Research ArticleClinical Studies

Complete Response to Immune Checkpoint Inhibition in a Platinum Resistant Primary Ovarian Cancer Patient With Lynch Syndrome: A Case Report and Review of the Literature

LUKAS CHINCZEWSKI, FELIX WILHELM FELDHAUS, WOLFGANG SCHMITT, IOANA BRAICU, EVA ROSER and JALID SEHOULI
Anticancer Research April 2023, 43 (4) 1655-1662; DOI: https://doi.org/10.21873/anticanres.16317

Abstract

Background/Aim: Lynch syndrome (LS) is the secondary cause of hereditary ovarian cancer (OC). Germline mutations in the DNA-mismatch repair (MMR) genes cause tumorigenesis and a high immunogenicity. Recent studies showed a promising use of immunotherapy in MMR deficient (MMRd) tumors. This is a case report of a patient with LS-associated OC and a complete response to pembrolizumab. Case Report: A 44-year-old patient was admitted to the hospital with lower abdominal pain. The patient’s history showed LS with a germline mutation in the MSH2-gene. Initial diagnostics showed a pelvic tumor mass and a highly elevated cancer antigen 125. After debulking surgery, histopathological findings showed a high-grade serous OC with mutations in the MSH2 and MSH6 genes. Only 5 weeks after operation with no residual tumor mass, a quick and significant intraabdominal progression of the disease was diagnosed. Adjuvant therapy with carboplatin and paclitaxel in a weekly course did not lead to sustainable response. An anti-PD-L1 antibody therapy with pembrolizumab was initiated. After only two courses of therapy, the laboratory results and clinical status of the patient improved tremendously. Shortly after, a complete response was detected, and therapy is still ongoing. The patient remains tumor free for 21 months now. Conclusion: The significance of germline compared to somatic mutations has not yet been sufficiently investigated. To our knowledge, this is the first case with complete response to checkpoint inhibition in OC associated with LS. Regarding LS-associated OC, immune checkpoint inhibition is an efficient therapy in tumors nonresponsive to standard therapy.

Key Words:

Lynch syndrome (LS) is the most common cause for hereditary colorectal carcinoma (1). Germline mutations in the DNA-mismatch-repair (MMR) genes MLH1, MSH2, MSH6, PMS2 or EPCAM cause genomic instability and therefore tumorigenesis (1). Due to loss of expression of these proteins, mutations in microsatellite regions (repetitive DNA sequences) accumulate, resulting in microsatellite instability (MSI) and a high tumor mutational burden (TMB). Secondary to BRCA1/2 mutations, hereditary ovarian cancer (OC) can be associated with LS. The lifetime risk of women with LS to develop OC approximates 12-15% (2, 3). The age of diagnosis is comparably younger (43-48 years versus 60 years median age in sporadic OC) and is diagnosed at an earlier stage (4-7). In histopathological findings, LS-associated OCs are epithelial, mainly of endometrioid subtype. Synchronous and metachronous LS-related cancers as endometrial, colon, or urinary carcinomas are common (4). Recent studies found that MMR deficient tumors show a good response to immunotherapy, especially to immune checkpoint inhibition (ICI), e.g., anti-programmed cell death (PD)-1 antibodies (8). In this study we present a case report concerning a patient with a complete response to ICI in an aggressive, primary platinum-resistant LS-associated OC.

Case Report

A 44-year-old patient was admitted to hospital with lower abdominal pain. Initial ultrasonography showed a multicystic tumor of 9×10 cm diameter with solid parts of the right ovary. The left ovary was 7 cm enlarged and showed multicystic formations with papillary structures. An abnormal uterus or ascites could not be seen. In the patient’s history, a germline mutation of the MSH2 gene and LS were known. Her mother died of colorectal cancer around the age of 40. The last surveillance check-up, in terms of a gynecological assessment and colonoscopy, was 3 months prior to hospital admission and showed no suspicious lesions.

After admittance to a hospital in France, a computed tomography (CT) of the lung and abdomen was performed. The CT-scan showed an enlarged pelvic mass with contact to the neighboring sigmoid colon, caecum, and small intestine. Moreover, peritoneal implants and right pleural effusion were detected. Metastasis in the liver, lung or lymph nodes could not be shown via imaging.

Laboratory results showed an elevated tumor marker cancer antigen (CA) 12-5 of 4,808 kU/l and a human epididymis protein 4 (HE4) of 58 pmol/l resulting in a low premenopausal risk of ovarian malignancy algorithm (ROMA) - index of 14.6%. CA 15-3, CA 19-9, and CA 72-4 were slightly elevated with 68, 117, and 25 kU/l, respectively. The carcinoembryonic antigen (CEA) was normal with 1.2 μg/l. When the patient first presented at our hospital (Charité – University Medicine of Berlin) after primary diagnosis in France, we indicated primary debulking operation and the patient underwent surgery in June 2020. Laparotomy and en-bloc resection of the uterus, adnexa, peritoneum of the small pelvis, sigmoid colon, caecum, and parts of ileum was performed. Two enteral anastomoses were constructed and partial resection of the diaphragm, omentectomy and the resection of enlarged pelvic and paraaortic lymph nodes was performed. The patient was macroscopically clear of tumor mass. The initial postoperative course was normal.

Histopathological findings showed a high-grade FIGO IIIC serous ovarian cancer. Six lymph nodes were involved. Hormonal receptor expression was negative, the proliferation index Ki-67 averaged to 40%. Immunohistochemically, cytokeratin (CK) and hepatocyte nuclear factor 1-beta were slightly positive; Napsin, p16, CK20, B-lymphocyte antigen CD20 and CD117 were negative. Concerning mismatch-repair proteins, MLH1 and PMS2 were intact, but MSH2 and MSH6 showed loss of expression (Figure 1), resulting in a MSI high status. Moreover, PD-L1 expression scores were examined immunohistochemically. Positive tumor cells (TC) score was 60% and positive immune cells (IC) score was 0% resulting in a combined positive score (CPS) of 60.

Figure 1.
Figure 1.

Immunohistochemical staining of mismatch-repair proteins. A) Loss of MSH6. B) Maintained expression of PMS2.

Only 5 weeks after debulking operation and prior to adjuvant chemotherapy, the patients clinical condition worsened rapidly, and she was again referred to our hospital from France. She suffered of partial bowel obstruction, a new swelling of the lower abdomen and pain in the right leg. A renewed CT scan showed multiple new pelvic tumor masses, highly progressive peritoneal implants subphrenically and perihepatically with collateral ascites (Figure 2). The laparotomy scar was infiltrated with metastasis that could easily be palpated in the abdominal wall. No pulmonary or bone lesions were seen. Laboratory findings showed a CA 12-5 of 623 kU/l, only one week later even increasing to 1,113 kU/l. A biopsy of the abdominal wall metastasis confirmed the diagnosis of recurrent OC. Due to the patient’s bad clinical condition, immediate start of chemotherapy with the combination of carboplatin AUC2 and paclitaxel 80 mg/m2 in a weekly dose regimen was conducted. The CA 12-5 decreased from a 4,531 kU/l to 1,762 kU/l before and after 10 courses of chemotherapy. While chemotherapy was still administered, the CA 12-5 rose again to 2,553 kU/l and former clinical symptoms aggravated. Due to this massive tumor progression in the sense of a chemotherapy refractory disease, we indicated a change in therapy and started ICI with the PD-1 antibody pembrolizumab in a dosage of 200 mg every 3 weeks used off-label. After only two doses the patient showed a tremendous serological regress with a CA 12-5 level of 127 kU/l. Clinically, the patients’ condition improved rapidly, and the abdominal wall metastasis was highly regredient. After four courses, a positron emission tomography- computed tomography (PET-CT) scan was performed (Figure 3). A partial response was noticed, only a few peritoneal implants in the pelvis and perihepatically could be seen. ICI was continued and the serum levels of the CA 12-5 dropped further to 25 U/l after eight courses. The patient is still on pembrolizumab and showed further regress of tumor mass in PET scans, the serum CA 12-5 levels continue to stay low resulting in a complete response (Figure 4). Until now, a total of 28 cycles have been applied, and the patient remains free of tumor for 21 months and no toxicities are detected.

Figure 2.
Figure 2.

Fluorodeoxyglucose-18 positron emission tomography-computed tomography (PET-CT) scan in recurrent situation after primary debulking and platinum-based chemotherapy before admission to pembrolizumab therapy. Peritoneal carcinosis with marked hypermetabolism throughout the abdomen and pelvis. No visceral metastasis. A) Coronary PET-CT, B) maximum intensity projection, C) axial PET-CT, D) axial PET.

Figure 3.
Figure 3.

Fluorodeoxyglucose-18 positron emission tomography-computed tomography (PET-CT) scan after three cycles of pembrolizumab. Significantly regressing peritoneal carcinosis with residual hypermetabolic implants. A) Coronary PET-CT, B) maximum intensity projection, C) axial PET-CT, D) axial PET.

Figure 4.
Figure 4.

Fluorodeoxyglucose-18 positron emission tomography-computed tomography (PET-CT) scan after admission to six cycles of pembrolizumab therapy. Further reduction in tumor mass and hypermetabolism in peritoneal carcinosis. Unspecific lymphatic node in the left axilla and left paraaortic. A) Coronary PET-CT, B) maximum intensity projection, C) axial PET-CT, D) axial PET.

Discussion

We described the case of a 44-year-old woman with previously known LS and primary diagnosis of highly aggressive and rapidly progressive OC. After initial complete debulking surgery and development of platinum refractory disease, we indicated immunotherapy which led to remarkable response in short time.

Due to the MMR deficiency, genome mutations are less likely to be recognized and repaired. Therefore, a high number of mutations are generated within the genome, especially within microsatellites, resulting in MS instability (MSI) (9). Defective proteins are produced, and the tumor cell presents neoantigens on their surface. This is being used as an immune escape mechanism through a missing recognition of T-cells. Moreover, MSI correlates with the amount of activated cytotoxic intraepithelial lymphocytes (10). Surrounding tumor cells undergo apoptosis more often due to lymphocyte recognition. Concluding from this, MMR deficient (MMRd) tumor cells seem to have a higher immunogenicity. The response to ICI has not yet been fully understood. One approach to explanation is as follows: the increased rate of neoantigens can cause an immune response and an up-regulation of PD-1 ligands within the immunogenic tumor environment (11-13).

Learning from the KEYNOTE studies, MMRd tumors can be treated with ICI independent from histological cancer subtype (14). Several studies like the IMAgyn-, KEYNOTE-100, NINJA- or JAVELIN-trial suggested negative results for ICI in primary or advanced OC (15-18). The amount of mutations per megabase or the formation of neoantigens within all OCs is comparatively significantly lower to other tumor entities (19). MMR deficiency is described as high as 5.2% in all OCs (20). Our presented case shows that ICI can be used in ovarian cancer but a careful patient selection for therapy is mandatory.

The germline mutation in our case was localized in the MSH2 gene resulting in the diagnosis of LS. According to the prospective Lynch Syndrome Database, the incidences for OC depending on the mutated gene differ between 10% for MLH1, 17% for MSH2, and 13% for MSH6, respectively (21). The 5-year and 10-year survival rates approximate 83% and 74%. OC associated with LS is 89% more likely to be diagnosed at an early stage (I-II) (22). Histologically, it usually shows a low-grade endometrioid subtype. In 93%, the tumor shows MMR deficiency but is not necessarily considered MSI-high. The combined positive score (CPS) is in only 28% of OCs above 1 (22). Therefore, the value of different biomarkers concerning a predictive response to immunotherapy in OC remains unclear (23). Different markers like CPS, tumor mutational burden (TMB), MMRd, MSI-status, number of neoantigens or many more could be discussed.

Germline mutations in the MMR genes are detectable in fewer than 1% of all cases of epithelial OC (24, 25). Akbari et al. showed that among 656 women with OC, only 4 (0.6%) had a germline mutation and 84 (13%) a somatic mutation resulting in MMRd (25).

For tumorigenesis in LS, a loss of heterozygosity consisting of a germline and somatic mutation needs to be present. In our patient, the tumor showed the previously known mutation of MSH2 in terms of germline mutation and a somatic mutation in MSH6. Therefore, this could be an explanation for the rapid clinical progress as well as for the high response to ICI. Concluding from this, the MSI-status is a marker for clinical response to immunotherapy.

The KEYNOTE-158 study shows the association of high TMB and the response to immunotherapy in advanced solid tumors (8). A large cohort of 1,066 patients with MMRd tumors received pembrolizumab, 200 mg every 3 weeks. The objective response rate (ORR) was 29% in the TMB-high and 6% in the TMB-low group. Regularly testing of TMB in advanced solid tumors is suggested. Within the study, no difference was found in MMRd due to germline or somatic mutations. Therefore, referring to this study, the significance of germline mutations remains unclear. Somatic mutations show similar characteristics in cellular phenotypes as germline mutations (26) – that is, similarities in general tumor behavior, no matter what mutational origin is present. Indeed, the exact phenotypic differences between germline and somatic mutations in genes resulting in MMRd and thus TMB have not yet been evaluated in detail. The reason for this lack of knowledge in the current literature might be the sporadic testing for germline mutations, which has resulted in the identification of only a small number of mutations.

Concerning the development of a platinum-refractory disease in our case, there is one case report dealing with two women with ovarian cancer and MSH2 germline mutations that show platinum resistance in first-line treatment as well as rapid progression and aggressive recurrence (27). It was stated that there might be a relation between MMR-gene mutations and reduced response to platinum therapy. Some previous reports have shown that resistance to platinum-based chemotherapy was associated with loss of MLH1 expression (28-31).

There are few case reports in literature that show promising response to immunotherapy in LS-associated cancers (32-37). Patil et al. described a case of complete response after only one cycle of pembrolizumab in a patient with metastatic adenocarcinoma of the pancreas associated with LS (37). Keating et al. treated a young patient with pre-treated metastatic colon cancer with pembrolizumab exclusively for 3 years and achieved a decrease in CEA levels and significant weight gain (33). Furthermore, Micheel et al. described a complete response in a recurrent rectum carcinoma with pembrolizumab in a neoadjuvant treatment strategy (36). To our knowledge, there is no case report in the literature dealing with a LS-associated gynecological malignancy that showed such tremendous response to immunotherapy as the patient in our case report did. We therefore highly suggest the conduction of more studies investigating the significance of germline mutations in comparison to sporadic MMRd tumors. Germline mutations could be associated with significantly higher response rates to immunotherapy than somatic mutations only (38). In analogy to poly ADP ribose polymerase inhibition with olaparib in germline BRCA-mutations as maintenance therapy for newly diagnosed OC (39), ICI could reach equivalent importance regarding the treatment of tumors with germline mutations in MMR genes. Furthermore, a concept of neoadjuvant treatment before debulking operation may be considered.

Therefore, clinician’s awareness needs to be more trained to identify patients with characteristic germline mutations and increase testing. Regarding LS, the Manchester International Consensus Group recommends testing all women for a germline mutation that suffer from disease before the age of 50 and/or have any other grade than serous or mucinous histology (40). Furthermore, somatic next-generation sequencing including BRCA, and LS-associated genes on formalin-fixed paraffin-embedded or fresh frozen tumor tissue of non-mucinous invasive epithelial tumors should be performed. Comprehensive methods in testing, screening, and treating patients with germline mutations have to be established in clinical routines.

Footnotes

  • Authors’ Contributions

    Lukas Chinczewski was responsible for the study cooperation, acquisition, analysis, and interpretation of data and drafting of the manuscript. Felix Wilhelm Feldhaus and Wolfgang Schmitt were responsible for the radiological and pathological findings. Jalid Sehouli was involved in the acquisition of data as well as the analysis and interpretation of data and critical revision. All Authors discussed the results and contributed to the final manuscript.

  • Conflicts of Interest

    Elena Ioana Braicu MD, PhD receives research funding from: Bayer, Roche Diagnostics, Tesaro, GSK, AstraZeneca and personal fees from: AstraZeneca, Clovis, GSK, Tesaro, EISAI, RochePharma, Roche Diagnostics. Dr. Sehouli receives Research Funding from: Roche Pharma, AstraZeneca, Bayer, Clovis, GlaxoSmith, Lilly, Tesaro, honorary from: Tesaro, GlaxoSmith, PharmaMar, AstraZeneca, Clovis, Bayer, Roche PharmaMar, Vifor Pharma, Hexal AG, Novartis Pharma, and consulting: Tesaro, Merck/Pfizer, PharmaMar, Clovis Oncology, AstraZeneca, Roche Pharma; GlaxoSmith, MSD, Eisai, Novocure, Oncoinvent. Mr. Chinczewski, Dr. Schmitt, Dr. Feldhaus, and Dr. Roser have nothing to disclose.

  • Received December 12, 2022.
  • Revision received January 25, 2023.
  • Accepted January 26, 2023.

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Complete Response to Immune Checkpoint Inhibition in a Platinum Resistant Primary Ovarian Cancer Patient With Lynch Syndrome: A Case Report and Review of the Literature
LUKAS CHINCZEWSKI, FELIX WILHELM FELDHAUS, WOLFGANG SCHMITT, IOANA BRAICU, EVA ROSER, JALID SEHOULI
Anticancer Research Apr 2023, 43 (4) 1655-1662; DOI: 10.21873/anticanres.16317
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