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ijcimr · 2 years ago

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Hereditary breast ovarian cancer syndrome: One case, multiple lessons by Ikram Burney in International Journal of Clinical Images and Medical Reviews

Abstract

Ovarian cancer is one the most common gynecological cancers, and epithelial ovarian cancer is the commonest sub-type. Between 10 and 15% of all epithelial ovarian cancers occur secondary to a mutation in BRCA1 or BRCA2 gene, and may be associated with breast cancer, known as hereditary breast ovarian cancer syndrome (HBOCS). We report a case of HBOCS, highlight the importance of family history and treatment history and discuss the recent developments in surgery and systemic treatment for patients in relation to the presentation of this case.

Introduction

Ovarian cancer is one the most common gynecological cancers (Bray 2018). Epithelial ovarian cancer is the commonest sub-type (Kurman 2014). Between 10 and 15% of all ovarian cancers occur secondary to a mutation in a cancer susceptibility gene (Zhang 2011). Mutations in BRCA1 and BRCA2 gene are the commonest cause of hereditary ovarian cancer (Mikki 1994; Claus 1996). These mutations also predispose the individuals to other cancers. Patients with epithelial ovarian cancer may also develop breast cancer (Easton 1993; Easton 1997). We report one such case here, and discuss the recent advances in the medical and surgical management of hereditary breast ovarian cancer syndrome (HBOCS).

Case

A 57 year-old lady presented with abnormal vaginal bleeding and abdominal distention. She was diagnosed to have high grade ovarian cancer, underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy and omentectomy, and was found to have stage IIIC serous papillary type of high grade ovarian cancer. The patient was treated with 6 cycles of Carboplatin and Paclitaxel to complete serological and radiological remission, however, she tolerated the chemotherapy with frequent episodes of febrile neutropenia. Three years later, the disease relapsed and the patient was treated with 6 cycles of Liposomal Doxorubicin to state of complete serological remission. One year later, the disease relapsed yet again, and this time, she received Carboplatin as a single agent. The disease entered serological remission after 3 cycles, however, the patient could not continue treatment because of repeated febrile neutropenia and thrombocytopenia

One year later, the disease relapsed a 3rd time. CT scan showed disease only at one site (figure 1a) and the patient was treated with Carboplatin at a reduced dose, once again to a state of complete serological and radiological remission (figure 1b). A surveillance mammogram was reported as BIRADS II and the bone mineral density revealed osteopenia. One year later, the disease relapsed a 4th time, again in a solitary site, and the patient was counseled about treatment with chemotherapy followed by a secondary cyto-reductive surgery, to which the patient agreed. The patient received 6 cycles of chemotherapy at reduced doses, followed by surgery. There was no residual disease and the patient remained in complete remission for more than one year and 3 months.

At this stage the CA-125 was seen to rise again serially, and mammogram showed a 2.2 cm speculated lesion in the left breast. A fine needle aspiration was highly suggestive of breast cancer, and a core biopsy revealed an infiltrating ductal carcinoma, grade II, estrogen and progesterone receptor positive, but negative for HER-2/neu protein (ER positive; PR positive; HER-2/neu negative). The proliferation fraction measured by Ki-67 was 40%. The morphologic and immunohistochemical patterns were consistent with a diagnosis of a primary in the breast (Table 1). Staging CT scan revealed a metastatic lesion in liver and bilateral pulmonary metastases. An attempt at guided biopsy from the pulmonary lesion was unsuccessful and led to pneumothorax. The patient refused further attempt at biopsy and agreed to be treated with Letrozole, considering that the pattern of metastases was more likely secondary to breast cancer rather than the ovarian cancer. Ten months later, the CT scan showed a marked regression in the size of pulmonary lesions, but a stable liver lesion (Figure 2).

Table 1: Immunohistochemical staining patterns of breast and ovarian cancer. WT-1 (wilm’s Tumor 1); PAX 8 (Paired box gene 8); CA 125 (Cancer antigen 125); ER/PgR (Estrogen receptor / Progesterone receptor); CK 7 (Cytokeratin 7); GCDFP-15 (Gross cystic disease fluid protein-15); TP 53 (Tumor protein 53)

Figure 1: CT scan at the time of the 3rd relapse (Figure 1A) shows a 35 mm x 28 mm mass in the region of omentum, which disappeared completely after 6 cycles of carboplatin AUC 4 (Figure 1B).

Considering that the patient had HBOCS, the patient was referred to the cancer geneticist. A detailed history revealed that her mother had dies of a malignancy of unknown primary site, her sister died at the age of 40 years, of a malignancy with ascites, but the primary site was not known to the patient or the family. The patient underwent counseling followed by assessment with a germline mutational analysis for breast and ovarian cancer panel, which revealed a pathogenic mutation in BRCA2 gene (c.4243G>T), and a variant of unknown significance in the NBN gene (c.425A>G). The BRCA2 mutation was consistent with a diagnosis of HBOCS. One year later, the CA 125 was seen to rise again serially, while the metastatic lesions in the lung and liver were under good remission. The patient was commenced on treatment with Olaparib, and the CA 125 dropped from 324 to 26 in one year (figure 3). The patient continued to receive Letrozole. Twelve years after the diagnosis of ovarian cancer, and while still on treatment for breast and ovarian cancer, the patient passed away of an unrelated cause. During the course of the treatment, patient’s three daughters agreed for mutational analysis; two tested positive for mutation on the BRCA2 gene, and one of those two was screen-detected to have a breast cancer.

Figure 3: Serum CA 125 levels (IU/L) plotted over time. The patient was commenced on treatment with olaparib in Nov 2015. The levels dropped to within the normal limits (<36IU/L) in March 2016 (within 4 months of the treatment).

Discussion

We report the case of a woman diagnosed to have HBOCS, who lived 12 years after the diagnosis of high grade ovarian cancer, received multiple lines of intra-venous chemotherapy, albeit with difficulty, underwent a secondary cyto-reductive surgery, and in the last 4 years of her illness was treated for the two cancers with an oral aromatase inhibitor and a PARP inhibitor. Both breast and ovarian cancers responded to the treatment with the two oral agents. We would like to highlight several aspects of management for the general readership of this journal.

The median survival of patients diagnosed to have high grade ovarian cancer, stage IIIC is dismal at around 3-4 years (Peres 2019). This patient lived for 12 years. Complete response to chemotherapy on five occasions, and a poor tolerance to chemotherapy, even at an age of 57-65 years indicate the tumor is exquisitely sensitive, especially to platinum containing chemotherapy. Platinum derivatives (Cisplatin, Carboplatin and Oxaliplatin) are alkylating agents, which act by disrupting the DNA repair pathways. Usually, PARP (Poly (ADP-ribose) polymerase) enzyme is required for base excision repair (BER). If the enzyme were inhibited, DNA repair would be affected. Also, if one allele is inactivated on the BRCA 1 or 2 gene, such as, because of mutations or methylation, DNA repair will be grossly affected, leading to a process called ‘synthetic lethality’ (Konstantinopoulos 2010; Helleday 2011). In the last few years, three such compounds (Olaparib, Niraparib and Rucaparib) have been developed, tested, and have become the standard of care for patients with either germline BRCA mutations, or even in patients who may have homologous reconstitution deficiency (Ledermann 2014, Mirza 2016; Pujade-Lauraine 2017; Coleman 2017). The first-in-class compound was Olaparib, approved by the FDA in 2014 for use as a single agent in patients who had germline BRCA mutations and had failed three lines of chemotherapy (Ledermann 2012). Our patient was treated and responded to the treatment.

BRCA 1 mutation is more common than mutation in BRCA 2 gene, and it is important to distinguish between the two. Although, response to platinum chemotherapy or PARP inhibitors is the same (Konstantinopoulos 2010), there are phenotypic differences, especially for breast cancer, and the susceptibility to develop other cancers, required for counseling the family members. Patients with BRCA 1 mutation are associated with triple-negative breast cancer (ER negative; PR negative; HER-2/neu negative) in more than 75% of the cases, whereas, patients with BRCA 2 mutations are associated with hormone-receptor positive breast cancer in more than two thirds of the cases (Hartmann 2016). Our patient had BRCA 2 mutation and hormone-receptor positive breast cancer, which was treated with aromatase inhibitor for more than 4 years. Although the life-time risk of developing breast cancer is same (65-70%) in the patients and the first-degree relatives, the life-time risk of ovarian cancer is 40-45% in case of BRCA 1 mutation carrier and 10-15% in case of BRCA 2 mutation career (Antoniou 2003; Hartmann 2016). Our patient had three daughters and they were counseled. Two tested positive for the same mutation. Because of their relatively young age, and the minimal increased risk of ovarian cancer in BRCA 2 mutation carriers, till the age of 45 years, they were advised to consider delaying BSO.

The role of secondary cyto-reductive surgery in ovarian cancer has been contemplated and debated over the last several years. Three major phase III trials have been reported in the past 2 years (Please see table 2). The GOG-0213 trial was the first trial to have been reported (Coleman 2019). The primary end point was overall survival (OS); 485 patients were randomized to receive standard of care chemotherapy with or without secondary cyto-reductive surgery. The patients were selected if the treatment free interval from the last dose of platinum containing chemotherapy was more than 6 months. Although, there was a non-significant prolongation in the progression-free survival (PFS) (18.9 vs 16.2 month; HR 0.82), there was no difference in OS. Actually, the OS was inferior in the group which received secondary cyto-reductive surgery (50.6 vs 64.7 months; HR 1.29). However, a sub-set of patients who achieved R0 resection had a better PFS and OS, compared to those who could not have a R0 resection. The DESKTOP III trial randomized 407 patients to receive standard of care chemotherapy with or without secondary cyto-reductive surgery (du Bois 2017). There was a clinically and statistically significant prolongation in the PFS (19.6 vs 14 months; HR 0.66). Also, the primary end-point was met (du Bois et al 2020). The was a significant 7.6 months prolongation in OS (53.6 vs 46 months; 0.75 (0.58-0.96; P = 0.02). In addition to the criteria of treatment free interval of more than 6 months, the investigators also used the AGO criteria. The AGO criteria was developed after the DESKTOP I trial, and women with no gross residual disease after primary surgery, ECOG performance status of <1, and no ascites on CT scan at recurrence were classified as AGO score positive (Harter 2006). Subsequently, the DESKTOP II trial suggested that patients with a good performance status, absence of ascites at the time for secondary cyto-reductive surgery, more than 12 months of platinum-free interval, isolated site of recurrence, and the possibility of complete resection of disease were likely to benefit from the secondary cyto-reductive surgery (Harter 2011). The 3rd trial (SOC-1 trial) randomly assigned 356 patients with recurrent ovarian cancer in first relapse to either chemotherapy, or cyto-reductive surgery and chemotherapy (Zhang R 2020). There was a clinically meaningful (5.5 months), and statistically significant prolongation in the PFS (17.4 vs 11.9 months; HR 0.58) for the combination of cyto-reductive surgery and chemotherapy arm. The eligibility criterion was different from the first two studies. The SOC1 investigators selected patients if the platinum-free interval was at least 6 months, and an integrative model score was <4.7. However, at the time of management of our patient, results of the randomized trials were not available. We based our decision on the available data from DESKTOP I and II trials. The patient fit both the AGO score positive and the subsequent criterion developed after DESKTOP II trial. Our patient lived more than 5 years after the cyto-reductive surgery without a subsequent recurrence in the abdominal cavity.

Taken together, the three randomized trials comparing chemotherapy with or without cyto-reductive surgery suggest that there may be a benefit for surgery in carefully selected patients who can undergo potentially complete (RO) resection in women who have recurrent platinum-sensitive ovarian cancer. Although, results of randomized trials should not be compared, however, it would be useful to note that the magnitude of benefit seen in the DESKTOP III trial (HR 0.75), is similar to the recently reported SOLO2 study. The later study compared the OS in patients with platinum-sensitive ovarian cancer, but who also had a BRCA mutation, and who were treated with the PARP inhibitor, olaparib and had a median OS of 51.7 months compared to 38.8 months in the placebo arm with a HR of 0.74 (Poveda 2020). Although, olparaib is the standard of care for maintenance treatment in patients with BRCA mutated platinum-sensitive ovarian cancer, the cost of drug and the overall cost of management remains very high. Cyto-reductive surgery in carefully selected patients, with a potential to achieve R0 resection may be an alternative, especially for patients with BRCA negative platinum sensitive ovarian cancer in first relapse.

In conclusion, we report the case of a patient with HBOCS, and highlight the recent developments in the systemic and surgical management of patients with ovarian cancer.

Table 2

SCS: Secondary cyto-reductive surgery; CT: Chemotherapy; OS: Overall survival; HR: Hazard ratio; PFS: Progression-free survival

Conflict of Address

Ikram Burney:

Principal Investigator for the hospital site for Astra-Zeneca sponsored PREDICT study Served on the advisory board for Astra Zeneca Other authors declare no conflict of interest

Author’s contribution:

Dr Juhaina Al Hinai – Data curation; Writing – original draft.

Dr Moza Al Kalbani – Surgical Oncology management, Methodology; Writing – review & editing.

Dr Marwa Al Riyami – Pathology reporting, methodology; Writing – review & editing.

Dr Abeer Al Sayegh – Clinical Genetics management, methodology; Writing – review & editing.

Dr Ikram A Bunrey - Conceptualization; Formal analysis; Supervision; Writing – original draft; Writing – review & editing.

Informed Consent:

All data are anonymised, and patient identification is not possible.

For more details: https://ijcimr.org/editorial-board/

#Ovarian cancer #gynecological cancers #HBOCS #Epithelial #abnormal vaginal #bleeding and abdominal #Liposomal #Doxorubicin #chemotherapy #Immunohistochemical #pulmonary #Olaparib #Ikram Burney #ijcimr

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niicktedd · 6 months ago

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Olaparib tablets are used to help maintain the response of certain types of ovarian (female reproductive organs where eggs are formed), fallopian tube (tube that transports eggs released by the ovaries to the uterus), and peritoneal (layer of tissue that lines the abdomen) cancer in people who have completely responded or partially responded to their first or later chemotherapy treatments. Olaparib tablets are also used to treat certain types of breast cancer that has spread to other parts of the body and has not improved or has worsened after treatment with other therapies.

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ptmasterguide · 1 year ago

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Olaparib and Obatoclax

Olaparib and Obatoclax In this study, we explored the antitumor activities of the PARP inhibitor AZD2281 (Olaparib) and the pan-Bcl-2 inhibitor GX15-070 (Obatoclax) in six pancreatic cancer cell lines. While both agents were able to cause growth arrest and limited apoptosis, the combination of the two was able to synergistically cause growth arrest and non-apoptotic cell death. Furthermore, in an…

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#Anticancer Drugs #Medicine #Olaparib #Oncology #Pharmacology #Physiotherapy

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iebpharma · 9 months ago

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Olakin 150mg (Olaparib) | Order Now At IEB Pharma

Olakin 150mg, also known as Olaparib, is a medication belonging to the class of drugs called PARP inhibitors. Developed and marketed by AstraZeneca, Olaparib has gained significant attention in the medical community for its efficacy in treating certain types of cancer, particularly ovarian and breast cancers. In this comprehensive overview, we will delve into the mechanism of action, indications, dosage, side effects, and recent advancements related to Olakin 150mg.

Mechanism of Action:

Olaparib works by inhibiting the enzyme poly ADP-ribose polymerase (PARP). PARP is involved in the repair of damaged DNA in cells. By inhibiting PARP, Olaparib prevents cancer cells from repairing their damaged DNA, ultimately leading to their death. This mechanism is particularly effective in cancer cells that already have impaired DNA repair mechanisms, such as those with mutations in BRCA genes.

Indications:

Olaparib is primarily indicated for the treatment of advanced ovarian cancer and metastatic breast cancer in patients with mutations in BRCA1 or BRCA2 genes. Additionally, it has shown promising results in other types of cancer, including prostate cancer and pancreatic cancer, especially in patients with BRCA mutations or other DNA repair deficiencies.

Dosage:

The recommended dosage of Olakin 150mg (Olaparib) may vary depending on the type of cancer being treated, the patient's overall health, and other medications they may be taking. It is typically administered orally in the form of tablets and is usually taken once or twice daily with or without food. The dosage should be determined by a healthcare professional based on individual patient factors.

Side Effects:

Like any medication, Olaparib can cause side effects, although not everyone experiences them. Common side effects may include nausea, vomiting, diarrhea, fatigue, loss of appetite, headache, and anemia. More serious side effects such as bone marrow suppression, which can lead to an increased risk of infection or bleeding, may also occur but are less common. Patients should report any persistent or severe side effects to their healthcare provider promptly.

Recent Advancements:

In recent years, research on Olaparib has expanded beyond its initial indications. Studies have explored its efficacy in combination with other cancer treatments, such as chemotherapy and immunotherapy, as well as its potential for use in earlier stages of cancer treatment. Additionally, ongoing clinical trials are investigating Olaparib's effectiveness in various cancer types and patient populations, including those without BRCA mutations.

Conclusion:

In conclusion, Olakin 150mg (Olaparib) represents a significant advancement in the treatment of certain types of cancer, particularly ovarian and breast cancers with BRCA mutations. Its unique mechanism of action, coupled with ongoing research and clinical trials, holds promise for improving outcomes for cancer patients in the future. However, it is essential for healthcare providers to closely monitor patients receiving Olaparib for potential side effects and adjust treatment as needed to ensure optimal safety and efficacy.

#medicine #medicinestore #onlinemedicine #health #Olakin 150 mg #Olaparib 150 mg

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iebpharma360 · 10 months ago

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#Olanib (Olaparib) 150 mg #anticancer #iebpharma #medicinestore

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boome11 · 3 days ago

Link

Lynparza (olaparib), a product of Fortune 500 pharmaceutical firm Merck and Fortune 500 Europe company AstraZeneca, showed meaningful improvements in overall survival in people with germline BRCA-mutated (gBCRCAm), HER2-negative high-risk early breast cancer, 2024 clinical trial data suggest.Jaime Grajales Benjumea—Getty Images https://fortune.com/img-assets/wp-content/uploads/2024/12/GettyImages-1400144048-e1734034203890.jpg?resize=1200,600 2024-12-20 21:30:00

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sbircialanotiziamagazine · 5 days ago

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roshankumar7904800 · 6 days ago

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Ovarian Cancer Market

Ovarian Cancer Market Size, Share, Trends: AstraZeneca plc Leads

Emergence of PARP Inhibitors as a Breakthrough in Ovarian Cancer Treatment

Market Overview:

The global ovarian cancer market is expected to increase at 12.3% CAGR from 2024 to 2031. The market will grow from USD XX in 2024 to USD YY by 2031. North America presently dominates the market, with Europe following closely behind. Key metrics include rising ovarian cancer incidence, advances in diagnostic and treatment technology, rising healthcare costs, and increased awareness of early cancer diagnosis.

The ovarian cancer market is expanding rapidly, owing to the rising global prevalence of the disease and the discovery of new treatments. The market has a robust pipeline of pharmaceuticals, particularly in targeted therapy and immunotherapy. Furthermore, the emphasis on personalised medicine and the use of artificial intelligence in cancer diagnosis and treatment planning are influencing the future of ovarian cancer therapy.

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Market Trends:

The development of poly(ADP-ribose) polymerase (PARP) inhibitors as a breakthrough therapy option has marked a significant trend in the ovarian cancer industry. PARP drugs have demonstrated great success in treating ovarian cancer, particularly in patients with BRCA mutations. This family of medications has transformed the treatment landscape, providing a focused approach with fewer adverse effects than standard chemotherapy.

For example, global sales of PARP inhibitors for ovarian cancer treatment climbed by 35% over the last year. The success of PARP inhibitors has fuelled additional research and development in this field, with several pharmaceutical companies investing considerably in the creation of new and improved PARP inhibitors. This trend is projected to continue, fuelling market expansion as new PARP inhibitors get regulatory approval and become available to a larger patient population.

Market Segmentation:

Epithelial ovarian cancer dominates the ovarian cancer market, accounting for over YY% of all occurrences. This dominance is due to the high incidence of this cancer type and the availability of targeted medicines designed exclusively for epithelial ovarian cancer. The epithelial ovarian cancer segment has grown significantly in recent years, with diagnosed cases increasing by 7.5% year on year.

The market for epithelial ovarian cancer treatment has made significant strides in recent years, notably in the area of targeted medicines. For example, the approval of Lynparza (olaparib) for first-line maintenance treatment of BRCA-mutated advanced epithelial ovarian cancer has resulted in a 25% rise in adoption rate over the last year. This has considerably increased progression-free survival rates for patients carrying this specific mutation.

Market Key Players:

AstraZeneca plc

Roche Holding AG

GlaxoSmithKline plc

Novartis AG

Pfizer Inc.

Merck & Co., Inc.

Name: Hari Krishna

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ashish2018 · 3 months ago

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ptmasterguide · 1 year ago

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Olaparib and BRCA Mutations: Synthetic Lethality

In this article, we will discuss Olaparib and BRCA Mutations: Synthetic Lethality. So, let’s get started. Synthetic lethality refers to a state where the combination of two genetic alterations leads to cell death, while each alteration alone is survivable. In the context of olaparib and BRCA mutations, the drug exploits this phenomenon by inhibiting PARP in cells already compromised by BRCA…

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#Anticancer Drugs #Medicine #Olaparib #Oncology #Pharmacology #Physiotherapy

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iebpharma · 9 months ago

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Olanib (Olaparib) 150 mg | Order Now At IEB Pharma

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