Second primary cancers in patients with sporadic deficient mismatch repair (dMMR) colorectal cancer (CRC).

45 Background: Patients with hereditary non polyposis colorectal cancer (HNPCC) diagnosed with CRC have an elevated risk of a second primary CRC (SPCRC) and of rapid primary cancer development. This informs both initial surgical approach and endoscopic surveillance intervals. A feature of HNPCC is dMMR, also found in 15% of sporadic CRC, where the risk of SPCRC has yet to be defined. Methods: We examined a multi-site comprehensive CRC database (Melbourne, Australia), where prospectively collected data includes family history (including HNPCC), histology, surgery performed and incidence of second primary cancer. Sporadic dMMR included any case with a BRAF V600E mutation, confirmed hypermethylation, negative germline testing, or age over 60 years. We explored the incidence and timing of SPCRC in patients with early stage sporadic dMMR (or MSI-H) versus pMMR cancers. Results: From February 2004 to December 2019, 7442 patients diagnosed with stage I-III CRC were recorded. MMR status was known in 4079 (54.8%), including 714 with dMMR colorectal cancer (17.4%) of which 575 (14.6%) were deemed sporadic dMMR. Sporadic dMMR patients were older (mean 76.2 years vs 65.9 years, p = < 0.001), more likely to be female (65.2% vs 42%, p = < 0.001) and have a right sided primary (80.9% vs 32.8%, p = < 0.001), compared to patients with pMMR CRC. A SPCRC was diagnosed in 11/575 patients (1.91%) with sporadic dMMR CRC versus 27/3365 (0.83%) patients with pMMR CRC (HR = 2.57, 95% CI 1.28 - 5.17, p = 0.008). Median time to SPCRC was 1.13 years vs 2.38 years (p = 0.49). The SPCRC diagnosed in sporadic dMMR CRC vs pMMR CRC were more likely to be dMMR ((72.7%) vs (25.9%), p = 0.03), but a similar number were stage I or II ((81.8%) vs (81.5%)) and a similar number were surveillance detected ((72.7%) vs (77.8%). Conclusions: Patients with sporadic dMMR appear to have a significantly elevated risk of SPCRC compared to the pMMR population and were diagnosed at a shorter interval. The SPCRC is also more likely to also be dMMR. Increased colonoscopic surveillance of patients presenting with an initial sporadic dMMR cancer should be considered where clinically appropriate.

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Prognostic value of RAS, BRAF, and PIK3CA mutations in early-stage colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.3_suppl.594 ◽

2015 ◽

Vol 33 (3_suppl) ◽

pp. 594-594

Author(s):

Jennifer Elizabeth Byer ◽

Nishi Kothari ◽

TzuHua Juan ◽

Jamie K. Teer ◽

Michael J. Schell ◽

...

Keyword(s):

Colorectal Cancer ◽

Survival Data ◽

Braf Mutation ◽

Prognostic Value ◽

Early Stage ◽

Stage I ◽

Braf V600e ◽

Pik3ca Mutations ◽

1000 Genomes ◽

Braf Mutant

594 Background: Activating mutations in the KRAS, BRAF and PIK3CA oncogenes deregulate growth-factor pathways and promote metastasis in colorectal cancer (CRC). The prognostic value of these mutations has been reported with conflicting results in early CRC. We evaluated RAS, BRAF, and PIK3CA mutations as prognostic biomarkers in early stage (stage I-III) colorectal cancer (CRC) patients. Methods: Tumor samples collected from 302 early stage CRC patients diagnosed between 1998 and 2010 were analyzed as part of a multi-institutional observational study. Targeted exome sequencing was performed using the Illumina NGS platform with 50-100X coverage of mutations. The BWA/GATK pipeline was used to identify variants and indels. Matched normal samples were not available for comparison to identify somatic mutations, therefore 1000 Genomes was used to filter normal variants. Variants identified in 1000 Genomes with an MAF <0.01 were filtered. Overall survival data was collected via retrospective chart review. Extended RAS, BRAF V600E, and PIK3CA (exon 9 and 20) mutations were evaluated. The log-rank test was used to compare survival distributions. Results: 302 patients were eligible for analysis (53 stage I, 125 stage II, 124 stage III). 109 patients had RAS mutations (KRAS or NRAS), 41 patients had BRAF mutations, and 29 patients had PIK3CA mutations. Of the 247 patients with microsatellite stability (MSS) 98 were RAS mutant, 10 were BRAF mutant, and 19 were PIK3CA mutant. Of the 55 patients with microsatellite instability high (MSI-H) 11 were RAS mutant, 31 were BRAF mutant, and 10 were PIK3CA mutant. BRAF mutation was prognostic for decreased OS (p= 0.0245), particularly in patients with MSS tumors (p=0.0141). RAS and PIK3CA mutations did not have prognostic value for OS (p =0.72 and 0.23 respectively). Conclusions: In early stage colorectal cancer, we confirmed BRAF mutation is prognostic for OS particularly in MSS patients. RAS and PIK3CA mutations did not confer prognostic value.

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Second primary cancers and recurrence in patients after resection of colorectal cancer: An integrated analysis of trials by Japan Clinical Oncology Group: JCOG1702A

Japanese Journal of Clinical Oncology ◽

10.1093/jjco/hyaa184 ◽

2020 ◽

Author(s):

Kiyo Tanaka ◽

Gakuto Ogawa ◽

Junki Mizusawa ◽

Tomohiro Kadota ◽

Kenichi Nakamura ◽

...

Keyword(s):

Colorectal Cancer ◽

General Population ◽

Cumulative Incidence ◽

National Database ◽

Integrated Analysis ◽

Second Primary ◽

Primary Cancer ◽

Second Primary Cancer ◽

Surveillance Strategy ◽

Second Primary Cancers

Abstract Background Improvements in early detection and treatment have resulted in an increasing number of long-term survivors of colorectal cancer (CRC). For the survivors, second primary cancer and recurrence are important issues; however, evidence for an appropriate surveillance strategy remains limited. This study aimed to investigate the frequency and timing of second primary cancer in patients after surgery for exploring an appropriate surveillance strategy by using an integrated analysis of three large-scale randomized controlled trials in Japan. Methods The eligibility criteria of three trials included histologically confirmed CRC and having received surgery. The timing, site and frequency of second primary cancers and recurrence were investigated. Risk factors associated with second primary cancers were also examined. The standardized incidence ratio (SIR) of second primary cancers compared with the national database of the Japan Cancer Registry was estimated. Results A total of 2824 patients were included in this study. The cumulative incidence of second primary cancer increased over time. The SIR of any second primary cancer was 1.07 (95% CI: 0.94–1.21). The SIR for second primary cancers of colon was 1.09 (95% CI: 0.79–1.47). The cumulative incidence of recurrence almost reached plateau at 3 years. Conclusions A common surveillance strategy for the general population can be applied even for curatively resected CRC patients, as the risk of second primary cancers was almost the same as that of the general population.

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Second primary cancers and recurrence in patients after resection of colorectal cancer: An integrated analysis of trials by Japan Clinical Oncology Group: JCOG0205, JCOG0212, JCOG0404 (JCOG1702A).

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.561 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 561-561

Author(s):

Kiyo Tanaka ◽

Gakuto Ogawa ◽

Junki Mizusawa ◽

Junko Eba ◽

Hiroshi Katayama ◽

...

Keyword(s):

Colorectal Cancer ◽

Risk Factors ◽

Cumulative Incidence ◽

Second Primary ◽

Primary Cancer ◽

Second Primary Cancer ◽

Surveillance Strategy ◽

Second Primary Cancers ◽

Over Time

561 Background: Improvements in early detection and treatment have resulted in an increasing number of long-term survivors of colorectal cancer (CRC). For the survivors, Second primary cancers and recurrence are important issues, but the evidence for appropriate surveillance strategy is limited. The aim of this study was to investigate the frequency and the timing of second primary cancers and recurrence in patients (pts) after surgery using 3 randomized trials (J0205, J0212 and J0404) conducted by Colorectal Cancer Study Group of JCOG. Methods: Eligibility criteria included histologically proven CRC and having received surgery. The timing, site and frequency of second primary cancer and recurrence were investigated. Risk factors associated with the events were explored. Standardized incidence ratio (SIR) about second primary cancer compared with national database of Japan Cancer Registry was estimated. Results: A total of 2,824 pts with a median follow-up time of 6 years were included. Median age was 62 years old (23-75), male/female was 58%/42%, and stage 0/I/II/III/IV was 0.2%/8.7%/25.4%/64.8%/0.9%. Pts with 5-FU based adjuvant chemotherapy were 63%. Cumulative incidence of second primary cancer increased constantly over time (Table). Among 240 pts, the most common site was lung (37), stomach (35) and colon (32). In multivariable analysis, age (over 64 years old) and sex (male) were risk factors (age HR: 1.60 (95% CI: 1.24-2.07), sex HR: 1.36 (95% CI: 1.04-1.78)). The SIR of any second primary cancers was 1.07 (95% CI: 0.94-1.21). The SIR for second primary cancers of colon was 1.09 (95% CI: 0.79-1.47). On the other hand, cumulative incidence of recurrence almost reached at 3 years. Conclusions: Common surveillance strategy can be applied even for curatively resected CRC pts after 3 years from surgery, because the risk of second primary cancer was almost same as general population over time. The necessity of intensive follow-up to detect recurrence decreases after 3 years. [Table: see text]

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Results from an institutional universal reflex testing program for MSI/MMR in colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.796 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 796-796 ◽

Cited By ~ 1

Author(s):

Aaron J Franke ◽

Maira Gaffar ◽

Michael Feely ◽

Jason Scott Starr ◽

Hiral D. Parekh ◽

...

Keyword(s):

Colorectal Cancer ◽

Impact Analysis ◽

Early Stage ◽

Stage Iv ◽

Stage I ◽

Braf V600e ◽

Mismatch Repair Gene ◽

Protein Loss ◽

System Solution ◽

Reflex Testing

796 Background: In colorectal cancer (CRC), clinical guidelines and immunotherapy treatment selection requires knowledge of tumor DNA mismatch repair gene deficiencies (dMMR) or accumulation of microsatellite repeats through genomic errors (MSI-H). Tumors harboring dMMR/MSI-H are found in 15- 20% of early stage CRC while the prevalence is ~5% in metastatic disease. Reflex testing of CRC to identify these important subsets has been proposed as a system-solution to improve identification. We present a large, single-institutional database of CRC reflexively profiled for MSI/MMR status at the University of Florida (UF). Methods: Beginning in 2009, stage IV CRC underwent reflex testing for MSI/MMR status. Earlier stage CRC testing began in subsequent years. For all new CRC diagnosed at UF, concurrent testing for dMMR by IHC (MLH1, PMS2, MSH2, MSH6), MSI by PCR (Promega MSI kit) and NGS is performed with appropriate positive and negative controls. IHC protein loss is confirmed by second GI pathologist. MSI is not performed if inadequate adjacent normal tissue. We conducted a retrospective analysis of all CRC samples analyzed between 2009 and 2017. Clinical data was collected from the EMR. This study was approved by the UF IRB. Results: A total of 388 new CRC cases were reflex tested (16% Stage I, 23% Stage II, 35% Stage III, and 25% Stage IV). Median age at diagnosis was 63 yrs (range: 17-98 yrs), 51% male and 79% white. Both MMR and MSI were performed in 244 (63%) tumors with 100% concordance when concurrently tested. dMMR/MSI-H incidence (20% in overall population) decreased with stage: I/II (31%), III (18%) and IV (~9%) and was associated with BRAF V600E mut in 36/76 cases (47%). Importantly, in pts < 50 yrs, 13% of stage IV patients were dMMR/MSI-H. Conclusions: Reflex testing of MMR/MSI status in CRC is feasible with concordant results. Routine testing results in identification of dMMR/MSI-H at or higher than published rates. Notable findings include the high prevalence in those with sporadic CRC and/or younger than 50 yrs. Continued impact analysis of this approach is warranted to maximize IO therapy offering.

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Occurrence of second primary cancer after curative resection of cholangiocarcinoma: a report of 5 cases

International Surgery Journal ◽

10.18203/2349-2902.isj20171157 ◽

2017 ◽

Vol 4 (4) ◽

pp. 1455

Author(s):

Hao Long ◽

Menghao Wang ◽

Jianping Gong ◽

Lan Hu

Keyword(s):

Curative Resection ◽

Early Stage ◽

Second Primary ◽

Primary Cancer ◽

Second Primary Cancer ◽

Second Primary Cancers ◽

History Of ◽

Well Differentiated ◽

Operative Excision ◽

History Of Cancer

The second primary cancer, a new cancer subsequent to the initial cancer, usually occurs in a person who has a history of cancer or the patient treated with curative resection. Although the pathogenesis of second primary cancer is unclear, it is always found that occurrence of second primary cancer is related to the age and family history. In our 5 cases’ reports, second primary cancer occurs after curative resection of cholangiocarcinoma. And most of the second primary cancers belong to well differentiated adenocarcinomas which grow slowly and never metastasize distally in early stage. Therefore, operative excision is the most effective treatment. At the same time, conventional examination after operation could improve early diagnosis and timely surgical treatment.

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Second Primary Cancers in Subsites of Colon and Rectum in Patients With Previous Colorectal Cancer

Diseases of the Colon & Rectum ◽

10.1097/dcr.0b013e318279eb30 ◽

2013 ◽

Vol 56 (2) ◽

pp. 158-168 ◽

Cited By ~ 20

Author(s):

Lifang Liu ◽

Valery E. P. P. Lemmens ◽

Ignace H. J. T. De Hingh ◽

Esther de Vries ◽

Jan Anne Roukema ◽

...

Keyword(s):

Colorectal Cancer ◽

Second Primary ◽

Second Primary Cancers ◽

Colon And Rectum

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Elevated risk of second primary cancer in patients with cutaneous malignant melanoma: A nationwide cohort study in Taiwan

Journal of Dermatological Science ◽

10.1016/j.jdermsci.2010.10.004 ◽

2010 ◽

Vol 60 (3) ◽

pp. 167-172 ◽

Cited By ~ 6

Author(s):

Chian-Yaw Hwang ◽

Yi-Ju Chen ◽

Ming-Wei Lin ◽

Tzeng-Ji Chen ◽

Szu-Ying Chu ◽

...

Keyword(s):

Cohort Study ◽

Malignant Melanoma ◽

Cutaneous Malignant Melanoma ◽

Elevated Risk ◽

Second Primary ◽

Primary Cancer ◽

Second Primary Cancer

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Effects of metformin and sulfonylureas on overall and colorectal cancer-specific mortality.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.2599 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 2599-2599

Author(s):

Susan Spillane ◽

Kathleen Bennett ◽

Linda Sharp ◽

Thomas Ian Barron

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Proportional Hazards ◽

Early Stage ◽

Population Based ◽

Cox Proportional Hazards ◽

Stage I ◽

Early Stage Disease ◽

All Cause Mortality ◽

Specific Mortality

2599 Background: Preclinical studies have suggested a role for metformin in the treatment of colorectal cancer (CRC). Associations between metformin versus sulfonylurea exposure and mortality (all-cause and colorectal cancer specific) are assessed in this population-based study of patients with a diagnosis of stage I-IV CRC. Methods: National Cancer Registry Ireland records were linked to prescription claims data and used to identify a cohort of patients with incident TNM stage I-IV CRC diagnosed 2001-2006. From this cohort, 2 patient groups were identified and compared for outcomes - those who received a prescription for metformin +/- a sulfonylurea (MET) or a prescription for sulfonylurea alone (SUL) in the 90 days pre CRC diagnosis. Adjusted hazard ratios (HR) with 95% confidence intervals (CI) were estimated using Cox proportional hazards models adjusted for age, sex, stage, grade, site, comorbidities, year of diagnosis, and insulin, aspirin or statin exposure. Analyses were repeated stratifying by stage and site. Results: 5,617 patients with stage I-IV CRC were identified, of whom 369 received a prescription for metformin or a sulfonylurea in the 90 days pre diagnosis (median follow-up 1.6 years; MET: n=257; SUL: n=112). In adjusted analyses metformin exposure was associated with a 28% lower risk of all-cause mortality relative to sulfonylurea exposure (HR 0.72, 95% CI 0.53-0.98) and a non-significant 24% reduction in CRC-specific mortality (HR 0.76, 95% CI 0.52-1.13). In analyses stratified by site, in colon cancer, metformin exposure was associated with a significant one-third reduction in all-cause mortality (HR 0.66, 95% CI 0.46-0.95) and a non-significant reduction in site-specific mortality (HR 0.64, 95% CI 0.40-1.02). No mortality benefit was observed for rectal cancer. The association between metformin exposure and reduced mortality was strongest for stage I/II disease (all-cause mortality: HR 0.56, 95% CI 0.32-0.98; CRC-specific mortality: HR 0.48, 95% CI 0.21-1.11). Conclusions: Pre-diagnosis metformin exposure in CRC patients was associated with a significant reduction in mortality relative to sulfonylurea exposure. This benefit was greatest in patients with colon cancer and early stage disease.

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Development of second primary cancers in breast cancer survivors.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.3_suppl.257 ◽

2016 ◽

Vol 34 (3_suppl) ◽

pp. 257-257

Author(s):

Hong Kyu Jung ◽

Jihyoun Lee ◽

Zisun Kim ◽

Min Hyuk Lee ◽

Ilkyun Lee

Keyword(s):

Breast Cancer ◽

Endometrial Cancer ◽

Thyroid Cancer ◽

Cancer Survivors ◽

Breast Cancer Survivors ◽

Second Primary ◽

Primary Cancer ◽

Second Primary Cancer ◽

Breast Cancer Patients ◽

Second Primary Cancers

257 Background: Breast cancer survivors have slightly increased risk of second primary cancers. Importance of screening for second cancers has been raised due to increased survival in those populations. Not only having genetic risk such as BRCA mutation, but also treatment-related risk presents. The most common second primary cancer is breast cancer. Colon cancer, uterine cancer, and ovarian cancer showed increased cumulative incidence. In this study, we assessed development second primary cancers in breast cancer survivors. Methods: Medical record of breast cancer patients was reviewed retrospectively in three tertiary medical institutions. Available data of ICD-9 record after breast cancer diagnosis was evaluated. Diagnosis of second primary breast cancer was excluded in evaluation. Results: Since Jan 1989 to Jan 2014, available medical records were reviewed in breast cancer patients(N = 5880) in three institutions(one urban and the other two rural institutions). Cumulative incidence of overall second primary cancers was 4.57%. Among 269 second primary cancers, thyroid cancer(44.2%) was most common second primary cancer, followed by gastric cancer(10.0%). Gastric cancers were more common in rural institution than urban area(14.2 % vs 5.5%), while incidence of thyroid cancer is elevated in urban institution(57.8% vs 31.9%). Among 9 patients who has been diagnosed endometrial cancer, 7 patients had history of selective estrogen receptor modulator(tamoxifen or toremifen) treatment. Development of lung cancer was not related to breast cancer radiation treatment(4 of 15 patients). Leukemia after breast cancer treatment was diagnosed in 5 patients (8.5% of second primary cancers), three of them were adult T cell leukemia and two of them were acute myeloid leukemia. Conclusions: Incidence of cancer in general population was reflected to development of second primary cancer in breast cancer survivors. Endocrine treatment was related increased incidence of endometrial cancer, respectively. Application of personalized cancer screening plan would be important in this patient group.

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