Pseudo progression in heterogeneity of right-sided metastatic colon carcinoma during nivolumab therapy

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Abstract

Rationale:

Pseudo progression is a noted phenomenon of immune checkpoint inhibitors therapy, which has been defined as a response after an initial enlargement of the tumor followed by tumor reduction. In July 2017, the Food and Drug Administration granted accelerated approval of nivolumab for the treatment of metastatic colorectal cancer patients whose tumor harbors deficient mismatch repair.

Patient concerns and diagnosis:

We present a patient who received nivolumab for heterogeneity of right-sided metastatic colon carcinoma.

Intervention:

The patient was treated with nivolumab combined with chemotherapy.

Outcome:

The computed tomography showed mass lesion in the left lobe of liver remained stable while metastasis tumors under envelop of liver were exacerbated after 6 cycles of nivolumab combined with chemotherapy, and later regressed.

Lessons:

The status of mismatch repair in primary tumor and metastatic liver carcinoma is contradictory but using nivolumab demonstrated encouraging efficacy. This is the first case of pseudo progression undergoing immunotherapy for heterogeneity of right-sided metastatic colon carcinoma.

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Most cited references 10

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Prevalence and heterogeneity of KRAS, BRAF, and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases.

Stephan E Baldus, Karl-L Schaefer, Rainer Engers … (2010)

Epidermal growth factor receptor (EGFR) antibody therapy is established in patients with wild-type KRAS colorectal carcinoma; however, up to 50% of these patients do not respond to this therapy. To identify the possible causes of this therapy failure, we searched for mutations in different EGFR-dependent signaling proteins and analyzed their distribution patterns in primary tumors and corresponding metastases. Tumor tissues, macrodissected from tumor centers, invasion fronts (n = 100), lymph nodes (n = 55), and distant metastases (n = 20), respectively, were subjected to DNA extraction and mutation analysis of KRAS, BRAF, and PIK3CA. Activating mutations were detected in 41% (KRAS), 7% (BRAF), and 21% (PIK3CA) of the primary tumors. By comparing tumor centers and invasion fronts, the intratumoral heterogeneity of KRAS, BRAF, and PIK3CA mutations was observed in 8%, 1%, and 5% of primary tumors, respectively. Heterogeneity between primary tumors and lymph node metastases was found in 31% (KRAS), 4% (BRAF), and 13% (PIK3CA) of the cases. Heterogeneity between primary tumors and distant metastases was present in two patients (10%) for KRAS and one patient for PIK3CA (5%), but not for BRAF. Discordant results between primary tumors and metastases could markedly be reduced by testing the additional tumor samples. Failure of EGFR antibody therapy in patients with wild-type KRAS colorectal cancer may result from activating BRAF or PIK3CA mutations and false-negative sequencing results caused by intratumoral heterogeneity. Due to the particularly high rates of heterogeneity between primary tumors and lymph node metastases, the latter are least suitable for diagnostic mutation analysis.

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Pseudoprogression in Previously Treated Patients with Non–Small Cell Lung Cancer Who Received Nivolumab Monotherapy

Daichi Fujimoto, Hiroshige Yoshioka, Yuki Kataoka … (2019)

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Immunohistochemical staining for DNA mismatch repair proteins in intestinal tract carcinoma: how reliable are biopsy samples?

Geoffrey Markowitz, Hailin Tang, Efsevia Vakiani … (2011)

In recent years, immunohistochemistry has emerged as an efficient tool in the detection of DNA mismatch repair protein abnormality in colorectal cancers. Currently, the immunohistochemical test is mainly applied to cancer resection specimens. Detection of mismatch repair abnormality in biopsies carries obvious clinical importance, as it would allow informed decision about the extent of surgery (segmental resection vs total colectomy, prophylactic hysterectomy or not). Moreover, in the case of treated rectal carcinoma with no residual tumor, it provides a means to evaluate the mismatch repair proteins. However, whether biopsy samples can be reliably used for mismatch repair protein detection remains to be determined. Paired biopsy and resection specimens of adenocarcinomas of the gastrointestinal tract, enriched for patients at increased risk for Lynch syndrome, were analyzed for immunohistochemical staining patterns for MLH1, MSH2, MSH6, and PMS2. Abnormal staining was defined as total loss of protein in the tumor with appropriate control. Cases with focal and weak staining, defined as staining of no more than moderate intensity present in <10% of the tumor cells, were recorded. Correlation analysis with germline mutation data was in a subset of cases. Among 70 gastrointestinal tract cancers (3 from the small bowel, 36 from the right colon, 15 from the left colon, and 16 from the anorectum), both the biopsy and resection specimens detected the same 29 cancers as having loss of staining for at least 1 protein, 14 affecting MLH1/PMS2 and 15 affecting MSH2/MSH6. Focal and weak staining was most commonly seen for MLH1 stain in biopsies (4 of 70, 6%), followed by MSH6 stain in biopsies (3 of 70, 4%). Concordant staining patterns between biopsies and resections were reached in all 70 cases for MSH2 and PMS2, whereas discordant patterns were identified in 3 cases (3 of 70, 4%) for MLH1 and in 2 cases (2 of 70, 3%) for MSH6. None of the discordant patterns affected the final interpretation of whether the immunohistochemistry test was normal or abnormal in either the biopsy or the resection. In 13 of the 13 cases that were known to have a pathogenic germline mutation (5 in MLH1 and 8 in MSH2), the stains were abnormal for the corresponding protein and/or its partner protein in both the biopsy and the resection specimens. This study provides data indicating that biopsy samples are as reliable as resections in the immunohistochemical detection of mismatch repair protein abnormality in intestinal cancers. Our study also shows that various staining variations can occur in both biopsies and resections. Awareness and further understanding of such variations will enhance the use of immunohistochemistry, a commonplace tool that is being increasingly used in the screening workup for Lynch syndrome.

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Author and article information

Journal

Journal ID (nlm-ta): Medicine (Baltimore)

Journal ID (iso-abbrev): Medicine (Baltimore)

Journal ID (publisher-id): MEDI

Title: Medicine

Publisher: Wolters Kluwer Health

ISSN (Print): 0025-7974

ISSN (Electronic): 1536-5964

Publication date Collection: August 2019

Publication date (Electronic): 09 August 2019

Volume: 98

Issue: 32

Electronic Location Identifier: e16490

Affiliations

[a ]Department of Graduate Administration, Chinese PLA General Hospital/Medical School of Chinese PLA

[b ]Department of Oncology, The Sixth Medical Center

[c ]Department of Oncology, The First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China.

Author notes

[∗ ]Correspondence: Xindan Kang, Department of Oncology, Chinese PLA General Hospital, Beijing, China (e-mail: kxdfhtd@ 123456126.com ).

Article

Publisher ID: MD-D-18-09797 Accession ID: 16490

DOI: 10.1097/MD.0000000000016490

PMC ID: 6709191

PubMed ID: 31393352

SO-VID: 069d4c5c-da00-4ef6-bd21-544773d1315a

License:

This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

History

Date received : 9 January 2019

Date revision received : 16 May 2019

Date accepted : 25 June 2019

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Keywords: heterogeneity,metastatic colon carcinoma,mismatch repair,nivolumab,pseudo progression

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Keywords: heterogeneity, metastatic colon carcinoma, mismatch repair, nivolumab, pseudo progression

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Pseudo progression in heterogeneity of right-sided metastatic colon carcinoma during nivolumab therapy : A case report

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Abstract

Rationale:

Patient concerns and diagnosis:

Intervention:

Outcome:

Lessons:

Related collections

Network Medicine

Most cited references 10

Prevalence and heterogeneity of KRAS, BRAF, and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases.

Pseudoprogression in Previously Treated Patients with Non–Small Cell Lung Cancer Who Received Nivolumab Monotherapy

Immunohistochemical staining for DNA mismatch repair proteins in intestinal tract carcinoma: how reliable are biopsy samples?

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Cited by 3

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