Purpose of Review
Resection of metastatic colorectal cancer (mCRC) can dramatically improve overall survival (OS), particularly in patients with isolated colorectal liver metastases (CLMs). In this ...review, we summarize recent findings and studies addressing chemotherapy ± targeted therapy before and after metastatectomies in patients with CLM.
Recent Findings
For initially unresectable CLM that could become resectable after response to medical therapy, FOLFIRINOX has the highest response and conversion rates and is safely administered with bevacizumab. In RAS wild-type, left-sided tumors, chemotherapy with Epidermal Growth Factor Receptor-targeted therapy should be strongly considered given high (~ 70%) response rates. In patients who present with resectable CLM, there is no clear indication that neoadjuvant chemotherapy improves OS. While the New EPOC trial showed detrimental progression-free survival in the combination arm containing cetuximab in this setting, methodologic issues with that trial have raised questions about the strength of these data.
Summary
Through multidisciplinary management in patients with isolated CLM, the best course of action to effect an R0 resection of all known disease-coupling surgery with medical therapy can significantly improve patient outcomes.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Immune checkpoint inhibitor (ICI) therapy is highly effective in metastatic mismatch repair‐deficient (MMR‐D) colorectal cancer (CRC). In this study, we evaluated molecular and clinical ...predictors of ICI response in MMR‐D CRC.
Materials and Methods
Patient databases at four cancer institutions were queried. The Fisher exact test was performed to test the association of clinical and molecular markers. The Kaplan‐Meier method was used to estimate progression‐free survival (PFS) and compared by the log‐rank test. Twelve‐ and 24‐month PFS rates were compared by the Z test.
Results
A total of 60 patients with CRC with MMR‐D/microsatellite instability‐high who previously received ICIs were identified. Patients with liver metastasis had a lower overall response rate as compared with other sites of metastasis (36.4% vs. 68.7%; p = .081). Patients with MLH1/PMS2 loss had worse 1‐year and 2‐year PFS rates compared with patients with MSH2/MSH6 loss (84.2% vs. 57.8% and 78.2% vs. 54.2%, respectively; p < .001). There were improved 1‐year and 2‐year PFS rates in patients with wild‐type BRAF when compared with patients with BRAF V600E mutation (73.3% vs. 40%, and 73.3% vs. 26.7%; respectively; p < .001). Patients aged >65 had significantly worse PFS rates as compared with patients aged ≤65 (p < .001).
Conclusion
BRAF V600E mutation, MLH1 and/or PMS2 loss, as well as age >65 years and liver metastasis, may be predictive of duration of ICI response in patients with MMR‐D CRC. Larger cohorts are needed to confirm our findings.
Implications for Practice
The results of this study reveal clinically important biomarkers that potentially predict immune checkpoint inhibitor response in patients with mismatch repair‐deficient colorectal cancer.
This article examines the effect of molecular subsets of mismatch repair‐deficient (MMR‐D) colorectal cancer and BRAF V600E mutation status as a molecular biomarker of immune checkpoint inhibitor efficacy in patients with MMR‐D colorectal cancer.
Universal screening for Lynch syndrome (LS) on resected colorectal carcinomas (CRCs) and endometrial carcinomas (ECs) was implemented in Iceland in 2017 using immunohistochemistry (IHC) for mismatch ...repair (MMR) proteins. We examined the efficacy of the universal screening algorithm to detect LS and the diagnostic accuracy of MMR IHC by comparing results with a population-based genotype database.
All patients diagnosed with CRC or EC per the Icelandic Cancer Registry from 2017 to 2019 who had tumor MMR IHC performed were included. Pathology reports and patient charts were reviewed. MMR IHC stains were crossmatched with genotyping results obtained from the deCODE database.
IHC staining was done on 404 patients with CRC and 74 patients with EC. A total of 61 (15.1%) patients with CRC and 15 (20.3%) patients with EC were MMR-deficient. MMR IHC had 88.9% sensitivity in identifying patients with LS and a positive predictive value of 10.7%. Only 50% of individuals were appropriately referred for genetic testing, leading to underdiagnosis of LS.
Universal screening for LS using MMR protein IHC in CRC and EC accurately identified patients appropriate for genetic testing in a population with MSH6 and PMS2 LS predominance. Because of lack of referral to genetic counseling, only 50% of patients with LS were identified through the screening algorithm.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
24.
Colorectal cancer - review Haraldsdottir, Sigurdis; Einarsdottir, Hulda M; Smaradottir, Agnes ...
Laeknabladid,
02/2014, Volume:
100, Issue:
2
Journal Article
Peer reviewed
Open access
Colorectal cancer is the third most common cancer in the Western hemisphere and the incidence increases with increasing age. Most colorectal cancers are localized with or without lymph node ...metastases. Up to 20% of patients present with metastatic disease, most commonly to the liver. Surgery is the only curative therapy for localized colorectal cancer and adjuvant chemotherapy is usually recommended for patients with lymph node metastases. Surgery, radiation therapy and chemotherapy are the key components of rectal cancer therapy. Selected patients with recurrent and metastatic disease can be salvaged with surgery but chemotherapy remains the mainstay of therapy for advanced colorectal cancer. Substantial progress has been observed in the treatment of metastatic colorectal cancer in recent years.
An increased risk of prostate cancer is currently not considered a part of the Lynch syndrome spectrum. The purpose of this study was to retrospectively examine prostate cancer incidence in the Lynch ...syndrome cohort at the Ohio State University in comparison with that in the general population.
We included all males diagnosed with Lynch syndrome from June 1998 to June 2012 at the Ohio State University and obtained baseline information including cancer history. If patients had not been seen in the 12 months before June 2012, they were contacted to document changes in their cancer history. We compared prostate cancer incidence among the Lynch syndrome families with that of the general population by using the Surveillance, Epidemiology, and End RESULTS registry 1999-2009.
Of the 188 males identified with Lynch syndrome, 11 males were diagnosed with prostate cancer during the study period. The ratio of observed to expected numbers of prostate cancer cases resulted in a standardized rate ratio of 4.87 (95% confidence interval: 2.43-8.71). Impaired mismatch repair expression and microsatellite instability were seen in one out of two prostate cancer specimens available for testing.
Males with Lynch syndrome had a nearly fivefold increased risk of developing prostate cancer but did not appear to have earlier onset or a more aggressive phenotype.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Management of Borderline Resectable Pancreatic Cancer Toesca, Diego A S; Koong, Amanda J; Poultsides, George A ...
International journal of radiation oncology, biology, physics,
04/2018, Volume:
100, Issue:
5
Journal Article
Peer reviewed
Open access
With the rapid development of imaging modalities and surgical techniques, the clinical entity representing tumors that are intermediate between resectable and unresectable pancreatic adenocarcinoma ...has been identified has been termed "borderline resectable" (BR). These tumors are generally amenable for resection but portend an increased risk for positive margins after surgery and commonly necessitate vascular resection and reconstruction. Although there is a lack of consensus regarding the appropriate definition of what constitutes a BR pancreatic tumor, it has been demonstrated that this intermediate category carries a particular prognosis that is in between resectable and unresectable disease. In order to downstage the tumor and increase the probability of clear surgical margins, neoadjuvant therapy is being increasingly utilized and studied. There is a lack of high-level evidence to establish the optimal treatment regimen for BR tumors. When resection with negative margins is achieved after neoadjuvant therapy, the prognosis for BR tumors approaches and even exceeds that for resectable disease. This review presents the current definitions, different treatment approaches, and the clinical outcomes of BR pancreatic cancer.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
Introduction
Immune‐related adverse event (IRAE) onset may represent a clinical biomarker for anti‐programmed cell death protein 1 (PD‐1) antibody response based on emerging evidence from patients ...with various advanced malignancies. This phenomenon has not been previously reported in a multidisease cohort of patients with gastrointestinal (GI) cancer with Food and Drug Administration (FDA)‐approved indications to receive immune checkpoint inhibitor therapy.
Materials and Methods
The study was a multicenter retrospective cohort analysis of 76 patients with GI cancer who had received anti‐PD‐1 antibodies for FDA‐approved indications. The primary and secondary outcomes of the study were progression‐free survival (PFS) and overall survival (OS) in patients based upon IRAE presence, respectively. PFS and OS were estimated by the Kaplan‐Meier method; a Cox proportional‐hazards model adjusted for IRAE onset, patient age, and enrolling institution was used to analyze outcomes.
Results
Median PFS and OS were prolonged in patients who experienced IRAEs compared with those who did not experience them (PFS: not reached NR vs. 3.9 months hazard ratio (HR) 0.13, 95% confidence interval (CI) 0.05–0.3, p < .001; OS: NR vs. 7.4 months HR 0.11, 95% CI 0.03–0.36, p < .001). Among patients who experienced IRAEs, there were no significant differences in PFS and OS by either initial IRAE severity, management, or time to onset.
Conclusion
Patients with gastrointestinal cancer who experienced IRAEs while on anti‐PD‐1 antibodies demonstrated significant improvements in PFS and OS compared with their counterparts who did not develop IRAEs. Although these findings add to results from studies in other tumor types, larger prospective studies are needed prior to clinical adoption of IRAE onset as a biomarker for immune checkpoint inhibitor response.
Implications for Practice
Predictive clinical biomarkers for immune checkpoint inhibitor response have been understudied in the field of immuno‐oncology. Immune‐related adverse event onset appears to be one such biomarker. Across tumor types, immune‐related adverse event onset has been associated with response to anti‐programmed cell death protein 1 (PD‐1) antibodies. The results of this study demonstrate this for the first time in patients with gastrointestinal cancer receiving anti‐PD‐1 antibodies. Before immune‐related adverse event onset can be adopted clinically as a predictive biomarker for immune checkpoint inhibitor response, however, larger prospective studies are needed to better understand the nuances between immune‐related adverse event characteristics (severity, site, management, timing of onset) and immune checkpoint inhibitor effectiveness.
Despite the potential of immune checkpoint inhibitors, few patients with gastrointestinal cancer are eligible to receive these therapeutic agents. The search for biomarkers to better select patients who might respond is ongoing. This article assesses immune‐related adverse events as a possible biomarker in gastrointestinal cancer.
Lynch syndrome (LS) is the most common form of hereditary colon cancer. Germline mutations in the mismatch-repair (MMR) genes MLH1, MSH2 (EPCAM), MSH6, and PMS2, followed by a second hit to the ...remaining allele, lead to cancer development. Universal tumor screening for LS is routinely performed on colon cancer, and screening has identified patients with unexplained MMR deficiency that lack MLH1 methylation and a germline mutation. Tumor sequencing has since identified double somatic (DS) mutations in the MMR gene corresponding with the absent protein in 69% of these patients. We assessed whether histomorphology could distinguish patients with DS mutations from those with LS. Colorectal cancer patients with DS mutations were identified from population-based cohorts from Iceland (2000-2009); Columbus, Ohio (1999-2005); and the state of Ohio (2013-2016). Next-generation sequencing was performed on tumors with unexplained MMR deficiency. Patients with LS from Ohio cohorts were the comparison group. The histologic features associated with MMR deficiency (tumor-infiltrating lymphocytes, Crohn-like reaction, histologic subtype, necrosis) were evaluated. We identified 43 tumors with DS mutations and 48 from patients with LS. There was no significant difference in histologic features between tumors in LS patients and tumors with DS mutations. Because histology of tumors with DS mutations is indistinguishable from those caused by LS, tumor sequencing for evaluation of DS mutations should be considered to help clarify sporadic versus hereditary causes of unexplained MMR deficiency.
•Double somatic mutations in mismatch-repair (MMR) genes can cause MMR deficiency.•Lynch syndrome and double somatic colorectal carcinomas have similar histology.•Tumor sequencing can help in cases of unexplained MMR deficiency.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
It is now an exciting time for the specialty as strong collaborative research initiated by academia, industry, and governmental agencies has revolutionised treatment for thyroid cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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