTANCE: Chemotherapy may result in a detrimental effect on ovarian function and fertility in premenopausal women undergoing treatment for early-stage breast cancer (EBC). To minimize risk of harm to ovarian function and fertility for patients in this setting, careful considerations should be made. Gonadotropin-releasing hormone agonists (GnRHa) have been suggested as an alternative to prevent the loss of ovarian function due to exposure to cytotoxic agents, but GnRHa use for ovarian protection in EBC patients is not fully resolved. OBJECTIVE: To determine the effectiveness of GnRHa administered concurrently with chemotherapy for ovarian function preservation. DATA SOURCES: PubMed, SCOPUS, and Cochrane databases were searched for studies published between January 1975 and March 2015. The abstracts of the American Society of Clinical Oncology Annual Meeting between 1995 and 2014 and the San Antonio Breast Cancer Symposium between 2009 and 2014 were searched as well. STUDY SELECTION: Prospective, randomized, clinical trials addressing the role of ovarian suppression with GnRHa in preventing early ovarian dysfunction in premenopausal women undergoing treatment for EBC were selected. DATA EXTRACTION AND SYNTHESIS: Data extraction was performed independently by 2 authors. The methodology and the risk of bias were assessment based on the description of randomization method, withdrawals, and blinding process. MAIN OUTCOMES AND MEASURES: Rate of resumption of regular menses after a minimal follow-up period of 6 months following chemotherapy was used as a surrogate to assess the incidence of ovarian dysfunction. Additional secondary outcomes included hormone levels and number of pregnancies. Risk ratio estimates were calculated based on the number of evaluable patients. Analyses were conducted using a random effect model. RESULTS: Seven studies were included in this analysis, totaling 1047 randomized patients and 856 evaluable patients. The use of GnRHa was associated with a higher rate of recovery of regular menses after 6 months (odds ratio [OR], 2.41; 95% CI, 1.40-4.15; P = .002) and at least 12 months (OR, 1.85; 95% CI, 1.33-2.59; P < .001) following the last chemotherapy cycle. The use of GnRHa was also associated with a higher number of pregnancies (OR, 1.85; 95% CI, 1.02-3.36; P = .04), although this outcome was not uniformly reported and fertility or rate of pregnancy was not the primary outcome in any of the trials. CONCLUSIONS AND RELEVANCE: Gonadotropin-releasing hormone agonists given with chemotherapy was associated with increased rates of recovery of regular menses in this meta-analysis. Evidence was insufficient to assess outcomes related to GnRHa and ovarian function and fertility and needs further investigation.

The significance of circulating tumor cells in prostate cancer patients undergoing adjuvant or salvage radiation therapy.

BACKGROUND: Following radical prostatectomy, success of adjuvant and salvage radiation therapy (RT) is dependent on the absence of micrometastatic disease. However, reliable prognostic/predictive factors for determining this are lacking. Therefore, novel biomarkers are needed to assist with clinical decision-making in this setting. Enumeration of circulating tumor cells (CTCs) using the regulatory-approved CellSearch System (CSS) is prognostic in metastatic prostate cancer. We hypothesize that CTCs may also be prognostic in the post-prostatectomy setting. METHODS: Patient blood samples (n=55) were processed on the CSS to enumerate CTCs at 0, 6, 12 and 24 months after completion of RT. CTC values were correlated with predictive/prognostic factors and progression-free survival. RESULTS: CTC status (presence/absence) correlated significantly with positive margins (increased likelihood of CTC(neg) disease; P=0.032), and trended toward significance with the presence of seminal vesicle invasion (CTC(pos); P=0.113) and extracapsular extension (CTC(neg); P=0.116). Although there was a trend toward a decreased time to biochemical failure (BCF) in baseline CTC-positive patients (n=9), this trend was not significant (hazard ratio (HR)=0.3505; P=0.166). However, CTC-positive status at any point (n=16) predicted for time to BCF (HR=0.2868; P=0.0437). CONCLUSIONS: One caveat of this study is the small sample size utilized (n=55) and the low number of patients with CTC-positive disease (n=16). However, our results suggest that CTCs may be indicative of disseminated disease and assessment of CTCs during RT may be helpful in clinical decision-making to determine, which patients may benefit from RT versus those who may benefit more from systemic treatments.

Circulating tumour cells in prostate cancer patients receiving salvage radiotherapy

INTRODUCTION: Within 10 years of radical prostatectomy (RP), up to 30% of prostate cancer (PCa) patients will have a rise in prostate-specific antigen (PSA), requiring radiation therapy (RT). However, with current technology, distinction between local and distant recurrent PCa is not possible. This lack of an accurate test constrains the decision whether to offer systemic or local treatment. We hypothesise tests for detecting circulating tumour cells (CTCs) within the blood may assist with clinical decision-making and in this pilot study we investigated whether CTCs could be detected in this patient population using the CellSearch® system. MATERIALS AND METHODS: Blood samples were collected from PCa patients (n=26) prior to RT and 3 months following completion of RT. Samples were analysed for PSA level via immunoassay and CTC number using the CellSearch® system. RESULTS: CTCs could be detected in this patient population and following RT CTCs appeared to decrease. However, no association was observed between a higher PSA and an increased number of CTCs pre- or post-RT. Interestingly, patients who failed RT trended toward an increased/ unchanged number of CTCs following RT vs. a decreased number in patients with RT response. CONCLUSIONS: Our results demonstrate that CTCs can be detected in early-stage PCa and suggest the possibility that post-treatment reduction in CTC levels may be indicative of RT response . We are currently evaluating CTCs in a larger cohort of patients to validate our preliminary findings and further investigate the prognostic value of CTCs in this patient population (AU)

Cx43 suppresses mammary tumor metastasis to the lung in a Cx43 mutant mouse model of human disease.

Gap junctions, the channels formed by the connexin (Cx) family of proteins, are responsible for direct intercellular communication. Although connexins are considered as tumor suppressors, their overall role in cancer onset, progression and metastasis is somewhat controversial. This study uses a novel Cx43 mutant mouse model (G60S mice) and cross-breeding strategies to determine the role of Cx43 in all stages of breast tumorigenesis. G60S mice were cross-bred with ErbB2 overexpressing mice, and spontaneous and 7,12-dimethylbenz[α]anthracene (DMBA)-induced tumor development was evaluated. Mice were killed when tumors reached ∼1 cm(3) or when mice showed signs of critical illness. In both spontaneous and DMBA studies, onset of palpable tumors was delayed in G60S mice compared with mice in control groups. Moreover, while tumors from control mice reached the size threshold, most DMBA-exposed Cx43 mutant mice were killed prematurely because of labored breathing, independent of the presence of a palpable tumor. Reduced Cx43 levels in Cx43 mutant mice were accompanied by extensive mammary gland hyperplasia. Lung histology revealed that all Cx43 mutant mice exhibited mammaglobin-positive mammary gland metastases to the lung, and the number of metastases was increased by threefold in Cx43 mutant mice on treatment with DMBA. Thus, while reduced levels of Cx43 delayed the onset of palpable tumors, normal Cx43 levels inhibited mammary gland tumor metastasis to the lungs. Understanding the mechanisms of how Cx43, which is expressed primarily in myoepithelial cells, inhibits mammary gland tumor metastasis is critical as Cx43 is assessed as a candidate for therapeutic intervention.

Cancer stem cells: implications for the progression and treatment of metastatic disease.

Metastasis is the major cause of death for cancer patients with solid tumours, due mainly to the ineffectiveness of current therapies once metastases begin to form. Further insight into the biology of metastasis is therefore essential in order to gain a greater understanding of this process and ultimately to develop better cancer therapies. Metastasis is an inefficient process, such that very few cells that leave a tumour successfully form macrometastases in distant sites. This suggests that only a small subset of cells can successfully navigate the metastatic cascade and eventually re-initiate tumour growth to form life-threatening metastases. Recently, there has been growing support for the cancer stem cell (CSC) hypothesis which stipulates that primary tumours are initiated and maintained by a small subpopulation of cancer cells that possess "stem-like" characteristics. Classical properties of normal stem cells are strikingly reminiscent of the observed experimental and clinical behaviour of metastatic cancer cells, including an unlimited capacity for self renewal; the requirement for a specific 'niche' or microenvironment to grow; use of the stromal cell-derived factor 1 (SDF-1)/chemokine receptor 4 (CXCR4) axis for migration; enhanced resistance to apoptosis and an increased capacity for drug resistance. Therefore, in addition to playing a role in primary tumour formation, we believe that CSCs are also key players in the metastatic process. We will review the current evidence supporting this idea and discuss the potential implications of the CSC hypothesis with regards to experimental investigation and treatment of metastatic disease.

Activating transcription factor 3 induces DNA synthesis and expression of cyclin D1 in hepatocytes.

Activating transcription factor 3 (ATF3) is an early response gene that is induced rapidly during in vivo situations of cellular growth such as liver regeneration. However, neither the physiological function nor the potential target genes of this transcription factor related to cellular proliferation have been identified in the liver or other tissues. We demonstrate here that endogenous ATF3 mRNA expression is rapidly induced up to 4-fold upon mitogenic stimulation of quiescent Hepa 1-6 mouse hepatoma cells. Overexpression of exogenous ATF3 results in a significant, dose-dependent increase in DNA synthesis of up to 140% over control cells. ATF3-transfected cells also display significantly higher rates of [(3)H]thymidine incorporation in comparison with nontransfected controls in the presence of serum. Northern blot analysis and co-transfection experiments demonstrate that overexpression of ATF3 enhances cyclin D1 mRNA expression and activates the cyclin D1 promoter 2.5-fold when activating protein-1 (AP-1) and cyclic AMP response element (CRE) sites within the promoter are intact. ATF3-mediated promoter activation is reduced to 1.3-fold and 1.6-fold respectively when the AP-1 or CRE sites are mutated, and mutation of both sites simultaneously leads to the complete abrogation of promoter activation. Furthermore, DNA-binding studies demonstrate that ATF3 binds directly to the AP-1 site within the cyclin D1 promoter. These results indicate that ATF3 expression stimulates hepatocellular proliferation, suggesting that this effect is mediated, at least in part, by the ATF3-dependent activation of cyclin D1 transcription.