Abstract

Platinum-based chemotherapy is the standard chemotherapy for high grade serous ovarian cancer and primary peritoneal high-grade serous carcinoma. PARP inhibitors have changed the paradigm of the treatment in platinum-sensitive ovarian cancers and primary peritoneal high-grade serous carcinoma with BRCA1/2 mutation or homologous recombination deficiency (HRD). Platinum-resistant ovarian and primary peritoneal high-grade serous carcinoma have a lower chance to treat and have worse outcomes. We described a case of patient with a platinum resistant primary peritoneal high-grade serous carcinoma with a rare somatic BRCA2 amplification. There are no guidelines for the treatment of ovarian cancer or primary peritoneal high-grade serous carcinoma with BRCA2 amplification. BRCA2 amplification could result in extreme homologous recombination repair (HRR) pathway efficiency and in less platinum sensitivity, which could be a molecular signature for platinum resistance. Free platinum chemotherapy regimens could be more effective in cases with BRCA2 amplification. Further studies are necessary to establish better approaches and strategies for oncological management and treatment in BRCA2 amplification high grade ovarian cancer and primary peritoneal high-grade serous carcinoma.

Introduction

Ovarian cancer ranks fifth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system. Ovarian cancer is classified according to morphological, immunohistochemical and molecular characteristics, into 5 main groups: high-grade serous carcinoma (70% of cases), endometrioid carcinoma (10%), clear cell carcinoma (10 %), mucinous carcinoma (3%) and low-grade serous carcinoma (< 5%) ¹. These neoplasms show important differences in terms of epidemiology and risk factors, dissemination pattern, genetic alterations, response to chemotherapy and prognosis. Immunohistochemical profile of high-grade serous carcinoma predicts involvement of p53, WT1, p16, BRCA1, and estrogen receptor and sometimes progesterone receptor. High grade serous ovarian cancer can have germline or somatic BRCA1 and BRCA2 mutations ¹. Homologous recombination deficiency has been observed not only in ovarian cancer patients with germline or somatic BRCA1 or BRCA2 mutations, but also in those with epigenetic silencing of BRCA1, or loss of function of other genes, such as RAD51, ataxia telangiectasia mutated protein (ATM), ataxia telangiectasia mutated, RAD3 related-protein (ATR), PALB2, genes of the Fanconi Anemia Complementation Group ².These patients have a “BRCAness” phenotype that is similar to that of patients with germline BRCA1 or BRCA2 mutations, and includes serous histology, high response rates to first and subsequent lines of platinum-based therapy, long time intervals between recurrences and better overall survival. The presence of such a BRCAness profile identifies a subgroup of patients with ovarian cancer with a better prognosis, and with excellent responsiveness to platinum and PARP inhibitors. PARP inhibitors have changed the paradigm in the treatment of platinum-sensitive ovarian cancer and primary peritoneal high-grade serous carcinoma. Platinum-resistant ovarian cancers, instead, have a lesser chance to treat. In 1959, Swerdlow et al. primary described peritoneal carcinoma. The Gynecologic Oncology group defines the diagnostic criteria for primary peritoneal carcinoma, where both ovaries were of normal size, with an extraovarian involvement greater than the surface ovarian involvement. We described a case of a patient with platinum resistant serous carcinoma of the peritoneum with a rare complete amplification of the BRCA2 gene. There are no guidelines for the treatment of ovarian cancer or primary peritoneal high-grade serous carcinoma with BRCA2 amplification, which would be a molecular signature for platinum resistance.

Case report

A 67-year-old woman was admitted for constipation, dyspnea and ascites in December 2021. She had no significant medical history except for high blood pressure and Hashimoto’s disease. She was taking ACE inhibitors and levothyroxine as medications. Whole-body computed tomography documented abdominal ascites, an omental cake and bilateral pleural effusions. Rapid intraoperative diagnosis showed a high-grade serous carcinoma. Both ovaries were of normal size, with an extraovarian involvement greater than the surface ovarian involvement. Our case met the diagnostic criteria for primary peritoneal carcinoma and was histologically diagnosed as high-grade serous carcinoma of the peritoneum. Tumor tissue was positive for PAX-8 and ER (Fig. 1). Tumor tissue revealed the complete amplification of BRCA2 gene. No germline BRCA2 amplification was detected. The patient started 3 weekly paclitaxel/carboplatin combination chemotherapy in January 2022. After three chemotherapy cycles a whole-body computed tomography documented stable disease. Bevacizumab was not administered for high-risk gastrointestinal perforation. In May 2022, a whole-body computed tomography documented a progressive disease, specifically abdominal ascites, peritoneal solid nodules, bilateral pleural effusions were increased. The Eastern Cooperative Oncology Group (ECOG) Performance Status increased rapidly from 1 to 3. After few days the patient died for progression disease.

Discussion

Carboplatin combination is the mainstay chemotherapy treatment for advanced and metastatic ovarian cancer and primary peritoneal cancer ³. Bevacizumab in combination with paclitaxel-carboplatin chemotherapy improves outcomes versus chemotherapy alone. Platinum chemotherapy can react with nucleophilic centers on purine bases of DNA, particularly the N7 positions of guanosine and adenosine residues and the platinum center can coordinate to guanine bases from different DNA strands to form interstrand cross-links. The major intrastrand dGpG cross-link induces a significant distortion in the DNA double helix. The DNA lesion is then recognized by cellular machinery that either repairs the lesion, bypasses it, or initiates apoptosis. BRCA1 and BRCA2 are proteins that are important for the repair of double-strand DNA breaks by the error-free homologous recombination pathway. PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP-ribose polymerase, causing multiple double strand breaks in the DNA and in tumors with BRCA1 or BRAC2 mutations these double strand breaks cannot be efficiently repaired, leading to the death of cells ⁴. BRCA1 and BRCA2 perform multiple functions ranging from DNA damage response and DNA repair activity, chromatin remodeling and transcription, and protein ubiquitination and are at the intersection of numerous key cellular pathways. The BRCA2 protein binds to and regulates the protein encoded by the RAD51 gene to fix breaks in the DNA. These breaks can be caused by medical or radiation or by exposure to other environmental causes, but they can also occur when chromosomes exchange genetic material during meiosis; RAD51 protein also interacts with BRCA1. By repairing DNA, these three proteins play a key role in keeping the stability of the genotype intact and in preventing dangerous genetic rearrangements, which can lead to cancer. PARP inhibitors have changed the natural history of ovarian cancer and primary peritoneal cancer in patients with BRCA1/2 mutations or in HRD-positive ovarian cancer. Cancers with mutations that disrupt BRCA1/2 protein activity are highly sensitive to treatment with PARP inhibitors. Germline BRCA1/2 mutations, somatic BRCA1/2 mutations, and BRCA gene promotor methylations are well-known causes of homologous recombination deficiency. Homologous recombination repair pathway deficiency is involved in the tumorigenesis and progression in ovarian cancers and primary peritoneal cancers as well as in the sensitivity to platinum chemotherapy drugs. Platinum-resistant ovarian and primary peritoneal cancers have fewer treatment options and worse outcomes. The pathogenesis of peritoneal serous carcinoma is similar to that of ovarian cancer and may be dependent on its origin from ovarian tissue remnants in the peritoneum remaining from embryonic development or from the mesoderm that gives rise to both the peritoneum and ovarian epithelium. Therefore, abdominal mesothelium and female pelvic may give rise to primary peritoneal carcinoma resembling ovarian cancer. Treatment strategy for advanced disease resembles the treatment of high-grade serous carcinoma, which includes aggressive cytoreductive surgery and platinum-based chemotherapy ³. In this case report, we reported a patient with platinum resistant primary peritoneal high-grade serous carcinoma with complete amplification of BRCA2 mutation. BRCA2 amplification is present in 0.25% of cancer cases, in particular in breast invasive ductal carcinoma, rectal adenocarcinoma, colorectal adenocarcinoma and pancreatic adenocarcinoma ⁵. HRD+ high grade serous ovarian and peritoneal cancers with BRCA1/2 mutations are treated with platinum chemotherapy combination. BRCA2 amplification could result in extreme HRR pathway efficiency and then in less platinum sensitivity. To our best knowledge, this is the first case report that underlines BRCA2 amplification and platinum resistance in a patient with high-grade serous carcinoma of the peritoneum. Platinum-free chemotherapy combinations or other mono-chemotherapy might be more effective in this setting. Alternative agents with different pharmacodynamic mechanisms to platinum chemotherapy could be more efficacy bypassing BRCA2 amplification pathway and the HRR pathway. In conclusion, BRCA2 amplification is a rare alteration observed in ovarian cancer and above all in high-grade serous carcinoma, which could be associated with intrinsic resistance to platinum treatment. Further studies are necessary to better understand the role of complete amplification of BRCA2 gene and to establish better approaches and strategies for its oncological management and treatment, especially in extreme rare conditions such as peritoneal carcinoma.

ACKNOWLEDGMENTS

We thank Dr Oriella Andresini for helpful scientific discussion.

CONFLICTS OF INTEREST

The authors declare no conflict of interest.

FUNDING

None.

ETHICAL CONSIDERATION

The information contained in this manuscript complies with the journal’s ethical standards.

AUTHOR CONTRIBUTIONS

All authors gave their approval for publication of the final version of the manuscript.

Figures and tables

Figure 1.(A,B) (C,D) Immunohistochemical profile shows positivity for PAX8 and estrogen receptor.

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