-
Journal of Clinical Oncology : Official... Apr 2020To provide recommendations on genetic and tumor testing for women diagnosed with epithelial ovarian cancer based on available evidence and expert consensus. (Meta-Analysis)
Meta-Analysis
PURPOSE
To provide recommendations on genetic and tumor testing for women diagnosed with epithelial ovarian cancer based on available evidence and expert consensus.
METHODS
A literature search and prospectively defined study selection criteria sought systematic reviews, meta-analyses, randomized controlled trials (RCTs), and comparative observational studies published from 2007 through 2019. Guideline recommendations were based on the review of the evidence.
RESULTS
The systematic review identified 19 eligible studies. The evidence consisted of systematic reviews of observational data, consensus guidelines, and RCTs.
RECOMMENDATIONS
All women diagnosed with epithelial ovarian cancer should have germline genetic testing for and other ovarian cancer susceptibility genes. In women who do not carry a germline pathogenic or likely pathogenic variant, somatic tumor testing for pathogenic or likely pathogenic variants should be performed. Women with identified germline or somatic pathogenic or likely pathogenic variants in genes should be offered treatments that are US Food and Drug Administration (FDA) approved in the upfront and the recurrent setting. Women diagnosed with clear cell, endometrioid, or mucinous ovarian cancer should be offered somatic tumor testing for mismatch repair deficiency (dMMR). Women with identified dMMR should be offered FDA-approved treatment based on these results. Genetic evaluations should be conducted in conjunction with health care providers familiar with the diagnosis and management of hereditary cancer. First- or second-degree blood relatives of a patient with ovarian cancer with a known germline pathogenic cancer susceptibility gene variant should be offered individualized genetic risk evaluation, counseling, and genetic testing. Clinical decision making should not be made based on a variant of uncertain significance. Women with epithelial ovarian cancer should have testing at the time of diagnosis.
Topics: Carcinoma, Ovarian Epithelial; Female; Genes, BRCA1; Genes, BRCA2; Genetic Counseling; Genetic Testing; Germ-Line Mutation; Health Status Disparities; Humans; Ovarian Neoplasms; Practice Guidelines as Topic; Randomized Controlled Trials as Topic
PubMed: 31986064
DOI: 10.1200/JCO.19.02960 -
Cancer Treatment Reviews Feb 2020The host anti-tumour inflammatory response is a strong prognostic indicator, and tumour infiltrating lymphocytes (TILs) are believed to have a complimentary role... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
The host anti-tumour inflammatory response is a strong prognostic indicator, and tumour infiltrating lymphocytes (TILs) are believed to have a complimentary role alongside TNM assessment in dictating future management. However, there is wide disagreement regarding the most efficacious and cost-effective method of assessment.
METHODS
A comprehensive literature search was performed of EMBASE, MedLine and PubMed as well as an assessment of references to identify all relevant studies relating to the assessment of the peri-tumoural inflammatory response or TILs and prognosis in colorectal cancer (CRC). A meta-analysis was performed of 67 studies meeting the REMARK criteria using RevMan software.
RESULTS
Intratumoural assessment of both CD3 and CD8 in CRC were significant for disease-free survival (DFS) (combined HRs 0.46; 95%CI: 0.39-0.54 and 0.54; 95%CI: 0.45-0.65), as well as overall survival (OS) and disease-specific survival (DSS). The same was true for assessment of CD3 and CD8 at the invasive margin (DFS: combined HRs 0.45; 95%CI: 0.33-0.61 and 0.51; 95%CI: 0.41-0.62). However, similar fixed effects summaries were also observed for H&E-based methods, like Klintrup-Makinen grade (DFS: HR 0.62; 95%CI: 0.43-0.88). Furthermore, inflammatory assessments were independent of MSI status.
CONCLUSION
The evidence suggests that it is the density of a co-ordinated local inflammatory infiltrate that confers survival benefit, rather than any individual immune cell subtype. Furthermore, the location of individual cells within the tumour microenvironment does not appear to influence survival. The authors advocate a standardised assessment of the local inflammatory response, but caution against emphasizing the importance of any individual immune cell subtype.
Topics: Colorectal Neoplasms; Humans; Inflammation; Lymphocytes, Tumor-Infiltrating; Prognosis; T-Lymphocyte Subsets; Tumor Microenvironment
PubMed: 31869737
DOI: 10.1016/j.ctrv.2019.101949 -
European Journal of Human Genetics :... Mar 2020The colorectal cancer spectrum has changed due to population screening programs, with a shift toward adenomas and early cancers. Whether it would be a feasible option to... (Meta-Analysis)
Meta-Analysis
The colorectal cancer spectrum has changed due to population screening programs, with a shift toward adenomas and early cancers. Whether it would be a feasible option to test these adenomas for detection of Lynch syndrome (LS) patients is unclear. Through meta-analysis and systematic review, risk factors for DNA mismatch repair deficiency (dMMR) and microsatellite instability (MSI) in adenomas were identified in LS and unselected patient cohorts. Data were extracted for patient age and MMR variant together with adenoma type, grade, size, and location. A total of 41 studies were included, and contained more than 519 LS patients and 1698 unselected patients with 1142 and 2213 adenomas respectively. dMMR/MSI was present in 69.5% of conventional adenomas in LS patients, compared with 2.8% in unselected patients. In the LS cohort, dMMR/MSI was more frequently present in patients older than 60 years (82% versus 54%). dMMR/MSI was also more common in villous adenomas (84%), adenomas over 1 cm (81%), and adenomas with high grade dysplasia (88%). No significant differences were observed for dMMR/MSI in relation to MMR variants and location of adenomas. In the context of screening, we conclude that detection of dMMR/MSI in conventional adenomas of unselected patients is uncommon and might be considered as indication for LS testing. Within the LS cohort, 69.5% of LS patients could have been detected through dMMR/MSI screening of their conventional adenomas.
Topics: Adenoma; Adult; Biomarkers, Tumor; Colorectal Neoplasms, Hereditary Nonpolyposis; Female; Humans; Male; Microsatellite Instability; Middle Aged
PubMed: 31695176
DOI: 10.1038/s41431-019-0538-7 -
Genetics in Medicine : Official Journal... Oct 2019Endometrial cancer (EC) is often the sentinel cancer in women with Lynch syndrome (LS). However, efforts to implement universal LS screening in EC patients have been... (Meta-Analysis)
Meta-Analysis
PURPOSE
Endometrial cancer (EC) is often the sentinel cancer in women with Lynch syndrome (LS). However, efforts to implement universal LS screening in EC patients have been hampered by a lack of evidence detailing the proportion of EC patients that would be expected to screen positive for LS.
METHODS
Studies were identified by electronic searches of Medline, Embase, Cochrane CENTRAL and Web of Science. Proportions of test positivity were calculated by random and fixed-effects meta-analysis models. I score was used to assess heterogeneity across studies.
RESULTS
Fifty-three studies, including 12,633 EC patients, met the inclusion criteria. The overall proportion of endometrial tumors with microsatellite instability or mismatch repair (MMR) deficiency by immunohistochemistry (IHC) was 0.27 (95% confidence interval [CI] 0.25-0.28, I: 71%) and 0.26 (95% CI 0.25-0.27, I: 88%), respectively. Of those women with abnormal tumor testing, 0.29 (95% CI 0.25-0.33, I: 83%) had LS-associated pathogenic variants on germline testing; therefore around 3% of ECs can be attributed to LS. Preselection of EC cases did increase the proportion of germline LS diagnoses.
CONCLUSION
The current study suggests that prevalence of LS in EC patients is approximately 3%, similar to that of colorectal cancer patients; therefore our data support the implementation of universal EC screening for LS.
Topics: Adult; Brain Neoplasms; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Comorbidity; DNA Mismatch Repair; Early Detection of Cancer; Endometrial Neoplasms; Female; Genetic Testing; Germ-Line Mutation; Humans; Immunohistochemistry; Microsatellite Instability; Middle Aged; Neoplastic Syndromes, Hereditary
PubMed: 31086306
DOI: 10.1038/s41436-019-0536-8 -
Annals of Oncology : Official Journal... Aug 2019Cancers with a defective DNA mismatch repair (dMMR) system contain thousands of mutations most frequently located in monomorphic microsatellites and are thereby defined...
ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach.
BACKGROUND
Cancers with a defective DNA mismatch repair (dMMR) system contain thousands of mutations most frequently located in monomorphic microsatellites and are thereby defined as having microsatellite instability (MSI). Therefore, MSI is a marker of dMMR. MSI/dMMR can be identified using immunohistochemistry to detect loss of MMR proteins and/or molecular tests to show microsatellite alterations. Together with tumour mutational burden (TMB) and PD-1/PD-L1 expression, it plays a role as a predictive biomarker for immunotherapy.
METHODS
To define best practices to implement the detection of dMMR tumours in clinical practice, the ESMO Translational Research and Precision Medicine Working Group launched a collaborative project, based on a systematic review-approach, to generate consensus recommendations on the: (i) definitions related to the concept of MSI/dMMR; (ii) methods of MSI/dMMR testing and (iii) relationships between MSI, TMB and PD-1/PD-L1 expression.
RESULTS
The MSI-related definitions, for which a consensus frame-work was used to establish definitions, included: 'microsatellites', 'MSI', 'DNA mismatch repair' and 'features of MSI tumour'. This consensus also provides recommendations on MSI testing; immunohistochemistry for the mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 represents the first action to assess MSI/dMMR (consensus with strong agreement); the second method of MSI/dMMR testing is represented by polymerase chain reaction (PCR)-based assessment of microsatellite alterations using five microsatellite markers including at least BAT-25 and BAT-26 (strong agreement). Next-generation sequencing, coupling MSI and TMB analysis, may represent a decisive tool for selecting patients for immunotherapy, for common or rare cancers not belonging to the spectrum of Lynch syndrome (very strong agreement). The relationships between MSI, TMB and PD-1/PD-L1 expression are complex, and differ according to tumour types.
CONCLUSIONS
This ESMO initiative is a response to the urgent questions raised by the growing success of immunotherapy and provides also important insights on the relationships between MSI, TMB and PD-1/PD-L1.
Topics: Antineoplastic Agents, Immunological; B7-H1 Antigen; Biomarkers, Tumor; DNA Mismatch Repair; DNA Mutational Analysis; European Union; Genetic Testing; High-Throughput Nucleotide Sequencing; Humans; Immunohistochemistry; Medical Oncology; Microsatellite Instability; Mutation; Neoplasms; Patient Selection; Practice Guidelines as Topic; Programmed Cell Death 1 Receptor; Societies, Medical
PubMed: 31056702
DOI: 10.1093/annonc/mdz116 -
Acta Obstetricia Et Gynecologica... Sep 2019Progestogens are widely used for the conservative treatment of endometrial hyperplasia and early endometrial cancer. Nevertheless, they do not achieve the regression in...
INTRODUCTION
Progestogens are widely used for the conservative treatment of endometrial hyperplasia and early endometrial cancer. Nevertheless, they do not achieve the regression in all cases. Although several immunohistochemical markers have been assessed to predict the response to treatment, their usefulness is still unclear. We aimed to analyze the usefulness of each immunohistochemical marker studied in predicting the response to progestogens in endometrial hyperplasia and early endometrial cancer.
MATERIAL AND METHODS
Electronic databases were searched for relevant articles from January 2000 to June 2018. All studies assessing the association of immunohistochemical markers with the outcome of the progestogen-based therapy in endometrial hyperplasia and early endometrial cancer were included. The expression of immunohistochemical markers in pretreatment phase and changes of expression during the follow-up were evaluated in relation to response to therapy and relapse.
RESULTS
Twenty-seven studies with 1360 women were included in the systematic review; 43 immunohistochemical markers were assessed. The most studied predictive markers in the pretreatment phase were progesterone and estrogen receptors, although with conflicting results; their isoforms, and in particular progesterone receptor B, appeared more promising. Further studies are needed to confirm the usefulness of mismatch repair proteins, Dusp6, GRP78 and PTEN combined with other molecules such as phospho-AKT or phospho-mTOR. In the follow-up phase, Nrf2 and survivin showed the stronger evidence; a role may also be played by Bcl2 and Ki67. Further studies are necessary for Fas, NCoR, AKR1C1, HE4, PAX2 and SPAG9.
CONCLUSIONS
Several immunohistochemical markers might be helpful in predicting the response to conservative treatment of endometrial hyperplasia and early endometrial cancer on pretreatment and follow-up specimens. Further studies are needed to confirm their usefulness and possibly integrate them in a predictive immunohistochemical panel.
Topics: Biomarkers, Tumor; Conservative Treatment; Endometrial Hyperplasia; Endometrial Neoplasms; Endoplasmic Reticulum Chaperone BiP; Female; Humans; Immunohistochemistry; Predictive Value of Tests; Progestins
PubMed: 30793281
DOI: 10.1111/aogs.13587 -
Bladder Cancer (Amsterdam, Netherlands) Jul 2018Lynch syndrome is an autosomal dominant disorder that predisposes individuals affected to certain malignancies. Colon and endometrial cancers are the malignancies most...
BACKGROUND
Lynch syndrome is an autosomal dominant disorder that predisposes individuals affected to certain malignancies. Colon and endometrial cancers are the malignancies most highly associated with Lynch syndrome. However, growing body of evidence links Lynch syndrome to urological cancers.
OBJECTIVE
This review aims to clarify the type of urological malignancies that fall under the Lynch-associated cancer spectrum.
METHODS
Using PRISMA guidelines, a systematic search between January 1990 to February 2018, was conducted using the MEDLINE database with the application of the following MESH terms: colorectal neoplasms, hereditary nonpolyposis; DNA mismatch repair; urologic neoplasms; kidney pelvis; ureteral neoplasms; urinary bladder; carcinoma, transitional cell; prostatic neoplasms; testicular neoplasms.
RESULTS
Upper tract urothelial cancers are well established under the Lynch spectrum. Increasing evidence supports its association with prostate cancer. However, there is, inconclusive and limited evidence for an association with bladder and testicular cancer.
CONCLUSIONS
The evidence underpinning certain urological malignancies associated with Lynch syndrome has expanded in recent years. Our review may assist in providing a summary of the current standing in literature. However, we recommend further investigations to better clarify associations, particularly with prostate, bladder and testicular cancer.
PubMed: 30112437
DOI: 10.3233/BLC-180180 -
Journal of Clinical Oncology : Official... Aug 2018Purpose In 2016, ASCO published a guideline to assist in clinical decision making in metastatic pancreatic cancer for initial assessment after diagnosis, first- and...
Purpose In 2016, ASCO published a guideline to assist in clinical decision making in metastatic pancreatic cancer for initial assessment after diagnosis, first- and second-line treatment options, palliative and supportive care, and follow-up. The purpose of this update is to incorporate new evidence related to second-line therapy for patients who have experienced disease progression or intolerable toxicity during first-line therapy. Methods ASCO convened an Expert Panel to conduct a systematic review of the literature on second-line therapy published between June 2015 and January 2018. Recommendations on other topics covered in the 2016 Metastatic Pancreatic Cancer Guideline were endorsed by the Expert Panel. Results Two new studies were found that met the inclusion criteria. Recommendations For second-line therapy, gemcitabine plus nanoparticle albumin-bound paclitaxel should be offered to patients with first-line treatment with FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin), an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1, and a favorable comorbidity profile; fluorouracil plus nanoliposomal irinotecan can be offered to patients with first-line treatment with gemcitabine plus NAB-paclitaxel, an ECOG PS of 0 to 1, and a favorable comorbidity profile; fluorouracil plus irinotecan or fluorouracil plus oxaliplatin may be offered when there is a lack of availability of fluorouracil plus nanoliposomal irinotecan; gemcitabine or fluorouracil should be offered to patients with either an ECOG PS of 2 or a comorbidity profile that precludes other regimens. Testing select patients for mismatch repair deficiency or microsatellite instability is recommended, and pembrolizumab is recommended for patients with mismatch repair deficiency or high microsatellite instability tumors. Endorsed recommendations from the 2016 version of this guideline for computed tomography, baseline performance status and comorbidity profile, defining goals of care, first-line therapy, and palliative care are also contained within the full guideline text. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .
Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Decision-Making; Female; Humans; Male; Neoplasm Metastasis; Pancreatic Neoplasms; Practice Guidelines as Topic
PubMed: 29791286
DOI: 10.1200/JCO.2018.78.9636 -
Familial Cancer Oct 2018Around 5% of colorectal cancers are due to mutations within DNA mismatch repair genes, resulting in Lynch syndrome (LS). These mutations have a high penetrance with... (Meta-Analysis)
Meta-Analysis
Around 5% of colorectal cancers are due to mutations within DNA mismatch repair genes, resulting in Lynch syndrome (LS). These mutations have a high penetrance with early onset of colorectal cancer at a mean age of 45 years. The mainstay of surgical management is either a segmental or extensive colectomy. Currently there is no unified agreement as to which management strategy is superior due to limited conclusive empirical evidence available. A systematic review and meta- analysis to evaluate the risk of metachronous colorectal cancer (MCC) and mortality in LS following segmental and extensive colectomy. A systematic review of the PubMed database was conducted. Studies were included/ excluded based on pre-specified criteria. To assess the risk of MCC and mortality attributed to segmental or extensive colectomies, relative risks (RR) were calculated and corresponding 95% confidence intervals (CI). Publication bias was investigated using funnel plots. Data about mortality, as well as patient ascertainment [Amsterdam criteria (AC), germline mutation (GM)] were also extracted. Statistical analysis was conducted using the R program (version 3.2.3). The literature search identified 85 studies. After further analysis ten studies were eligible for inclusion in data synthesis. Pooled data identified 1389 patients followed up for a mean of 100.7 months with a mean age of onset of 45.5 years of age. A total 1119 patients underwent segmental colectomies with an absolute risk of MCC in this group of 22.4% at the end of follow-up. The 270 patients who had extensive colectomies had a MCC absolute risk of 4.7% (0% in those with a panproctocolecomy). Segmental colectomy was significantly associated with an increased relative risk of MCC (RR = 5.12; 95% CI 2.88-9.11; Fig. 1), although no significant association with mortality was identified (RR = 1.65; 95% CI 0.90-3.02). There was no statistically significant difference in the risk of MCC between AC and GM cohorts (p = 0.5, Chi-squared test). In LS, segmental colectomy results in a significant increased risk of developing MCC. Despite the choice of segmental or extensive colectomies having no statistically significant impact on mortality, the choice of initial surgical management can impact a patient's requirement for further surgery. An extensive colectomy can result in decreased need for further surgery; reduced hospital stays and associated costs. The significant difference in the risk of MCC, following segmental or extensive colectomies should be discussed with patients when deciding appropriate management. An individualised approach should be utilised, taking into account the patient's age, co-morbidities and genotype. In order to determine likely germline-specific effects, or a difference in survival, larger and more comprehensive studies are required.
Topics: Adult; Aged; Aged, 80 and over; Colectomy; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Female; Humans; Male; Middle Aged; Mutation; Risk Factors
PubMed: 29189962
DOI: 10.1007/s10689-017-0062-2 -
Frontiers in Public Health 2017Lynch syndrome (LS) is the most common hereditary colon cancer syndrome, accounting for 3-5% of colorectal cancer (CRC) cases, and it is associated with the development...
BACKGROUND
Lynch syndrome (LS) is the most common hereditary colon cancer syndrome, accounting for 3-5% of colorectal cancer (CRC) cases, and it is associated with the development of other cancers. Early detection of individuals with LS is relevant, since they can take advantage of life-saving intensive care surveillance. The debate regarding the best screening policy, however, is far from being concluded. This prompted us to conduct a systematic review of the existing screening pathways for LS.
METHODS
We performed a systematic search of MEDLINE, ISI Web of Science, and SCOPUS online databases for the existing screening pathways for LS. The eligibility criteria for inclusion in this review required that the studies evaluated a structured and permanent screening pathway for the identification of LS carriers. The effectiveness of the pathways was analyzed in terms of LS detection rate.
RESULTS
We identified five eligible studies. All the LS screening pathways started from CRC cases, of which three followed a universal screening approach. Concerning the laboratory procedures, the pathways used immunohistochemistry and/or microsatellite instability testing. If the responses of the tests indicated a risk for LS, the genetic counseling, performed by a geneticist or a genetic counselor, was mandatory to undergo DNA genetic testing. The overall LS detection rate ranged from 0 to 5.2%.
CONCLUSION
This systematic review reported different existing pathways for the identification of LS patients. Although current clinical guidelines suggest to test all the CRC cases to identify LS cases, the actual implementation of pathways for LS identification has not been realized. Large-scale screening programs for LS have the potential to reduce morbidity and mortality for CRC, but coordinated efforts in educating all key stakeholders and addressing public needs are still required.
PubMed: 28955708
DOI: 10.3389/fpubh.2017.00243