The efficacy of immunotherapy varies widely among different gastrointestinal cancers. Response to immune checkpoint inhibitors is shown to correlate with tumor mutation load (TML), mismatch repair ...deficiency (dMMR) status, and programmed cell death-ligand 1 (PD-L1) expression. Herein, we quantify TML, dMMR, and PD-L1 expression and determine their interrelationship in gastrointestinal cancers. Here, a total of 4,125 tumors from 14 different gastrointestinal cancer sites were studied using validated assays. Next-generation sequencing was performed on genomic DNA isolated from formalin-fixed paraffin-embedded tumor specimens using the NextSeq platform. TML was calculated using only somatic nonsynonymous missense mutations sequenced with a 592-gene panel. Microsatellite instability (MSI) was assessed using direct analysis of altered known MSI loci in the target regions of the sequenced genes. PD-L1 expression was analyzed by IHC. Interestingly, right-sided colon and small-bowel adenocarcinomas had the highest prevalence of TML-high tumors (14.6% and 10.2%, respectively). Pancreatic neuroendocrine tumors and gastrointestinal stromal tumors had the lowest rates of TML-high (1.3% and 0%, respectively). TML-high was strongly associated with MSI-H (
< 0.0001). However, all TML-high anal cancers (8.3%) were microsatellite stable (MSS). Higher PD-L1 expression was more likely to be seen in MSI compared with MSS tumors (20.6% vs. 7.8%,
< 0.0001).
TML-high rate varied widely among gastrointestinal cancers. Although MSI is conceivably the main driver for TML-high, other factors may be involved. Future clinical trials are needed to evaluate whether the integration of TML, MSI, and PD-L1 could better identify potential responders to immunotherapy.
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Microsatellite instability‐high (MSI‐H) and tumor mutational burden (TMB) are predictive biomarkers for immune‐checkpoint inhibitors (ICIs). Still, the relationship between the underlying cause(s) of ...MSI and TMB in tumors remains poorly defined. We investigated associations of TMB to mismatch repair (MMR) protein expression patterns by immunohistochemistry (IHC) and MMR mutations in a diverse sample of tumors. Hypothesized differences were identified by the protein/gene affected/mutated and the tumor histology/primary site. Overall, 1057 MSI‐H tumors were identified from the 32 932 tested. MSI was examined by NGS using 7000+ target microsatellite loci. TMB was calculated using only nonsynonymous missense mutations sequenced with a 592‐gene panel; a subset of MSI‐H tumors also had MMR IHC performed. Analyses examined TMB by MMR protein heterodimer impacted (loss of MLH1/PMS2 vs. MSH2/MSH6 expression) and gene‐specific mutations. The sample was 54.6% female; mean age was 63.5 years. Among IHC tested tumors, loss of co‐expression of MLH1/PMS2 was more common (n = 544/705, 77.2%) than loss of MSH2/MSH6 (n = 81/705, 11.5%; P < .0001), and was associated with lower mean TMB (MLH1/PMS2: 25.03 mut/Mb vs MSH2/MSH6 46.83 mut/Mb; P < .0001). TMB also varied by tumor histology: colorectal cancers demonstrating MLH1/PMS2 loss had higher TMBs (33.14 mut/Mb) than endometrial cancers (20.60 mut/Mb) and other tumors (25.59 mut/Mb; P < .0001). MMR gene mutations were detected in 42.0% of tumors; among these, MSH6 mutations were most common (25.7%). MSH6 mutation patterns showed variability by tumor histology and TMB. TMB varies by underlying cause(s) of MSI and tumor histology; this heterogeneity may contribute to differences in response to ICI.
What's new?
Immunotherapy based on checkpoint inhibitors shows promising results in a variety of cancer types, but still benefits a minority of patients. High microsatellite instability (MSI) and tumor mutational burden (TMB) have both been identified as biomarkers predictive of response to checkpoint inhibitors. Here, the authors investigated how the underlying causes of MSI influence TMB. Tumors lacking the mismatch repair protein duo MLH1/PMS2 had lower TMB than those lacking a different protein heterodimer, MLH2/MSH6. Even among tumors lacking the same mismatch repair proteins, the tissue of origin influenced mutational burden.
Survival of patients with stage III colon cancer varies widely according to T-N sub-stages. Estimating the benefit of each therapeutic option in each T-N subgroup may provide more accurate ...information helping doctors and patients in the complex shared decision-making process surrounding adjuvant therapy.
The outcomes data of 12,834 patients with stage III colon cancer enrolled in the IDEA trial served as our database. Patients were categorised in 16 sub-stages, based on T-N categories. We created a meta-regression model to predict the expected 5-year DFS within each T-N sub-stage. We then evaluated the efficacy of each therapeutic option in every sub-stage, working backward by subtraction, using an average of the HRs reported in pertinent trial publications as a conversion factor.
Large differences in 5-year DFS rate were observed among the subgroups, ranging from 89% (T1N1a) to 31% (T4N2b) in the overall population. The contribution to the outcome of each therapeutic option in this setting varied widely across sub-stages. According to our model, patients with T1N1a cancers have a projected 5-year DFS of 79.6% with surgery alone. Adjuvant fluoropyrimidine alone results in 5.6% absolute DFS gain; an additional 2.3% and 0.8% gain is seen with oxaliplatin for 3 and 6 months, respectively. Patients with T4N2b cancers show a 13.9% 5-year DFS with surgery alone, and an 11.2%, 6.4%, 2.5% increase with the aforementioned adjuvant options, respectively.
The resulting overlay bar graph gives patients and doctors the projected relative benefit of each treatment option and may substantially help the shared decision-making process, although caution must be exercised in using this model due to the significant variance of the estimates.
•Survival of patients with stage III colon cancer varies according to T-N sub-stages.•Average risk and benefit of adjuvant therapy is not applicable to individual patients•We showed that T1N1a has 89% 5-year DFS and that T4N2b has 31% 5-year DFS.•The contribution of each therapeutic option varied widely across sub-stages.•The resulting overlay bar graph shows the absolute benefit of each treatment option.
To determine the specific types, durations, and intensities of recreational physical activity associated with the greatest improvements in disease-free survival (DFS) of patients with colon cancer.
...We conducted a prospective cohort study nested within a randomized multicenter trial of stage III colon cancer that compared 3 versus 6 months of fluorouracil, leucovorin, and oxaliplatin with or without celecoxib. We measured recreational physical activity in the first 3 months of chemotherapy and again 6 months after completion of chemotherapy. The primary end point was DFS.
During a median follow-up of 5.9 years, 457 of 1,696 patients experienced disease recurrence or death. For total recreational physical activity volume, the 3-year DFS was 76.5% with < 3.0 metabolic equivalent task hours per week (MET-h/wk) and 87.1% with ≥ 18.0 MET-h/wk (risk difference RD, 10.6%; 95% CI, 4.7 to 19.4;
< .001). For light-intensity to moderate-intensity activities, the 3-year DFS was 65.7% with 0.0 h/wk and 87.1% with ≥ 1.5 h/wk (RD, 21.4%; 95% CI, 9.2 to 37.1;
< .001). For vigorous-intensity activity, the 3-year DFS was 76.0% with 0.0 h/wk and 86.0% with ≥ 1.0 h/wk (RD, 10.0%; 95% CI, 4.5 to 18.9;
< .001). For brisk walking, the 3-year DFS was 81.7% with < 1.0 h/wk and 88.4% with ≥ 3.0 h/wk (RD, 6.7%; 95% CI, 3.0 to 13.8;
< .001). For muscle strengthening activity, the 3-year DFS was 81.8% with 0.0 h/wk and 88.8% for ≥ 0.5 h/wk (RD, 7.0%; 95% CI, 3.1 to 14.2;
= .003).
Among patients with stage III colon cancer enrolled in a trial of postoperative treatment, larger volumes of recreational physical activity, longer durations of light- to moderate-intensity aerobic physical activity, or any vigorous-intensity aerobic physical activity were associated with the greatest improvements in DFS.
Health providers' implicit racial bias negatively affects communication and patient reactions to many medical interactions. However, its effects on racially discordant oncology interactions are ...largely unknown. Thus, we examined whether oncologist implicit racial bias has similar effects in oncology interactions. We further investigated whether oncologist implicit bias negatively affects patients' perceptions of recommended treatments (i.e., degree of confidence, expected difficulty). We predicted oncologist implicit bias would negatively affect communication, patient reactions to interactions, and, indirectly, patient perceptions of recommended treatments.
Participants were 18 non-black medical oncologists and 112 black patients. Oncologists completed an implicit racial bias measure several weeks before video-recorded treatment discussions with new patients. Observers rated oncologist communication and recorded interaction length of time and amount of time oncologists and patients spoke. Following interactions, patients answered questions about oncologists' patient-centeredness and difficulty remembering contents of the interaction, distress, trust, and treatment perceptions.
As predicted, oncologists higher in implicit racial bias had shorter interactions, and patients and observers rated these oncologists' communication as less patient-centered and supportive. Higher implicit bias also was associated with more patient difficulty remembering contents of the interaction. In addition, oncologist implicit bias indirectly predicted less patient confidence in recommended treatments, and greater perceived difficulty completing them, through its impact on oncologists' communication (as rated by both patients and observers).
Oncologist implicit racial bias is negatively associated with oncologist communication, patients' reactions to racially discordant oncology interactions, and patient perceptions of recommended treatments. These perceptions could subsequently directly affect patient-treatment decisions. Thus, implicit racial bias is a likely source of racial treatment disparities and must be addressed in oncology training and practice.
Oxaliplatin is an integral component of colorectal cancer therapy, but its clinical use is associated with a dose-limiting peripheral neurotoxicity. We found that the organic cation transporter 2 ...(OCT2) is expressed on dorsal root ganglia cells within the nervous system where oxaliplatin is known to accumulate. Cellular uptake of oxaliplatin was increased by 16- to 35-fold in cells overexpressing mouse Oct2 or human OCT2, and this process was associated with increased DNA platination and oxaliplatin-induced cytotoxicity. Furthermore, genetic or pharmacologic knockout of Oct2 protected mice from hypersensitivity to cold or mechanical-induced allodynia, which are established tests to assess acute oxaliplatin-induced neurotoxicity. These findings provide a rationale for the development of targeted approaches to mitigate this debilitating toxicity.
Pegylated recombinant human hyaluronidase (PEGPH20) degrades hyaluronan (HA) and, in combination with chemotherapy, prolongs survival in preclinical models. The activity of PEGPH20 with modified ...fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) was evaluated in patients with metastatic pancreatic cancer (mPC).
Patients had untreated mPC, a performance status of 0 to 1, and adequate organ function. Tumor HA status was not required for eligibility. After a phase Ib dose-finding study of mFOLFIRINOX plus PEGPH20, the phase II open-label study randomly assigned patients (1:1) to the combination arm or to mFOLFIRINOX alone (n = 138). The primary end point was overall survival (OS).
PEGPH20 dosages of 3 µg/kg every 2 weeks were more tolerable than twice-weekly dosages used in the phase I study, so 3 µg/kg every 2 weeks was the phase II dosage. An amendment instituted enoxaparin prophylaxis in the PEGPH20 combination arm as a result of increased thromboembolic (TE) events. The planned interim futility analysis when 35 deaths (of 103 analyzable patients) occurred resulted in an OS hazard ratio (HR) of 2.07 that favored the control arm, and the study was closed to accrual. The treatment-related grade 3 to 4 toxicity was significantly increased in the PEGPH20 combination arm relative to control (odds ratio, 2.7; 95% CI, 1.1 to 7.1). The median OS in the mFOLFIRINOX arm was 14.4 months (95% CI, 10.1 to 15.7 months) versus 7.7 months (95% CI, 4.6 to 9.3 months) in the PEGPH20 combination arm.
Addition of PEGPH20 to mFOLFIRINOX seems to be detrimental in patients unselected for tumor HA status. This combination caused increased toxicity (mostly GI and TE events) and resulted in decreased treatment duration compared with mFOLFIRINOX alone. The median OS in the mFOLFIRINOX control arm (14.4 months) is, to our knowledge, the longest yet reported and can be considered for patients with good PS.
Under Medicare's Coverage with Evidence Development policy, positron emission tomography (PET)/computed tomography (CT) and PET became covered services for previously noncovered cancer indications if ...prospective registry data were collected. The National Oncologic PET Registry (NOPR) was developed to meet these coverage requirements and to assess how PET affects care decisions.
The NOPR collected questionnaire data from referring physicians on intended patient management before and after PET. After 1 year, the cohort included data from 22,975 studies (83.7% PET/CT) from 1,178 centers. The numbers of scans performed for diagnosis of suspected cancer (or unknown primary cancer), initial cancer staging, restaging, and suspected cancer recurrence were approximately equal. Prostatic, pancreatic and ovarian cancers represented approximately 30% of cases.
If PET data were not available, the most common pre-PET plan would have been other imaging. In these patients, the post-PET strategies changed to watching in 37% and treatment in 48%. In patients with planned biopsy before PET, biopsy was avoided in approximately 70%. If the pre-PET strategy was treatment, the post-PET strategy involved a major change in type in 8.7% and goal in 5.6%. When intended management was classified as either treatment or nontreatment, the post-PET plan was three-fold more likely to lead to treatment than nontreatment (28.3% v 8.2%; odds ratio = 3.4; 95% CI, 3.2 to 3.6). Overall, physicians changed their intended management in 36.5% (95% CI, 35.9 to 37.2) of cases after PET.
This large, prospective, nationally representative registry of elderly cancer patients found that physicians often change their intended management on the basis of PET scan results across the full spectrum of its potential uses.
National Surgical Adjuvant Breast and Bowel Project R-04 was designed to determine whether the oral fluoropyrimidine capecitabine could be substituted for continuous infusion 5-FU in the curative ...setting of stage II/III rectal cancer during neoadjuvant radiation therapy and whether the addition of oxaliplatin could further enhance the activity of fluoropyrimidine-sensitized radiation.
Patients with clinical stage II or III rectal cancer undergoing preoperative radiation were randomly assigned to one of four chemotherapy regimens in a 2x2 design: CVI 5-FU or oral capecitabine with or without oxaliplatin. The primary endpoint was local-regional tumor control. Time-to-event endpoint distributions were estimated using the Kaplan-Meier method. Hazard ratios were estimated from Cox proportional hazard models. All statistical tests were two-sided.
Among 1608 randomized patients there were no statistically significant differences between regimens using 5-FU vs capecitabine in three-year local-regional tumor event rates (11.2% vs 11.8%), 5-year DFS (66.4% vs 67.7%), or 5-year OS (79.9% vs 80.8%); or for oxaliplatin vs no oxaliplatin for the three endpoints of local-regional events, DFS, and OS (11.2% vs 12.1%, 69.2% vs 64.2%, and 81.3% vs 79.0%). The addition of oxaliplatin was associated with statistically significantly more overall and grade 3-4 diarrhea (P < .0001). Three-year rates of local-regional recurrence among patients who underwent R0 resection ranged from 3.1 to 5.1% depending on the study arm.
Continuous infusion 5-FU produced outcomes for local-regional control, DFS, and OS similar to those obtained with oral capecitabine combined with radiation. This study establishes capecitabine as a standard of care in the pre-operative rectal setting. Oxaliplatin did not improve the local-regional failure rate, DFS, or OS for any patient risk group but did add considerable toxicity.
The optimal chemotherapy regimen administered concurrently with preoperative radiation therapy (RT) for patients with rectal cancer is unknown. National Surgical Adjuvant Breast and Bowel Project ...trial R-04 compared four chemotherapy regimens administered concomitantly with RT.
Patients with clinical stage II or III rectal cancer who were undergoing preoperative RT (45 Gy in 25 fractions over 5 weeks plus a boost of 5.4 Gy to 10.8 Gy in three to six daily fractions) were randomly assigned to one of the following chemotherapy regimens: continuous intravenous infusional fluorouracil (CVI FU; 225 mg/m(2), 5 days per week), with or without intravenous oxaliplatin (50 mg/m(2) once per week for 5 weeks) or oral capecitabine (825 mg/m(2) twice per day, 5 days per week), with or without oxaliplatin (50 mg/m(2) once per week for 5 weeks). Before random assignment, the surgeon indicated whether the patient was eligible for sphincter-sparing surgery based on clinical staging. The surgical end points were complete pathologic response (pCR), sphincter-sparing surgery, and surgical downstaging (conversion to sphincter-sparing surgery).
From September 2004 to August 2010, 1,608 patients were randomly assigned. No significant differences in the rates of pCR, sphincter-sparing surgery, or surgical downstaging were identified between the CVI FU and capecitabine regimens or between the two regimens with or without oxaliplatin. Patients treated with oxaliplatin experienced significantly more grade 3 or 4 diarrhea (P < .001).
Administering capecitabine with preoperative RT achieved similar rates of pCR, sphincter-sparing surgery, and surgical downstaging compared with CVI FU. Adding oxaliplatin did not improve surgical outcomes but added significant toxicity. The definitive analysis of local tumor control, disease-free survival, and overall survival will be performed when the protocol-specified number of events has occurred.
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