#epithelial | Explore Tumblr posts and blogs

ijcimr · 2 years ago

Text

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

0 notes

aalt-ctrl-del · 2 years ago

Text

the new variant has drawn concern from me. The variant covid xbb 1.5 has made people - I am uncertain to the vaccine status, but likely unvaxxed - considerably ill. Either that, or it follows the same trace markers delta pursued - impregnating cells throughout prior damaged vascular tissue of epithelial and endothelial cells, where scarring or gouges have been left in prior significant covid infections.

It is an offshoot of omicron, meaning those who have had prior omicron infections should be wary and not fall for the narrative: "immunity of prior infection makes me super resistant." As in the case of the delta surge following the original 19 and its variants, xbb 1.5 may follow prior infections of covid omicron and make those who have had omicron infection sicker than normal.

The vlogger family my mom likes to follow, who work in a mega church following and are closet trump supporters, did make note of how sick they became from an undefined 'illness'. They were basically incapacitated and had to go on antibiotics - which is standard for any infection to this degree. Doctors can prescribe antibiotics over anti-viral agents, especially when there are shortages in supplies of the viral medications. Antibiotics prevent bacterial meningitis, sepsis - from an overflow of damaged and dying cells.

The family has been ill from 19 prior, 2 years ago - of course. Probably unvaxxed, and classified by a risk factor that makes them significantly endangered to the particular strains of covid they carry and spread. And they are prime spreaders - which is a factor of covid adaptation I have included in past reports. The silent hypoxia makes what would be typical introverted or private people, very friendly and overtly outgoing. Sort of like being under the influence of drugs, or altitude sickness.

I have made warning that the father - who is highest risk of the famly despite his age, it likely going to pass due to covid in the coming years. His infections to covid have had an increase risk factor since 19, but he will die for his faith.

As work and people return from the holiday migration, it is vital to mask up. Especially with an anticipated surge in cases from this new pathogen. Covid will never be a benign infection, regardless an individuals health or resilience to infections - covids legacy and relevance is not its rate of maiming nor killing, it is how well it spreads and how illusive it is, even in those who believe they are 'immune' to new variants.

Another note to add is that people keep repeating this mantra - "Covid is only dangerous to high risk individuals". These individuals may not understand the aging process, but at some point or another everyone does become high risk. Keeping covid mainstream to our culture is not a clever way of flexing. In actuality, you do not become "high-risk" by reaching some milestone age point in your lifecycle. Previously unknown health complications can manifest as the body endures, and those risk factors do increase with covid infections - it actively does age individuals.

Look at trump and deathsentence florida man - both have aged 5 decades in only a 6 year period. They look like crap.

Given the few cases I am studying in my spare time, I anticipate a moderate surge in hospitalizations and an increase of infection.

last note - a negative covid test does not indicate a negative infection off covid. It can take two days for the specific antigens of a test kit to detect the antiquate levels of immunity cells essential to determining if covid is present. The recommended take is wear a mask when sick, and then test once more as you begin to recover. This has an accuracy rate of about 75-80%.

Stay safe. Wash your hands. Wear a fucking mask.

#covid #xbb 1.5 #variant #coronavirus #covid infection #vaccine #antigen #endothelial #epithelial #wear a fucking mask #all these kids showing up to the grand parents for holiday makes me think someone is due to a grand ol'inheritance

1 note · View note