Exceptional Response to Nivolumab and Stereotactic Body Radiation Therapy (SBRT) in Neuroendocrine Cervical Carcinoma with High Tumor Mutational Burden: Management Considerations from the Center For Personalized Cancer Therapy at UC San Diego Moores Cancer Center

Sharabi, Andrew B.; Kim, Sangwoo Shawn; Kato, Shumei; Sanders, P. Dominick; Patel, Sandip Pravin; Sanghvi, Parag; Weihe, Elizabeth; Kurzrock, Razelle

doi:10.1634/theoncologist.2016-0517

Cited by 97 publications

(80 citation statements)

References 34 publications

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“…Mismatch‐repair status seems to predict response to immune checkpoint blockade, as seen with pembrolizumab in colorectal, gynaecological and biliary tract carcinoma . Immunotherapy (Nivolumab) combined with stereotactic body radiotherapy showed exceptional results in a patient with advanced, chemotherapy‐refractory large‐cell neuroendocrine carcinoma of the cervix with high mutational burden . As a virally mediated tumour, SmCC‐Cx is likely to harbour high antigenicity, which makes it an amenable target for immune modulation, similar to neoplasms with a high mutational burden .…”

Section: Discussionmentioning

confidence: 99%

“…PD‐1 modulates effector T cell activity by binding to one of its ligands, programmed cell death protein 1 ligand 1 (PD‐L1), which is expressed on a wide range of tumour cells. PD‐L1 overexpression has been associated with immune evasion in various tumour types, and provides a rationale for assessing tumour PD‐L1 expression in order to predict benefit from anti‐PD‐1/PD‐L1 immunotherapy, particularly in the setting of mismatch repair deficiency/microsatellite instability . Tumours with high mutational burden have been shown to be amenable to immune modulation .…”

Section: Introductionmentioning

confidence: 99%

“…PD-L1 overexpression has been associated with immune evasion in various tumour types, and provides a rationale for assessing tumour PD-L1 expression in order to predict benefit from anti-PD-1/PD-L1 immunotherapy, particularly in the setting of mismatch repair deficiency/microsatellite instability. [8][9][10] Tumours with high mutational burden have been shown to be amenable to immune modulation. 11,12 One explanation for this is that such tumours harbour a higher tumour-specific neoantigen load that stimulates recruitment of tumour-infiltrating lymphocytes, leading to overexpression of immune checkpoints such as PD-1 and PD-L1.…”

Section: Introductionmentioning

confidence: 99%

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PD‐L1, RB1 and mismatch repair protein immunohistochemical expression in neuroendocrine carcinoma, small cell type, of the uterine cervix

et al. 2019

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Aims Neuroendocrine carcinoma, small cell type, of the uterine cervix (SmCC‐Cx) is a rare human papilloma virus (HPV) related tumour with limited therapeutic options. Merkel cell carcinoma, another virus‐associated neuroendocrine malignancy, has significant programmed death ligand 1 (PD‐L1) expression rates. PD‐L1 expression has been reported in other malignancies of the cervix. We aimed to determine the prevalence of PD‐L1 in the context of mismatch repair protein (MMR) and RB1 expression status in SmCC‐Cx. Methods and results Ten cases of SmCC‐Cx were tested by immunohistochemistry for expression of PD‐L1, MLH1, MSH2, MSH6, PMS2, RB1, CD3, CD20 and for HPV by in‐situ hybridisation (ISH). PD‐L1 expression was scored quantitatively (H‐score) in tumour cells and lymphocytes (tumoral/peritumoral). PD‐L1 positivity was seen in seven cases, focal in most (H‐score range 3–140). Three of nine cases showed MMR deficiency. PD‐L1 expression levels correlated with MMR expression status: all three MLH1/PMS2‐deficient cases had a ≥5% PD‐L1 staining and an H‐score ≥10 (P = 0.01). RB1 was lost in four of nine cases, all PD‐L1 positive, but this correlation was not statistically significant. Seven of nine tumours were positive for HPV‐ISH; two of these had MLH1/PMS2 loss. Of the two HPV‐ISH negative tumours, one had MLS1/PMS2 loss. Conclusions PD‐L1 expression, predominantly focal, is seen in 70% of SmCC‐Cx, while loss of MMR expression is seen in 33% of SmCC‐Cx in our cohort. PD‐L1 expression in more than 10% of tumour cells is seen in a subset of tumours in association with loss of MMR expression. These patients may be amenable to immune checkpoint inhibitor therapy as a promising alternative for this aggressive disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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PD‐L1, RB1 and mismatch repair protein immunohistochemical expression in neuroendocrine carcinoma, small cell type, of the uterine cervix

et al. 2019

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“…Paraghamian et al used nivolumab in a patient with recurrent, metastatic, programmed cell death ligand-1 (PD-L1)-negative small-cell neuroendocrine cervical carcinoma, who experienced a complete response 60. Sharabi et al 61 reported a patient with metastatic, chemotherapy-refractory neuroendocrine carcinoma with bowel obstruction due to a large tumor burden.…”

Section: Recurrent Diseasementioning

confidence: 99%

Updates and management algorithm for neuroendocrine tumors of the uterine cervix

Salvo

Martín

Gonzales

et al. 2019

Int J Gynecol Cancer

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Neuroendocrine carcinomas of the cervix account for less than 2% of all invasive cervical cancers and are classified as low-grade (carcinoid, atypical carcinoid tumor) or high-grade (known as small- and large-cell) neuroendocrine carcinomas. There are increasing data showing that cervical neuroendocrine carcinomas may be associated with the human papillomavirus (HPV), especially HPV18, and most will stain positive for p16. Immunohistochemistry markers such as synaptophysin and CD56 are the most sensitive markers. Although there are no commonly associated mutations, PIK3CA, KRAS, and TP53 are the most frequently found mutations in neuroendocrine tumors. Neuroendocrine cervical carcinomas are exceedingly aggressive tumors with a high tendency for nodal involvement and distant metastases. Age, lymph node metastases, smoking, pure small-cell histology, and tumor size are independent prognostic factors. Overall, the 5-year survival rate is 36% and the median overall survival ranges between 22 and 25 months. Treatment options are often extrapolated from small-cell lung cancer and limited retrospective studies. The preferred treatment is a multimodal approach of surgery, chemoradiation, and systemic chemotherapy. The most common chemotherapy regimen used as initial therapy is a combination of cisplatin and etoposide. In the setting of recurrent disease, a combination of topotecan, paclitaxel, and bevacizumab has demonstrated favorable outcomes. Multicenter tumor registries, such as the Neuroendocrine Cervical Tumor Registry (NeCTuR), are an opportunity to evaluate patterns of disease treatment and oncologic outcomes.

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“…In another patient refractory to chemotherapy, nivolumab combined with stereotactic body radiation therapy (SBRT) and octreotide treatment resulted in near-complete systemic resolution of the disease for at least 101 months [47]. …”

Section: Clinical Experience With Checkpoint Inhibitors In Nensmentioning

confidence: 99%

Immune Checkpoint Inhibitors in the Treatment of Patients with Neuroendocrine Neoplasia

Weber

Fottner²

2018

Oncol Res Treat

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Background: Well-differentiated neuroendocrine neoplasms (NENs) are usually controlled by antiproliferative, local ablative and/or radionuclide therapies, whereas poorly differentiated NENs generally require cytotoxic chemotherapy. However, treatment options for patients with advanced/metastatic high-grade NENs remain limited. Method: Review of the literature and international congress abstracts on the efficacy and safety of immunotherapy by checkpoint inhibition in advanced/metastatic NENs. Results: Evidence points to an important role of immune phenomena in the pathogenesis and treatment of neuroendocrine tumors (NETs). Programmed cell death 1 (PD-1) protein and its ligand are mainly expressed in poorly differentiated NENs. Microsatellite instability and high mutational load are more pronounced in high-grade NENs and may predict response to immunotherapy. Clinical experience of immune checkpoint blockade mainly exists for Merkel cell carcinoma, a high-grade cutaneous neuroendocrine carcinoma (NEC), which has led to approval of the anti-PD-1 antibody avelumab. In addition, there is anecdotal evidence for the efficacy of checkpoint inhibitors in large-cell lung NECs, ovarian NECs and others, including gastroenteropancreatic NENs. Currently, phase II studies investigate PDR001, pembrolizumab, combined durvalumab and tremelimumab, and avelumab treatment in patients with advanced/metastatic NENs. Conclusion: Immune checkpoint inhibitors are a promising therapeutic option, especially in progressive NECs or high-grade NETs with high tumor burden, microsatellite instability, and/or mutational load.

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Exceptional Response to Nivolumab and Stereotactic Body Radiation Therapy (SBRT) in Neuroendocrine Cervical Carcinoma with High Tumor Mutational Burden: Management Considerations from the Center For Personalized Cancer Therapy at UC San Diego Moores Cancer Center

Cited by 97 publications

References 34 publications

PD‐L1, RB1 and mismatch repair protein immunohistochemical expression in neuroendocrine carcinoma, small cell type, of the uterine cervix

PD‐L1, RB1 and mismatch repair protein immunohistochemical expression in neuroendocrine carcinoma, small cell type, of the uterine cervix

Updates and management algorithm for neuroendocrine tumors of the uterine cervix

Immune Checkpoint Inhibitors in the Treatment of Patients with Neuroendocrine Neoplasia

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