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Prolonged Treatment Response to Pembrolizumab in a Patient with Pretreated Metastatic Colon Cancer and Lynch Syndrome

Prolonged Treatment Response to Pembrolizumab in a Patient with Pretreated Metastatic Colon... Hindawi Case Reports in Oncological Medicine Volume 2019, Article ID 3847672, 5 pages https://doi.org/10.1155/2019/3847672 Case Report Prolonged Treatment Response to Pembrolizumab in a Patient with Pretreated Metastatic Colon Cancer and Lynch Syndrome 1,2 1,2 1,2 2 Matthew Keating , Lisa Giscombe, Toufic Tannous, and Kevan Hartshorn Department of Hematology/Oncology, Roger Williams Medical Center, Providence, RI, USA Department of Hematology/Oncology, Boston University School of Medicine, Boston, MA, USA Correspondence should be addressed to Matthew Keating; mathewkeatingmd@gmail.com Received 20 May 2019; Accepted 18 August 2019; Published 2 September 2019 Academic Editor: Jose I. Mayordomo Copyright © 2019 Matthew Keating et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Pembrolizumab and other immunotherapies now play a prominent role in the treatment of metastatic colon cancer. Clinicians have achieved significant response rates even in heavily pretreated patients, particularly those with mismatched repair deficiencies. The endpoint of pembrolizumab treatment for patients who enjoy a strong response remains unclear. Herein, we present the case of a 33-year-old man with pretreated metastatic colon cancer and a prolonged treatment response of over three years to single-agent pembrolizumab even after treatment discontinuation in July 2018. Prior to pembrolizumab, he was found to have lung and liver metastases despite multiple lines of chemotherapy. With pembrolizumab, there was a persistent downtrend in CEA level and uptrend in weight. After nearly three years of pembrolizumab treatment from October 2015 through July 2018, PET scan showed no FDG-avid disease, and further treatment was placed on hold. He remains under surveillance, with CT scan in February 2019 again showing no evidence of local or metastatic disease. In patients whose treatment duration and disease course are not defined by toxicities/progressive disease but rather by sustained treatment responses, we propose that immunotherapy treatment duration be guided by close monitoring of CEA levels, weight, and clinical exams in addition to traditional imaging. 1. Introduction since 2018 based on results from the phase II CheckMate 142 trial [3]. Mismatch repair deficiencies (dMMRs) are predictive for The role of immunotherapy in various malignancies con- tinues to grow, and colon cancer is no exception. Pembrolizu- a response to immunotherapy in metastatic colorectal can- mab and nivolumab are two immune checkpoint inhibitors cers. A mismatch repair deficiency allows for markedly with key roles in various advanced malignancies including increased numbers of deoxyribonucleic acid (DNA) muta- the lung, kidney, colon, and bladder as well as melanoma tions to pass unrepaired during cell division, thereby promot- and lymphomas. These immunotherapies block the binding ing tumor growth. There are four main mismatch repair of programmed death-ligand 1 (PD-L1) to its receptor pro- genes including MLH1, MSH2, MSH6, and PMS2. Those grammed death-1 (PD-1) on activated T cells, thereby with MLH1 and MSH2 mutations tend to develop colorectal stimulating the immune system and thus the antitumor cancer earlier relative to those patients with PMS2 mutations. response. Significant response rates even in heavily pre- MSH2 mutations are thought to place the patient at higher treated patients have led to expedited approval of both pem- risk for extracolonic cancers relative to those with MLH1 brolizumab and nivolumab monotherapies in colon cancer, mutations [4]. in 2015 and 2017, respectively [1, 2]. Combination therapy In hereditary nonpolyposis colorectal cancer (Lynch with nivolumab and ipilimumab has also been approved syndrome), an inherited germline mutation in one of the 2 Case Reports in Oncological Medicine Treatment was prematurely terminated due to severe toxicities mismatch repair genes listed above coupled with a somatic mutation in the wild-type allele gives rise to dMMR. Lynch of diarrhea, dehydration, and fungal endophthalmitis. DPD syndrome is responsible for 2-5% of colorectal cancers. In mutation testing was negative. Another trial of capecitabine sporadic mismatch repair deficiency, both alleles are com- in July 2013 resulted in similar toxicities with the first cycle. promised by either somatic mutations or epigenetic silenc- His adjuvant chemotherapy regimen was switched to weekly ing [5]. Not all patients with Lynch syndrome will go on 5-FU+leucovorin which he received from August to to develop colorectal cancer over the course of their lifetime, November 2013, with some dosing adjustments due to and cancer risk profiles are thought to be specific to each dehydration, elevated liver function tests and creatinine, mismatch repair gene. Note that those with Lynch syndrome and abdominal pain. PET CT scan in December 2013 are also at risk for other cancers such as prostate and endo- showed pathologic lymphadenopathy of the left-sided metrial cancers. paraortic, mesenteric, and external iliac lymph nodes. Sub- Patients with dMMR typically manifest as microsatellite sequent CT scan in April 2014 showed further increase in instability-high (MSI-H) owing to the increased number size of these lymph nodes and a rise in CEA to 15 (versus of DNA mismatches that go unchecked. Immune check- 9 in November 2013). The next CT scan in October 2014 point inhibitor use in metastatic colon cancer is limited to showed stable lymph node size, and he was lost to follow- those with MSI-H or dMMR tumors; however, in the up at this time due to loss of insurance coverage. future, the treatment population may include those with He reestablished care in May 2015 and was found to have high tumor mutational burden due to mutated DNA poly- metastatic colon cancer with a new liver lesion and pulmo- nary nodules as well as increased size of lymph nodes. These merases or other abnormalities [6, 7]. Patients identified as MSI-H/dMMR with metastatic colon cancer are candi- lesions were clinically consistent with unresectable meta- dates for immunotherapy assuming they do not have signifi- chronous liver and lung metastases. CEA level was 47. CEA cant autoimmune disease history or other contraindications continued to rise, and he lost more weight despite adminis- to preclude the use of immune checkpoint inhibitors. Herein, tration of weekly 5-FU from June to August 2015. Irinotecan at slightly reduced dose and bevacizumab were given from we present the case of a 33-year-old man with pretreated metastatic colon cancer who is enjoying an ongoing, pro- August to October 2015, but despite marked drop in CEA, longed treatment response of over three years to single- he did not tolerate treatment well (diarrhea and elevated cre- agent pembrolizumab even after treatment discontinuation atinine requiring hospital admission). UGT1A1 testing had in July 2018. previously shown positive heterozygous TA7 polymorphism. A further dose reduction was made to try to achieve a toler- able but still effective dose, but this was still complicated by 2. Case Presentation diarrhea and, in addition, his CEA began to rise. A 33-year-old Caucasian man with asthma and active In October 2015, he was started on pembrolizumab smoking history initially presented in 2012 with severe 2 mg/kg every 21 days, with a corresponding drop in CEA level and clinical improvement. CEA decreased to within intermittent abdominal pain, constipation, and 50-pound weight loss over the past year. Family history was strongly normal limits, and his weight increased over the course of pembrolizumab treatment (Figures 1 and 2). He continued positive for colon cancer in his mother (diagnosed at 44), three aunts (all died of colon cancer in their 20s), and his pembrolizumab treatment through July 2018, at which time, uncle. In December 2012, he underwent colonoscopy and it was decided to implement a treatment break given stable disease with no FDG avidity on PET scan at that time a mass in the descending colon was identified which could not be traversed. A preoperative CEA level was not obtained. (though small calcified residual lymph node findings were In January 2013, he underwent subtotal colectomy and ileo- present). Aside from immunotherapy-induced hypothyroid- proctostomy for findings of nearly obstructing descending ism, he tolerated treatment well. He received a total of 48 colon cancer with abdominal sidewall invasion and involve- cycles of pembrolizumab. CEA remains within normal limits and surveillance CT scan in February 2019 showed no evi- ment of two loops of small bowel. Pathology showed stage IIIC pT4bN1bMX moderate to poorly differentiated colon dence of metastatic disease, indicating a remarkable response adenocarcinoma with 5% signet cell differentiation, 7.5 cm when compared to the CT prior to the initiation of immuno- in greatest dimension. Lymphovascular and perineural inva- therapy (Figure 3). He is being followed with yearly flex sion were present, and 3 of 29 lymph nodes were positive for sigmoidoscopy, upper endoscopy every two years, and oncol- ogy clinic visits with CEA checks every six weeks. adenocarcinoma. Margins were negative. Microsatellite insta- bility testing was positive with loss of MSH2 and MSH6 expression, and KRAS mutation was positive in codon 13. 3. Discussion Ultimately, he was diagnosed with Lynch syndrome based on genetic testing done on peripheral blood DNA which While durable responses to immunotherapy in dMMR met- showed a deleterious Y656X mutation in MSH2. It can be astatic colon cancer are not unusual, our patient’s case is inferred that loss of MSH2 subsequently led to loss of expres- exceptional because he has enjoyed over three years and sion of MSH6 secondarily [8]. Magnetic resonance and CT counting of progression-free survival, despite stopping pem- imaging were negative for distant metastases or pathologic brolizumab treatment over seven months ago. Leal et al. lymphadenopathy at this time. He underwent chemoradiation identified a median overall survival from pembrolizumab of treatment with capecitabine from February to March 2013. 16.1 months in a retrospective cohort of 19 patients with Case Reports in Oncological Medicine 3 CEA level according to chronological date Irinotecan+bevacizumab Initiation of 5-FU Pembrolizumab 3/6/2014 3/6/2015 3/6/2016 3/6/2017 3/6/2018 Figure 1: CEA level according to chronological date. The start dates of the patient’s most recent chemotherapy and immunotherapy regimens are marked for reference. Weight (kg) according to chronological date Initiation of 5-FU Irinotecan+bevacizumab Pembrolizumab Figure 2: Weight according to chronological date. The start dates of the patient’s most recent chemotherapy and immunotherapy regimens are marked for reference. (a) (b) Figure 3: CT contrast imaging before (a) (October 8, 2015) and after (b) (February 1, 2019) administration of pembrolizumab. The black arrow in panel (a) indicates a large retroperitoneal lymph node conglomerate which compressed the inferior vena cava, encased the aorta, and invaded the left renal vein. The lymph node conglomerate has since been reduced to small dense calcifications as seen in panel (b). 2/1/2013 5/1/2013 8/1/2013 11/1/2013 2/1/2014 5/1/2014 8/1/2014 11/1/2014 2/1/2015 5/1/2015 8/1/2015 11/1/2015 2/1/2016 5/1/2016 8/1/2016 11/1/2016 2/1/2017 5/1/2017 8/1/2017 11/1/2017 2/1/2018 5/1/2018 8/1/2018 11/1/2018 2/1/2019 4 Case Reports in Oncological Medicine of recurrent metastatic disease, continued to climb with dMMR metastatic colorectal cancer [9]. Most patients with dMMR metastatic colon cancer treated with immunotherapy 5-fluorouracil-based treatment, initially responded well to will survive at least 12 months after the initiation of immuno- irinotecan+bevacizumab-based treatment, and then began increasing again to 23 after a dose reduction of irinotecan therapy. One study did observe a large difference in overall response rate for patients with Lynch syndrome versus other was made due to severe toxicity. The CEA promptly dropped forms of dMMR. Lynch syndrome patients had a 27-percent to the normal range with pembrolizumab treatment overall response rate (11 patients) versus 100-percent overall (Figure 1). The chemotherapy treatment responses and response rate (6 patients) in those with dMMR not linked to CEA levels were in keeping with expectations that MSI patients tend to respond better to irinotecan than 5- Lynch syndrome [5]. This discrepant result between the dMMR subgroups has not been duplicated in other studies fluorouracil. False elevations of CEA levels are known to to date to our knowledge, but if true, would make our Lynch occur, but the degree of elevation tends to reinforce suspi- syndrome patient’s response all the more surprising. Further- cions of recurrent/metastatic disease particularly in patients more, our patient remains in remission per normal CEA and who had elevated CEA levels prior to initial resection of locoregional disease. A retrospective analysis found half of surveillance imaging despite stopping pembrolizumab over seven months ago to allow for an extended treatment break. elevated CEA levels to be false positives when presenting The endpoint of pembrolizumab treatment after a strong after R0 resections of locoregional colorectal cancer. How- response remains unclear, and further research is needed to ever, false positives for CEA levels over 15 ng/ml were rare, define treatment duration in this setting. Our patient showed and CEA levels exceeding 35 ng/ml all represented true pos- itives [12]. CEA levels often correlate to clinical responses excellent tolerance of immunotherapy despite suffering a high level of toxicity with standard chemotherapy and radi- even after a single dose of immunotherapy and precede the ation. While there are many known immunotherapy- corresponding radiographic responses by several months induced toxicities of PD-L1 inhibitors, these are generally [13]. Radiographic changes may even appear to falsely indi- well-managed when addressed early as with our patient’s cate disease progression in the setting of immunotherapy, particularly when scans are performed prematurely. Cer- immunotherapy-induced hypothyroidism, and side-effects do not usually compromise the intended treatment course. tainly more studies are needed to determine the appropriate Immunotherapy’s role in colorectal cancer may soon be surveillance regimen for metastatic colorectal cancer patients on extended courses of immunotherapy. There are patients refined beyond the dMMR and MSI-H populations. Anec- dotal evidence and small retrospective analyses have been such as ours whose treatment duration and disease course are not defined by toxicities/progressive disease but rather reported that link immunotherapy treatment response with high tumor mutational burden due to mutated DNA poly- by sustained treatment responses, and we would argue that merases or other abnormalities, independent of mismatch in these cases, the treatment duration should be guided by close monitoring of CEA levels, weight, and clinical exams repair status [6, 7]. DNA polymerase mutations are impli- cated in 1% of colorectal cancers and can even coexist with in addition to traditional imaging. mutated mismatch repair genes [10]. A more in-depth molecular analysis of dMMR and MSI-H populations may Conflicts of Interest hold the answer to why certain individuals enjoy prolonged immunotherapy responses as with our patient. Even if pre- The authors declare that there is no conflict of interest dictive significance remains elusive with future studies, the regarding the publication of this paper. complete molecular profile has already been shown to hold prognostic significance. Our patient has coexisting KRAS mutation and MSI-H status. KRAS mutations are inversely References associated with MSI, so our patient’s combined abnormalities are not common. When viewed alone, KRAS mutations have [1] K. Ganesh and L. A. Diaz, Immunotherapy for Metastatic Mismatch Repair-Deficient Colorectal Cancer: Game-Changer had mixed prognostic findings, with some studies showing for Small Group of Patients, The ASCO Post, 2017, February negative prognostic value and others showing unaffected 2019, http://www.ascopost.com/issues/october-10-2017/immu disease-specific outcomes. However, combined molecular notherapy-for-metastatic-mismatch-repair-deficient-metastatic- analyses have proven more instructive. One study evaluated colorectal-cancer-game-changer-for-small-group-of-patients/. disease-specific survival for KRAS and BRAF mutation status [2] M. J. Overman, R. McDermott, J. L. Leach et al., “Nivolumab in with MSI. The best prognostic group was KRAS and BRAF patients with metastatic DNA mismatch repair-deficient or wild-type with MSI, then KRAS or BRAF mutant with MSI, microsatellite instability-high colorectal cancer (CheckMate followed by KRAS and BRAF wild-type with MSS, and lastly, 142): an open-label, multicentre, phase 2 study,” The Lancet KRAS or BRAF mutant with MSS [11]. It would appear that Oncology, vol. 18, no. 9, pp. 1182–1191, 2017. KRAS and MSI yield the most prognostic value when inter- [3] M. J. Overman, S. Lonardi, K. Y. M. Wong et al., “Durable preted together, begging the question of what other underly- clinical benefit with nivolumab plus ipilimumab in DNA ing molecular abnormalities that are yet to be analyzed mismatch repair-deficient/microsatellite instability-high meta- collectively may add to prognostic and predictive data. static colorectal cancer,” Journal of Clinical Oncology, vol. 36, We would like to call attention to the close correlation of no. 8, pp. 773–779, 2018. CEA levels with immunotherapy response in our patient and [4] D. Ramsoekh, A. Wagner, M. E. van Leerdam et al., “Cancer in outside studies. Our patient’s CEA levels rose in the setting risk in MLH1, MSH2 and MSH6 mutation carriers; different Case Reports in Oncological Medicine 5 risk profiles may influence clinical management,” Hereditary Cancer in Clinical Practice, vol. 7, no. 1, p. 17, 2009. [5] D. T. Le, J. N. Uram, H. Wang et al., “PD-1 blockade in tumors with mismatch-repair deficiency,” The New England Journal of Medicine, vol. 372, no. 26, pp. 2509–2520, 2015. [6] L. F. Campesato, R. Barroso-Sousa, L. Jimenez et al., “Compre- hensive cancer-gene panels can be used to estimate mutational load and predict clinical benefit to PD-1 blockade in clinical practice,” Oncotarget, vol. 6, no. 33, pp. 34221–34227, 2015. [7] P. M. Boland and W. W. Ma, “Immunotherapy for colorectal cancer,” Cancers, vol. 9, no. 12, p. 50, 2017. [8] M. Morak, S. Käsbauer, M. Kerscher et al., “Loss of MSH2 and MSH6 due to heterozygous germline defects in MSH3 and MSH6,” Familial Cancer, vol. 16, no. 4, pp. 491–500, 2017. [9] A. D. Leal, J. Paludo, H. D. Finnes, and A. Grothey, “Response to pembrolizumab in patients with mismatch repair deficient (dMMR) colorectal cancer (CRC),” Journal of Clinical Oncol- ogy, vol. 35, article 3558, Supplement 15, 2017. [10] U. Testa, E. Pelosi, and G. Castelli, “Colorectal cancer: genetic abnormalities, tumor progression, tumor heterogeneity, clonal evolution and tumor-initiating cells,” Medical Sciences, vol. 6, no. 2, p. 31, 2018. [11] A. I. Phipps, D. D. Buchanan, K. W. Makar et al., “KRAS- mutation status in relation to colorectal cancer survival: the joint impact of correlated tumour markers,” British Journal of Cancer, vol. 108, no. 8, pp. 1757–1764, 2013. [12] A. Litvak, A. Cercek, N. Segal et al., “False-positive elevations of carcinoembryonic antigen in patients with a history of resected colorectal cancer,” Journal of the National Compre- hensive Cancer Network, vol. 12, no. 6, pp. 907–913, 2014. [13] B. D. Nicholson, B. Shinkins, I. Pathiraja et al., “Blood CEA levels for detecting recurrent colorectal cancer,” Cochrane Database of Systematic Reviews, no. 12, article CD011134, 2015. 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Prolonged Treatment Response to Pembrolizumab in a Patient with Pretreated Metastatic Colon Cancer and Lynch Syndrome

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Hindawi Publishing Corporation
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Copyright © 2019 Matthew Keating et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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2090-6714
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10.1155/2019/3847672
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Abstract

Hindawi Case Reports in Oncological Medicine Volume 2019, Article ID 3847672, 5 pages https://doi.org/10.1155/2019/3847672 Case Report Prolonged Treatment Response to Pembrolizumab in a Patient with Pretreated Metastatic Colon Cancer and Lynch Syndrome 1,2 1,2 1,2 2 Matthew Keating , Lisa Giscombe, Toufic Tannous, and Kevan Hartshorn Department of Hematology/Oncology, Roger Williams Medical Center, Providence, RI, USA Department of Hematology/Oncology, Boston University School of Medicine, Boston, MA, USA Correspondence should be addressed to Matthew Keating; mathewkeatingmd@gmail.com Received 20 May 2019; Accepted 18 August 2019; Published 2 September 2019 Academic Editor: Jose I. Mayordomo Copyright © 2019 Matthew Keating et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Pembrolizumab and other immunotherapies now play a prominent role in the treatment of metastatic colon cancer. Clinicians have achieved significant response rates even in heavily pretreated patients, particularly those with mismatched repair deficiencies. The endpoint of pembrolizumab treatment for patients who enjoy a strong response remains unclear. Herein, we present the case of a 33-year-old man with pretreated metastatic colon cancer and a prolonged treatment response of over three years to single-agent pembrolizumab even after treatment discontinuation in July 2018. Prior to pembrolizumab, he was found to have lung and liver metastases despite multiple lines of chemotherapy. With pembrolizumab, there was a persistent downtrend in CEA level and uptrend in weight. After nearly three years of pembrolizumab treatment from October 2015 through July 2018, PET scan showed no FDG-avid disease, and further treatment was placed on hold. He remains under surveillance, with CT scan in February 2019 again showing no evidence of local or metastatic disease. In patients whose treatment duration and disease course are not defined by toxicities/progressive disease but rather by sustained treatment responses, we propose that immunotherapy treatment duration be guided by close monitoring of CEA levels, weight, and clinical exams in addition to traditional imaging. 1. Introduction since 2018 based on results from the phase II CheckMate 142 trial [3]. Mismatch repair deficiencies (dMMRs) are predictive for The role of immunotherapy in various malignancies con- tinues to grow, and colon cancer is no exception. Pembrolizu- a response to immunotherapy in metastatic colorectal can- mab and nivolumab are two immune checkpoint inhibitors cers. A mismatch repair deficiency allows for markedly with key roles in various advanced malignancies including increased numbers of deoxyribonucleic acid (DNA) muta- the lung, kidney, colon, and bladder as well as melanoma tions to pass unrepaired during cell division, thereby promot- and lymphomas. These immunotherapies block the binding ing tumor growth. There are four main mismatch repair of programmed death-ligand 1 (PD-L1) to its receptor pro- genes including MLH1, MSH2, MSH6, and PMS2. Those grammed death-1 (PD-1) on activated T cells, thereby with MLH1 and MSH2 mutations tend to develop colorectal stimulating the immune system and thus the antitumor cancer earlier relative to those patients with PMS2 mutations. response. Significant response rates even in heavily pre- MSH2 mutations are thought to place the patient at higher treated patients have led to expedited approval of both pem- risk for extracolonic cancers relative to those with MLH1 brolizumab and nivolumab monotherapies in colon cancer, mutations [4]. in 2015 and 2017, respectively [1, 2]. Combination therapy In hereditary nonpolyposis colorectal cancer (Lynch with nivolumab and ipilimumab has also been approved syndrome), an inherited germline mutation in one of the 2 Case Reports in Oncological Medicine Treatment was prematurely terminated due to severe toxicities mismatch repair genes listed above coupled with a somatic mutation in the wild-type allele gives rise to dMMR. Lynch of diarrhea, dehydration, and fungal endophthalmitis. DPD syndrome is responsible for 2-5% of colorectal cancers. In mutation testing was negative. Another trial of capecitabine sporadic mismatch repair deficiency, both alleles are com- in July 2013 resulted in similar toxicities with the first cycle. promised by either somatic mutations or epigenetic silenc- His adjuvant chemotherapy regimen was switched to weekly ing [5]. Not all patients with Lynch syndrome will go on 5-FU+leucovorin which he received from August to to develop colorectal cancer over the course of their lifetime, November 2013, with some dosing adjustments due to and cancer risk profiles are thought to be specific to each dehydration, elevated liver function tests and creatinine, mismatch repair gene. Note that those with Lynch syndrome and abdominal pain. PET CT scan in December 2013 are also at risk for other cancers such as prostate and endo- showed pathologic lymphadenopathy of the left-sided metrial cancers. paraortic, mesenteric, and external iliac lymph nodes. Sub- Patients with dMMR typically manifest as microsatellite sequent CT scan in April 2014 showed further increase in instability-high (MSI-H) owing to the increased number size of these lymph nodes and a rise in CEA to 15 (versus of DNA mismatches that go unchecked. Immune check- 9 in November 2013). The next CT scan in October 2014 point inhibitor use in metastatic colon cancer is limited to showed stable lymph node size, and he was lost to follow- those with MSI-H or dMMR tumors; however, in the up at this time due to loss of insurance coverage. future, the treatment population may include those with He reestablished care in May 2015 and was found to have high tumor mutational burden due to mutated DNA poly- metastatic colon cancer with a new liver lesion and pulmo- nary nodules as well as increased size of lymph nodes. These merases or other abnormalities [6, 7]. Patients identified as MSI-H/dMMR with metastatic colon cancer are candi- lesions were clinically consistent with unresectable meta- dates for immunotherapy assuming they do not have signifi- chronous liver and lung metastases. CEA level was 47. CEA cant autoimmune disease history or other contraindications continued to rise, and he lost more weight despite adminis- to preclude the use of immune checkpoint inhibitors. Herein, tration of weekly 5-FU from June to August 2015. Irinotecan at slightly reduced dose and bevacizumab were given from we present the case of a 33-year-old man with pretreated metastatic colon cancer who is enjoying an ongoing, pro- August to October 2015, but despite marked drop in CEA, longed treatment response of over three years to single- he did not tolerate treatment well (diarrhea and elevated cre- agent pembrolizumab even after treatment discontinuation atinine requiring hospital admission). UGT1A1 testing had in July 2018. previously shown positive heterozygous TA7 polymorphism. A further dose reduction was made to try to achieve a toler- able but still effective dose, but this was still complicated by 2. Case Presentation diarrhea and, in addition, his CEA began to rise. A 33-year-old Caucasian man with asthma and active In October 2015, he was started on pembrolizumab smoking history initially presented in 2012 with severe 2 mg/kg every 21 days, with a corresponding drop in CEA level and clinical improvement. CEA decreased to within intermittent abdominal pain, constipation, and 50-pound weight loss over the past year. Family history was strongly normal limits, and his weight increased over the course of pembrolizumab treatment (Figures 1 and 2). He continued positive for colon cancer in his mother (diagnosed at 44), three aunts (all died of colon cancer in their 20s), and his pembrolizumab treatment through July 2018, at which time, uncle. In December 2012, he underwent colonoscopy and it was decided to implement a treatment break given stable disease with no FDG avidity on PET scan at that time a mass in the descending colon was identified which could not be traversed. A preoperative CEA level was not obtained. (though small calcified residual lymph node findings were In January 2013, he underwent subtotal colectomy and ileo- present). Aside from immunotherapy-induced hypothyroid- proctostomy for findings of nearly obstructing descending ism, he tolerated treatment well. He received a total of 48 colon cancer with abdominal sidewall invasion and involve- cycles of pembrolizumab. CEA remains within normal limits and surveillance CT scan in February 2019 showed no evi- ment of two loops of small bowel. Pathology showed stage IIIC pT4bN1bMX moderate to poorly differentiated colon dence of metastatic disease, indicating a remarkable response adenocarcinoma with 5% signet cell differentiation, 7.5 cm when compared to the CT prior to the initiation of immuno- in greatest dimension. Lymphovascular and perineural inva- therapy (Figure 3). He is being followed with yearly flex sion were present, and 3 of 29 lymph nodes were positive for sigmoidoscopy, upper endoscopy every two years, and oncol- ogy clinic visits with CEA checks every six weeks. adenocarcinoma. Margins were negative. Microsatellite insta- bility testing was positive with loss of MSH2 and MSH6 expression, and KRAS mutation was positive in codon 13. 3. Discussion Ultimately, he was diagnosed with Lynch syndrome based on genetic testing done on peripheral blood DNA which While durable responses to immunotherapy in dMMR met- showed a deleterious Y656X mutation in MSH2. It can be astatic colon cancer are not unusual, our patient’s case is inferred that loss of MSH2 subsequently led to loss of expres- exceptional because he has enjoyed over three years and sion of MSH6 secondarily [8]. Magnetic resonance and CT counting of progression-free survival, despite stopping pem- imaging were negative for distant metastases or pathologic brolizumab treatment over seven months ago. Leal et al. lymphadenopathy at this time. He underwent chemoradiation identified a median overall survival from pembrolizumab of treatment with capecitabine from February to March 2013. 16.1 months in a retrospective cohort of 19 patients with Case Reports in Oncological Medicine 3 CEA level according to chronological date Irinotecan+bevacizumab Initiation of 5-FU Pembrolizumab 3/6/2014 3/6/2015 3/6/2016 3/6/2017 3/6/2018 Figure 1: CEA level according to chronological date. The start dates of the patient’s most recent chemotherapy and immunotherapy regimens are marked for reference. Weight (kg) according to chronological date Initiation of 5-FU Irinotecan+bevacizumab Pembrolizumab Figure 2: Weight according to chronological date. The start dates of the patient’s most recent chemotherapy and immunotherapy regimens are marked for reference. (a) (b) Figure 3: CT contrast imaging before (a) (October 8, 2015) and after (b) (February 1, 2019) administration of pembrolizumab. The black arrow in panel (a) indicates a large retroperitoneal lymph node conglomerate which compressed the inferior vena cava, encased the aorta, and invaded the left renal vein. The lymph node conglomerate has since been reduced to small dense calcifications as seen in panel (b). 2/1/2013 5/1/2013 8/1/2013 11/1/2013 2/1/2014 5/1/2014 8/1/2014 11/1/2014 2/1/2015 5/1/2015 8/1/2015 11/1/2015 2/1/2016 5/1/2016 8/1/2016 11/1/2016 2/1/2017 5/1/2017 8/1/2017 11/1/2017 2/1/2018 5/1/2018 8/1/2018 11/1/2018 2/1/2019 4 Case Reports in Oncological Medicine of recurrent metastatic disease, continued to climb with dMMR metastatic colorectal cancer [9]. Most patients with dMMR metastatic colon cancer treated with immunotherapy 5-fluorouracil-based treatment, initially responded well to will survive at least 12 months after the initiation of immuno- irinotecan+bevacizumab-based treatment, and then began increasing again to 23 after a dose reduction of irinotecan therapy. One study did observe a large difference in overall response rate for patients with Lynch syndrome versus other was made due to severe toxicity. The CEA promptly dropped forms of dMMR. Lynch syndrome patients had a 27-percent to the normal range with pembrolizumab treatment overall response rate (11 patients) versus 100-percent overall (Figure 1). The chemotherapy treatment responses and response rate (6 patients) in those with dMMR not linked to CEA levels were in keeping with expectations that MSI patients tend to respond better to irinotecan than 5- Lynch syndrome [5]. This discrepant result between the dMMR subgroups has not been duplicated in other studies fluorouracil. False elevations of CEA levels are known to to date to our knowledge, but if true, would make our Lynch occur, but the degree of elevation tends to reinforce suspi- syndrome patient’s response all the more surprising. Further- cions of recurrent/metastatic disease particularly in patients more, our patient remains in remission per normal CEA and who had elevated CEA levels prior to initial resection of locoregional disease. A retrospective analysis found half of surveillance imaging despite stopping pembrolizumab over seven months ago to allow for an extended treatment break. elevated CEA levels to be false positives when presenting The endpoint of pembrolizumab treatment after a strong after R0 resections of locoregional colorectal cancer. How- response remains unclear, and further research is needed to ever, false positives for CEA levels over 15 ng/ml were rare, define treatment duration in this setting. Our patient showed and CEA levels exceeding 35 ng/ml all represented true pos- itives [12]. CEA levels often correlate to clinical responses excellent tolerance of immunotherapy despite suffering a high level of toxicity with standard chemotherapy and radi- even after a single dose of immunotherapy and precede the ation. While there are many known immunotherapy- corresponding radiographic responses by several months induced toxicities of PD-L1 inhibitors, these are generally [13]. Radiographic changes may even appear to falsely indi- well-managed when addressed early as with our patient’s cate disease progression in the setting of immunotherapy, particularly when scans are performed prematurely. Cer- immunotherapy-induced hypothyroidism, and side-effects do not usually compromise the intended treatment course. tainly more studies are needed to determine the appropriate Immunotherapy’s role in colorectal cancer may soon be surveillance regimen for metastatic colorectal cancer patients on extended courses of immunotherapy. There are patients refined beyond the dMMR and MSI-H populations. Anec- dotal evidence and small retrospective analyses have been such as ours whose treatment duration and disease course are not defined by toxicities/progressive disease but rather reported that link immunotherapy treatment response with high tumor mutational burden due to mutated DNA poly- by sustained treatment responses, and we would argue that merases or other abnormalities, independent of mismatch in these cases, the treatment duration should be guided by close monitoring of CEA levels, weight, and clinical exams repair status [6, 7]. DNA polymerase mutations are impli- cated in 1% of colorectal cancers and can even coexist with in addition to traditional imaging. mutated mismatch repair genes [10]. A more in-depth molecular analysis of dMMR and MSI-H populations may Conflicts of Interest hold the answer to why certain individuals enjoy prolonged immunotherapy responses as with our patient. Even if pre- The authors declare that there is no conflict of interest dictive significance remains elusive with future studies, the regarding the publication of this paper. complete molecular profile has already been shown to hold prognostic significance. Our patient has coexisting KRAS mutation and MSI-H status. KRAS mutations are inversely References associated with MSI, so our patient’s combined abnormalities are not common. When viewed alone, KRAS mutations have [1] K. Ganesh and L. A. Diaz, Immunotherapy for Metastatic Mismatch Repair-Deficient Colorectal Cancer: Game-Changer had mixed prognostic findings, with some studies showing for Small Group of Patients, The ASCO Post, 2017, February negative prognostic value and others showing unaffected 2019, http://www.ascopost.com/issues/october-10-2017/immu disease-specific outcomes. However, combined molecular notherapy-for-metastatic-mismatch-repair-deficient-metastatic- analyses have proven more instructive. One study evaluated colorectal-cancer-game-changer-for-small-group-of-patients/. disease-specific survival for KRAS and BRAF mutation status [2] M. J. Overman, R. McDermott, J. L. Leach et al., “Nivolumab in with MSI. The best prognostic group was KRAS and BRAF patients with metastatic DNA mismatch repair-deficient or wild-type with MSI, then KRAS or BRAF mutant with MSI, microsatellite instability-high colorectal cancer (CheckMate followed by KRAS and BRAF wild-type with MSS, and lastly, 142): an open-label, multicentre, phase 2 study,” The Lancet KRAS or BRAF mutant with MSS [11]. It would appear that Oncology, vol. 18, no. 9, pp. 1182–1191, 2017. KRAS and MSI yield the most prognostic value when inter- [3] M. J. Overman, S. Lonardi, K. Y. M. Wong et al., “Durable preted together, begging the question of what other underly- clinical benefit with nivolumab plus ipilimumab in DNA ing molecular abnormalities that are yet to be analyzed mismatch repair-deficient/microsatellite instability-high meta- collectively may add to prognostic and predictive data. static colorectal cancer,” Journal of Clinical Oncology, vol. 36, We would like to call attention to the close correlation of no. 8, pp. 773–779, 2018. CEA levels with immunotherapy response in our patient and [4] D. Ramsoekh, A. Wagner, M. E. van Leerdam et al., “Cancer in outside studies. Our patient’s CEA levels rose in the setting risk in MLH1, MSH2 and MSH6 mutation carriers; different Case Reports in Oncological Medicine 5 risk profiles may influence clinical management,” Hereditary Cancer in Clinical Practice, vol. 7, no. 1, p. 17, 2009. [5] D. T. Le, J. N. Uram, H. Wang et al., “PD-1 blockade in tumors with mismatch-repair deficiency,” The New England Journal of Medicine, vol. 372, no. 26, pp. 2509–2520, 2015. [6] L. F. Campesato, R. Barroso-Sousa, L. Jimenez et al., “Compre- hensive cancer-gene panels can be used to estimate mutational load and predict clinical benefit to PD-1 blockade in clinical practice,” Oncotarget, vol. 6, no. 33, pp. 34221–34227, 2015. [7] P. M. Boland and W. W. Ma, “Immunotherapy for colorectal cancer,” Cancers, vol. 9, no. 12, p. 50, 2017. [8] M. Morak, S. Käsbauer, M. Kerscher et al., “Loss of MSH2 and MSH6 due to heterozygous germline defects in MSH3 and MSH6,” Familial Cancer, vol. 16, no. 4, pp. 491–500, 2017. [9] A. D. Leal, J. Paludo, H. D. Finnes, and A. Grothey, “Response to pembrolizumab in patients with mismatch repair deficient (dMMR) colorectal cancer (CRC),” Journal of Clinical Oncol- ogy, vol. 35, article 3558, Supplement 15, 2017. [10] U. Testa, E. Pelosi, and G. Castelli, “Colorectal cancer: genetic abnormalities, tumor progression, tumor heterogeneity, clonal evolution and tumor-initiating cells,” Medical Sciences, vol. 6, no. 2, p. 31, 2018. [11] A. I. Phipps, D. D. Buchanan, K. W. Makar et al., “KRAS- mutation status in relation to colorectal cancer survival: the joint impact of correlated tumour markers,” British Journal of Cancer, vol. 108, no. 8, pp. 1757–1764, 2013. [12] A. Litvak, A. Cercek, N. Segal et al., “False-positive elevations of carcinoembryonic antigen in patients with a history of resected colorectal cancer,” Journal of the National Compre- hensive Cancer Network, vol. 12, no. 6, pp. 907–913, 2014. [13] B. D. Nicholson, B. Shinkins, I. Pathiraja et al., “Blood CEA levels for detecting recurrent colorectal cancer,” Cochrane Database of Systematic Reviews, no. 12, article CD011134, 2015. 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