KRAS inhibition in metastatic colorectal cancer: An update.

About half of colorectal cancers harbor mutations in the KRAS gene. The presence of these mutations is associated with worse prognosis and, until now, the absence of matched targeted therapy options. In this review, we discuss clinical efforts to target KRAS in colorectal cancer from studies of downstream inhibitors to recent direct inhibitors of KRASG12C and other KRAS mutants. Early clinical trial data, however, suggest more limited activity for these novel inhibitors in colorectal cancer compared to other cancer types, and we discuss the role of receptor tyrosine kinase signaling and parallel signaling pathways in modulating response to these inhibitors. We also review the effect of KRAS mutations on the tumor-immune microenvironment and efforts to induce an immune response against these tumors.

Radiation therapy for de novo anorectal cancer in patients with a history of prostate radiation therapy.

Introduction: Radiation therapy (RT) for anorectal cancer after prior prostate cancer RT is usually avoided due to concern for complications. Data on this topic is scarce. Our aim was to evaluate tolerability, toxicity, and clinical outcomes associated with a second course of pelvic radiation in men with de novo anorectal cancers previously treated with RT for prostate cancer. Materials/methods: We conducted a single-institution retrospective study of men treated with RT for rectal or anal cancer after prior prostate RT. Toxicity data were collected. Treatment plans were extracted to assess doses to organs at risk and target coverage. Cumulative incidence was calculated for local and distant progression. Kaplan-Meier curves were used to estimate overall survival (OS) and progression-free survival (PFS). Results: We identified 26 patients who received anorectal RT after prostate cancer RT: 17 for rectal cancer and 9 for anal cancer. None had metastatic disease. Prior prostate RT was delivered using low dose rate brachytherapy (LDR), external beam RT (EBRT), or EBRT + LDR. RT for rectal cancer was delivered most commonly using 50.4Gy/28 fractions (fr) or 1.5 Gy twice-daily to 30-45 Gy. The most used RT dose for anal cancer was 50Gy/25 fr. Median interval between prostate and anorectal RT was 12.3 years (range:0.5 - 25.3). 65% and 89% of rectal and anal cancer patients received concurrent chemotherapy, respectively. There were no reported ≥Grade 4 acute toxicities. Two patients developed fistulae; one was urinary-cutaneous after prostate LDR and 45Gy/25fr for rectal cancer, and the other was recto-vesicular after prostate LDR and 50Gy/25fr for anal cancer. In 11 patients with available dosimetry, coverage for anorectal cancers was adequate. With a median follow up of 84.4 months, 5-yr local progression and OS were 30% and 31% for rectal cancer, and 35% and 49% for anal cancer patients, respectively. Conclusion: RT for anorectal cancer after prior prostate cancer RT is feasible but should be delivered with caution since it poses a risk of fistulae and possibly bleeding, especially in patients treated with prior LDR brachytherapy. Further studies, perhaps using proton therapy and/or rectal hydrogel spacers, are needed to further decrease toxicity and improve outcomes.

Simplified Graded Infusion Strategy for Mitigation of Oxaliplatin Hypersensitivity.

BACKGROUND: Hypersensitivity reactions (HSRs) to oxaliplatin present a therapeutic challenge. The standard desensitization protocol consists of 12 infusion steps with 3 drug dilutions, often in an inpatient setting. Several years ago we implemented a simplified outpatient graded infusion protocol for oxaliplatin with 2 drug dilutions and 3 infusion steps. MATERIALS AND METHODS: We performed a retrospective analysis of our experience to define the safety and outcomes associated with this simplified, ambulatory, graded infusion strategy. RESULTS: Between January 1, 2011 and December 1, 2020, 374 patients who had experienced an oxaliplatin-related HSR were treated via a 3-step graded infusion in the outpatient setting. Of these 374 patients, 283 (76%) did not experience a subsequent HSR, while 91 (24%) did experience a breakthrough HSR. Of the 374 patients, 19 (5%) experienced a grade 3 or 4 HSR. Three patients (0.8%) were hospitalized. There was no grade 5 (fatal) HSRs. Overall, the 374 patients received a median additional 3 cycles of oxaliplatin (range 1-41). The most common reasons for treatment discontinuation were disease progression (35%), breakthrough HSRs (24%), completion of treatment (21%), and toxicity other than HSR (20%). Fifteen patients who experienced breakthrough HSRs during a graded infusion were subsequently treated with the standard 12-step desensitization. Five of these 15 patients had an HSR during their initial desensitization and 5 developed an HSR on subsequent 12-step desensitizations. Thus, treatment was discontinued in 67% of these 15 patients due to persistent HSRs. CONCLUSION: Our data indicate that the simplified 3-step graded infusion protocol is a safe outpatient strategy for patients with a history of HSR to oxaliplatin.

Factors Associated With Premature Ovarian Insufficiency in Young Women With Locally Advanced Rectal Cancer Treated With Pelvic Radiation Therapy.

PURPOSE: Pelvic radiation therapy (RT) is standard of care for patients with locally advanced rectal cancer (LARC). Premature ovarian insufficiency (POI) in premenopausal women is a possible side effect. The purpose of our study was to evaluate factors associated with POI in women younger than 50 years, treated with pelvic RT for LARC, including those who underwent ovarian transposition (OT). METHODS AND MATERIALS: We retrospectively reviewed the records of women younger than 50 years treated with pelvic RT for LARC at our institution between 2001 and 2019. Clinical and hormonal data were used to determine ovarian function. The ovaries and uterus were contoured and dose volume histograms were generated. Association of clinical and dosimetric factors with POI within 12 months of RT was evaluated using Wilcoxon-rank sum test and Fisher's exact test. RESULTS: We identified 76 premenopausal women at time of RT with median age of 43 years (range, 20-49). Twenty-six women (34%) underwent OT. Neoadjuvant, concurrent, and adjuvant chemotherapy was administered in 56 (74%), 69 (91%), and 26 (34%) women, respectively. Median RT dose was 50 Gy/25 fractions. Among 75 women with 12 months of follow-up, 25% had preservation of ovarian function, all in the OT group. Ovarian function was preserved in 19 (76%) women who underwent OT. The median of ovarian mean dose was 1.7 Gy in the OT group versus 44.8 Gy in the non-OT group (P < .001). OT and age at RT were significantly associated with POI (P < .001). No patient with ovarian mean dose less than 1.36 Gy developed POI. CONCLUSIONS: OT was significantly associated with reduced risk of POI by enabling lower radiation doses to the ovaries. OT should be considered in young patients undergoing pelvic RT. Although there appears to be a significant association between ovarian mean dose and POI, larger studies are needed to find a dosimetric threshold. Our results suggest keeping the dose to the ovaries as low as reasonably achievable in patients who undergo OT and pelvic RT.

Comprehensive Clinical and Molecular Characterization of KRAS G12C-Mutant Colorectal Cancer.

PURPOSE: KRAS p.G12C mutations occur in approximately 3% of metastatic colorectal cancers (mCRC). Recently, two allosteric inhibitors of KRAS p.G12C have demonstrated activity in early phase clinical trials. There are no robust studies examining the behavior of this newly targetable population. METHODS: We queried the MD Anderson Cancer Center data set for patients with colorectal cancer who harbored KRAS p.G12C mutations between January 2003 and September 2019. Patients were analyzed for clinical characteristics, overall survival (OS), and progression-free survival (PFS) and compared against KRAS nonG12C. Next, we analyzed several internal and external data sets to assess immune signatures, gene expression profiles, hypermethylation, co-occurring mutations, and proteomics. RESULTS: Among the 4,632 patients with comprehensive molecular profiling, 134 (2.9%) were found to have KRAS p.G12C mutations. An additional 53 patients with single gene sequencing were included in clinical data but excluded from prevalence analysis allowing for 187 total patients. Sixty-five patients had de novo metastatic disease and received a median of two lines of chemotherapy without surgical intervention. For the first three lines of chemotherapy, the median PFS was 6.4 months (n = 65; 95% CI, 5.0 to 7.4 months), 3.9 months (n = 47; 95% CI, 2.9 to 5.9 months), and 3.0 months (n = 21; 95% CI, 2.0 to 3.4 months), respectively. KRAS p.G12C demonstrated higher rates of basal EGFR activation compared with KRAS nonG12C. When compared with an internal cohort of KRAS nonG12C, KRAS p.G12C patients had worse OS. CONCLUSION: PFS is poor for patients with KRAS p.G12C metastatic colorectal cancer. OS was worse in KRAS p.G12C compared with KRAS nonG12C patients. Our data highlight the innate resistance to chemotherapy for KRAS p.G12C patients and serve as a historical comparator for future clinical trials.

Response to Anti-PD-1 in Microsatellite-Stable Colorectal Cancer: A STAT Need.

Most colorectal cancers are microsatellite-stable with no response to anti-PD-1 therapy, necessitating the development of new immunomodulatory treatment strategies. Coinhibition of anti-PD-1 and STAT3 can elicit an effective antitumor response in a small subset of patients with microsatellite-stable colorectal cancer, and biomarkers predictive of response are under investigation.See related article by Kawazoe et al., p. 5887.

Standardizing Opioid Prescribing Practices for Cancer-Related Pain Via a Novel Interactive Documentation Template at a Public Hospital.

PURPOSE: Opioid misuse during cancer pain management places patients at risk for harm and physicians for legal liability. Identifying and monitoring patients who are at risk is challenging given the lack of validated clinical tools and evidence-based guidelines. In the current study, we aimed to standardize opioid prescribing practices at a community oncology clinic to help ensure patient safety and physician compliance with Texas state regulations. METHODS: We used the Plan-Do-Study-Act methodology. In the planning phase, current practices of assessing opioid efficacy, toxicity, and misuse were determined by surveying clinic physicians and reviewing patients' charts. We developed a new standardized process that incorporated published literature, the Texas Administrative Code, and expert opinion. Two interactive documentation templates (SmartPhrases) were designed to implement the standardized process. The intervention was studied using repeat physician surveys and chart reviews, which prompted action for refinement and sustainability. RESULTS: At baseline, 9% of providers followed a systematic approach to prescribing opioids and 86% expressed an interest in process standardization. We noted high interprovider variability in the opioid risk stratification and refill process. At 2 months and 6 months postimplementation, provider satisfaction with the intervention was 83% and 75%, whereas compliance with SmartPhrase use was 70% and 54%, respectively. The frequency of state database check improved from 36% to 94% at 6 months. Improvement was also noted in assessment and documentation of baseline risk, chemical coping, and toxicity. CONCLUSION: We implemented a systematic approach for assessing opioid misuse, toxicity, and efficacy during cancer pain management at a community oncology clinic. The approach resulted in notable improvement in provider practices and documentation compliance.

Successful Implementation of a Multidisciplinary Chemotherapy Efficiency Initiative at a Community Hospital.

PURPOSE: Long wait times at chemotherapy infusion centers adversely affect patients' perception of quality of care and result in patient dissatisfaction. We conducted a quality improvement initiative at a busy community hospital to improve infusion center efficiency and reduce patient wait time, while maintaining patient safety and avoiding chemotherapy waste. METHODS: We used a coordinated and collaborative effort between providers, infusion center nurses, and pharmacists to ensure completion of orders, review of laboratory data, and prepreparation of chemotherapy 1 day ahead of each patient's scheduled infusion center appointment. Monthly Plan-Do-Study-Act cycles were conducted for 6 months beyond the pilot month to refine and sustain the intervention. RESULTS: The average patient cycle time, measured as time from patient check-in to check-out from the infusion chair, decreased from 252 minutes to 173 minutes in the last 4 months evaluated (30% decrease) after the intervention. Similarly, the average chemotherapy turnaround time, measured as time from chemotherapy request by nursing to pharmacy delivery, improved from 90 minutes to 27 minutes after the intervention (70% decrease). Infusion center capacity was unaffected by the intervention. The cost of wasted chemotherapy was minimal after the first postintervention month. Surveys revealed extremely high patient and employee satisfaction with the new system. CONCLUSION: A strategy involving prepreparation of chemotherapy on the day before the scheduled infusion is feasible to implement at a busy community hospital infusion center and is associated with significant improvement in infusion center efficiency as well as patient and employee satisfaction.

Deleterious Effect of RAS and Evolutionary High-risk TP53 Double Mutation in Colorectal Liver Metastases.

OBJECTIVE: To assess the impact of somatic gene mutations on survival among patients undergoing resection of colorectal liver metastases (CLM). BACKGROUND: Patients undergoing CLM resection have heterogeneous outcomes, and accurate risk stratification is necessary to optimize patient selection for surgery. METHODS: Next-generation sequencing of 50 cancer-related genes was performed from primary tumors and/or liver metastases in 401 patients undergoing CLM resection. Missense TP53 mutations were classified by the evolutionary action score (EAp53)-a novel approach that dichotomizes mutations as low or high risk. RESULTS: The most frequent somatic gene mutations were TP53 (65.6%), followed by KRAS (48.1%) and APC (47.4%). Double mutation in RAS/TP53, identified in 31.4% of patients, was correlated with primary tumor location in the right colon (P = 0.006). On multivariable analysis, RAS/TP53 double mutation was an independent predictor of shorter overall survival (hazard ratio 2.62, 95% confidence interval 1.41-4.87, P = 0.002). In patients with co-mutated RAS, EAp53 high-risk mutations were associated with shorter 5-year overall survival of 12.2%, compared with 55.7% for TP53 wild type (P < 0.001). The negative prognostic effects of RAS and TP53 mutations were limited to tumors harboring mutations in both genes. CONCLUSIONS: Concomitant RAS and TP53 mutations are associated with decreased survival after CLM resection. A high EAp53 predicts a subset of patients with worse prognosis. These preliminary analyses suggest that surgical resection of liver metastases should be carefully considered in this subset of patients.

Outcomes Among High-Risk and Standard-Risk Multiple Myeloma Patients Treated With High-Dose Chemotherapy and Autologous Hematopoietic Stem-Cell Transplantation.

BACKGROUND: Conventional cytogenetics and interphase fluorescence in-situ hybridization (FISH) identify a high-risk multiple myeloma population characterized by poor response and short survival. PATIENTS AND METHODS: We compared outcomes between high-risk and standard-risk myeloma patients who underwent autologous hematopoietic stem-cell transplantation (auto-HCT) at our institution between January 2005 and December 2009. High-risk myeloma was defined as -13/del(13q) or hypodiploidy in at least 2 metaphases of conventional cytogenetics, or -17/del(17p), t(4;14), t(14;16), t(14;20), hypodiploidy (< 45 chromosomes excluding -Y), or chromosome 1 abnormalities (+1q, -1p, t(1;x)) on FISH or conventional cytogenetics. RESULTS: Of 670 myeloma patients, 74 (11%) had high-risk myeloma. These high-risk patients had significantly lower overall response rates (74% vs. 85%; P < .01), shorter median progression-free survival (10.3 vs. 32.4 months; P < .001), and shorter overall survival (28 months vs. not reached; P < .001) than the standard-risk patients. Having only 1 high-risk cytogenetic abnormality or experiencing at least very good partial remission after auto-HCT independently predicted improved progression-free survival and overall survival (P < .05) in high-risk patients. CONCLUSION: Even in an era of novel therapies, cytogenetically identified high-risk myeloma patients have worse prognoses than standard-risk myeloma patients after auto-HCT, and having more than 1 high-risk cytogenetic abnormality further reduces survival.

Bedtime and its correlates among secondary school children in Karachi, Pakistan.

OBJECTIVES: To determine the demographic and lifestyle predictors of bedtime among secondary school children in Karachi, Pakistan, and to assess what variables of daytime functioning correlate with bedtimes. METHODS: The cross-sectional study was conducted between September and October 2007, among secondary school students aged 10-16 years, in the socio-economically diverse city of Karachi. Data was collected using a pre-tested self-reporting questionnaire, and analysed by univariate and multivariate logistic regression analysis on SPSS version 15. A p value of <0.05 was considered significant. All odds ratio were recorded with a 95% confidence interval. RESULTS: Of the 539 students in the study, 102 (18.92%) were male and 437 (81.07%) were female. Of the total, 401 (74.4%) slept late (after 10pm). Homework and TV shows were more frequent reasons of bedtime among the late-sleepers, whereas parental influence was reported more by the early-sleepers. Advancing grade at school, father's profession as doctor or engineer and sleeping alone in the room were independent predictors of late bedtime on multivariate analysis (p<0.05). Students who were older, did not share a bed, or slept for >3 hours during the afternoon, were more likely to sleep after 10pm on univariate analysis only (p<0.05). Students sleeping late were more likely to get less daily and nocturnal sleep, wake-up later, require multiple wake up reminders in the morning, fall asleep in a morning class and feel tired during the day (p<0.05). They were also 2.42 times less likely to feel that they got adequate sleep to be fresh in the morning (p<0.001; 95% CI 1.58-3.72). CONCLUSION: More than three-fourth of our secondary school children sleep late. Parents and teachers should foster healthy sleeping habits and early bedtimes among students to allow optimal daytime functioning.

An insight into the suspected HbA2' cases detected by high performance liquid chromatography in Pakistan.

BACKGROUND: Hemoglobin A2' (delta 16 Gly → Arg) is globally the commonest delta chain variant of HbA2. It is clinically and hematologically silent but its sole importance lies in the underestimation of HbA2 quantity during the workup of ß-thalassaemia trait. High performance liquid chromatography (HPLC) identifies it as a small S-window peak with a mean retention time of 4.59 ± 0.03 minutes. This study aims at describing the frequency of detection of HbA2' by HPLC in Pakistan and its confirmation at a molecular level. Potential HbA2' cases were identified by a retrospective review of 10186 HPLC chromatograms in year 2006. Prospective samples were collected for polymerase chain reaction (PCR) amplification, restriction digestion and nucleotide sequencing. FINDINGS: One hundred and ninety two potential cases (1.89%) of HbA2' were detected on HPLC, having mean retention time of 4.59 ± 0.05 minutes. Sixty four (0.6%) new cases were suspected of having co-existing ß-thalassaemia trait when the quantity of S-window peaks was taken into account. Thirteen samples with presumed HbA2' on HPLC were subjected to molecular analysis and the said mutation (δ 16 GGC → CGC) was not detected in any sample. CONCLUSIONS: It is concluded that diagnosis of HbA2' on HPLC alone is not justified, as evidence of the presence of this delta chain variant in Pakistani population is yet to be proven. Such small S-window peaks should be either disregarded or confirmed at molecular level, and only then should influence the diagnosis of ß-thalassaemia trait. Further studies are required to determine the true nature of these peaks.

Chromatographic analysis of Hb S for the diagnosis of various sickle cell disorders in Pakistan.

Sickle cell disease remains a relatively obscure theme in research on haemoglobinopathies in Pakistan. Limited data is available regarding its prevalence in the country. The objective of our study was not only to estimate the frequency of different sickle cell diseases but also to provide quantitative estimation of haemoglobin S and other haemoglobin variants using an automated high-performance liquid chromatography (HPLC) system. For this purpose, we retrospectively evaluated the results of HPLC performed on all patients with suspected haemoglobinopathies during the years 2005 and 2006. Information derived from various sources was used to identify a particular genotype by analysing each sample containing Hb S with respect to haemoglobin, red cell indices and levels of various associated haemoglobin variants. Analysis of 15,699 samples identified 302 patients with Hb S (1.92%). The genotypes identified included Sbeta(0) (46.7%), SS (19.2%), SA (11.6%), Sbeta(+) (8.6%) and SD (2.3%). Thirty-five cases could not be categorised and were labelled 'unclassified'. Majority of the patients (62.3%) were below the age of 18 years. Balochistan, which is the largest province based on the area, yielded the highest number of patients (n = 140). In the Sbeta(0) group, the mean haemoglobin and Hb S were lower in children compared to adults (p value of 0.001 and 0.016, respectively). We conclude that sickle cell disorders are prevalent in Pakistan to a significant extent, being concentrated in certain areas of the country. We present the first report of various haemoglobin S genotypes from our population. It is hoped that it will act as a database to characterise the same for our population.