...I ignored those who told me I was too opinionated and pushed back when I was encouraged to focus my surgery practice solely on taking care of women with breast cancer. Important and unprecedented ...progress has been made in cancer research in just the past three decades in the USA, with cancer mortality declining by a third in that timeframe.4 Yet, women still face unique gender-based barriers and challenges when interacting with cancer as patients, caregivers, researchers, or health-care providers.5–10 Achieving gender equality in the context of cancer research and care will require broad implementation of the recommendations in The Lancet Commission on women, power, and cancer, including the overarching priority action that sex and gender be included in all cancer-related policies and guidelines so that they are responsive to the needs and aspirations of women in all of their diversities. The oncology community, together with all of society, needs to harness the tremendous value that women bring to developing and implementing cancer policy, leading and conducting research, providing care, and engaging communities.
Background
The prognosis for gastric cancer is better for Asian than for Caucasian patients. The primary driver of this difference is unknown. This study determined whether the survival advantage of ...Asian ethnicity continued to hold after control was used for other well-known prognostic factors.
Methods
In this study, 12,773 patients who underwent gastrectomy for treatment of adenocarcinoma of the stomach were identified from the Surveillance, Epidemiology, and End Results cancer registry. Patients with cardia tumor were excluded from the study. The independent prognostic effect of ethnicity was evaluated by adjusting for other known factors.
Results
The Asian patients tended to have a diagnosis at an earlier age (66.8 vs. 68.5 years), more lymph nodes examined (16 vs. 13), and more positive lymph nodes (5.1 vs. 4.8). Survival was better for the Asian patients than for the Caucasian patients, with a 12 % 5-year survival difference. Among the patients with IB, IIA, and IIB disease, the Asian patients had 37, 72, and 13 months longer median survival time than the corresponding Caucasian patients. The multivariate Cox model showed persistence of this result after adjustment for imbalances of age, gender, tumor grade, and number of examined and positive lymph nodes. The largest risk reduction was observed for the stage IA patients (31 %) and the smallest for the stage IIIC patients (9 %).
Conclusion
After excluding proximal gastric cancers, controlling for the imbalance of known prognostic factors, and decreasing in the influence of D2 lymphadenectomy, stage migration, and chemo/radiation therapy by including only patients treated in the United States, this study found that the survival advantage of Asian ethnicity continued to be present.
CALGB/SWOG 80405 was a randomized phase III trial that found no statistically significant difference in overall survival (OS) in patients with first-line metastatic colorectal cancer treated with ...chemotherapy plus either bevacizumab or cetuximab. Primary tumor DNA from 843 patients has been used to discover genetic markers of OS.
Gene mutations were determined by polymerase chain reaction. Microsatellite status was determined by genotyping of microsatellites. Tumor mutational burden (TMB) was determined by next-generation sequencing. Cox proportional hazard models were used, with adjusting factors. Interaction of molecular alterations with either the bevacizumab or the cetuximab arms was tested.
Patients with high TMB in their tumors had longer OS than did patients with low TMB (hazard ratio HR, 0.73 95% CI, 0.57 to 0.95;
= .02). In patients with microsatellite instability-high (MSI-H) tumors, longer OS was observed in the bevacizumab arm than in the cetuximab arm (HR, 0.13 95% CI, 0.06 to 0.30; interaction
< .001 for interaction between microsatellite status and the two arms). Patients with
mutant tumors had shorter OS than did patients with wild-type (WT) tumors (HR, 2.01 95% CI, 1.49 to 2.71;
< .001). Patients with extended
mutant tumors had shorter OS than did patients with WT tumors (HR, 1.52 95% CI, 1.26 to 1.84;
< .001). Patients with triple-negative tumors (WT for
/
/
) had a median OS of 35.9 months (95% CI, 33.0 to 38.8 months) versus 22.2 months (95% CI, 19.6 to 24.4 months ) in patients with at least one mutated gene in their tumors (
< .001).
In patients with metastatic colorectal cancer treated in first line, low TMB, and
and
mutations are negative prognostic factors. Patients with MSI-H tumors benefited more from bevacizumab than from cetuximab, and studies to confirm this effect of MSI-H are warranted.
Combining biologic monoclonal antibodies with chemotherapeutic cytotoxic drugs provides clinical benefit to patients with advanced or metastatic colorectal cancer, but the optimal choice of the ...initial biologic therapy in previously untreated patients is unknown.
To determine if the addition of cetuximab vs bevacizumab to the combination of leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) regimen or the combination of leucovorin, fluorouracil, and irinotecan (FOLFIRI) regimen is superior as first-line therapy in advanced or metastatic KRAS wild-type (wt) colorectal cancer.
Patients (≥18 years) enrolled at community and academic centers throughout the National Clinical Trials Network in the United States and Canada (November 2005-March 2012) with previously untreated advanced or metastatic colorectal cancer whose tumors were KRAS wt chose to take either the mFOLFOX6 regimen or the FOLFIRI regimen as chemotherapy and were randomized to receive either cetuximab (n = 578) or bevacizumab (n = 559). The last date of follow-up was December 15, 2015.
Cetuximab vs bevacizumab combined with either mFOLFOX6 or FOLFIRI chemotherapy regimen chosen by the treating physician and patient.
The primary end point was overall survival. Secondary objectives included progression-free survival and overall response rate, site-reported confirmed or unconfirmed complete or partial response.
Among 1137 patients (median age, 59 years; 440 39% women), 1074 (94%) of patients met eligibility criteria. As of December 15, 2015, median follow-up for 263 surviving patients was 47.4 months (range, 0-110.7 months), and 82% of patients (938 of 1137) experienced disease progression. The median overall survival was 30.0 months in the cetuximab-chemotherapy group and 29.0 months in the bevacizumab-chemotherapy group with a stratified hazard ratio (HR) of 0.88 (95% CI, 0.77-1.01; P = .08). The median progression-free survival was 10.5 months in the cetuximab-chemotherapy group and 10.6 months in the bevacizumab-chemotherapy group with a stratified HR of 0.95 (95% CI, 0.84-1.08; P = .45). Response rates were not significantly different, 59.6% vs 55.2% for cetuximab and bevacizumab, respectively (difference, 4.4%, 95% CI, 1.0%-9.0%, P = .13).
Among patients with KRAS wt untreated advanced or metastatic colorectal cancer, there was no significant difference in overall survival between the addition of cetuximab vs bevacizumab to chemotherapy as initial biologic treatment.
clinicaltrials.gov identifier: NCT00265850.
The association of deficient DNA mismatch repair (dMMR) with prognosis in patients with colon cancer treated with adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy remains ...unknown.
Resected, stage III colon carcinomas from patients (N = 2,686) randomly assigned to FOLFOX ± cetuximab (North Central Cancer Treatment Group N0147 trial) were analyzed for mismatch repair (MMR) protein expression and mutations in BRAF(V600E) (exon 15) and KRAS (codons 12 and 13). Association of biomarkers with disease-free survival (DFS) was determined using Cox models. A validation cohort (Cancer and Leukemia Group B 88903 trial) was used.
dMMR was detected in 314 (12%) of 2,580 tumors, of which 49.3% and 10.6% had BRAF(V600E) or KRAS mutations, respectively. MMR status was not prognostic overall (adjusted hazard ratio HR, 0.82; 95% CI, 0.64 to 1.07; P = .14), yet significant interactions were found between MMR and primary tumor site (P(interaction) = .009) and lymph node category (N1 v N2; P(interaction) = .014). Favorable DFS was observed for dMMR versus proficient MMR proximal tumors (HR, 0.71; 95% CI, 0.53 to 0.94; P = .018) but not dMMR distal tumors (HR, 1.71; 95% CI, 0.99 to 2.95; P = .056), adjusting for mutations and covariates. Any survival benefit of dMMR was lost in N2 tumors. Mutations in BRAF(V600E) (HR, 1.37; 95% CI, 1.08 to 1.70; P = .009) or KRAS (HR, 1.44; 95% CI, 1.21 to 1.70; P < .001) were independently associated with worse DFS. The observed MMR by tumor site interaction was validated in an independent cohort of stage III colon cancers (P(interaction) = .037).
The prognostic impact of MMR depended on tumor site, and this interaction was validated in an independent cohort. Among dMMR cancers, proximal tumors had favorable outcome, whereas distal or N2 tumors had poor outcome. BRAF or KRAS mutations were independently associated with adverse outcome.
To determine the predictive and prognostic value of the consensus molecular subtypes (CMSs) of colorectal cancer (CRC) that represent a merging of gene expression-based features largely in primary ...tumors from six independent classification systems and provide a framework for capturing the intrinsic heterogeneity of CRC in patients enrolled in CALGB/SWOG 80405.
CALGB/SWOG 80405 is a phase III trial that compared the addition of bevacizumab or cetuximab to infusional fluorouracil, leucovorin, and oxaliplatin or fluorouracil, leucovorin, and irinotecan as first-line treatment of advanced CRC. We characterized the CMS classification using a novel NanoString gene expression panel on primary CRCs from 581 patients enrolled in this study to assess the prognostic and predictive value of CMSs in these patients.
The CMSs are highly prognostic for overall survival (OS;
< .001) and progression-free survival (PFS;
< .001). Furthermore, CMSs were predictive for both OS (
for interaction < .001) and PFS (
for interaction = .0032). In the CMS1 cohort, patients treated with bevacizumab had a significantly longer OS than those treated with cetuximab (
< .001). In the CMS2 cohort, patients treated with cetuximab had a significantly longer OS than patients treated with bevacizumab (
= .0046).
These findings highlight the possible clinical utility of CMSs and suggests that refinement of the CMS classification may provide a path toward identifying patients with metastatic CRC who are most likely to benefit from specific targeted therapy as part of the initial treatment.
Abstract
Desmoid tumors (DTs) are unusual neoplasms of mesenchymal origin that exhibit locally invasive behavior. Surgical resection is the initial treatment of choice for DTs. For patients with ...recurrent or unresectable disease, however, medical options are limited. Sorafenib is a multikinase inhibitor with known antitumor activity in various cancers via suppression of the PI3K/Akt/mTOR pathway. Here, we examined the effects of sorafenib on patient-derived DT cell lines, with the aim of characterizing the efficacy and molecular mechanism of action. Early passage DT-derived cells were treated with increasing doses of sorafenib (0-10 µM) and demonstrated up to 90% decrease in proliferation and invasion relative to controls. Signaling arrays identified multiple potential targets of sorafenib in the Ras/MEK/ERK and PI3K/Akt/mTOR signaling cascades. Immunoblot analysis revealed that sorafenib inhibited Akt, MEK and ERK phosphorylation, and this effect correlated with inhibition of total Akt and total MEK, while total ERK levels remained unchanged. Sorafenib also inhibited 4E-BP1 phosphorylation, and this effect correlated with decrease of p-eIF4E and total eIF4E. Finally, in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus, sorafenib decreased phosphorylation of the ribosomal protein and mTOR effector S6K in an additive manner. Taken together, our results suggest that sorafenib suppresses DT proliferation and invasion via inhibition of Ras/MEK/ERK and PI3K/Akt/mTOR signaling pathways with additional effects on translation. Sorafenib may be a promising therapeutic option in the treatment of DTs. Additional studies in DT patients are warranted to examine the efficacy of combination therapy using sorafenib.
Sorafenib is a multikinase inhibitor that demonstrates antitumor effects in patient-derived desmoid tumor (DT) cell lines including decreased proliferation and invasion. Signaling pathways targeted by sorafenib in DTs include Ras/MEK/ERK and PI3K/Akt/mTOR pathways with additional effects on translation.
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