Constitutional BRCA1 and MGMT Methylation Are Significant Risk Factors for Triple-Negative Breast Cancer and High-Grade Serous Ovarian Cancer in Saudi Women.

Breast cancer (BC) and ovarian cancer (OC) are rapidly increasing in Saudi Arabia. BRCA1 and MGMT epimutations have been linked to a higher risk of these malignancies. The present research investigated the impact of these epimutations on the prevalence of BC and OC among Saudi women. DNA methylation was evaluated using methylation-specific PCR, whereas mRNA expression levels were assessed using qRT-PCR. We evaluated white blood cell (WBC)-BRCA1 methylation in 1958 Saudi women (908 BC patients, 223 OC patients, and 827 controls). MGMT methylation was determined in 1534 of the 1958 women (700 BC patients, 223 OC patients, and 611 controls). BRCA1 methylation was detected in 8.6% of the controls and 11% of the BC patients. This epimutation was linked to 13.8% of the early-onset BC patients (p = 0.003) and 20% of the triple-negative breast cancer (TNBC) patients (p = 0.0001). BRCA1 methylation was also detected in 14% of the OC patients (p = 0.011), 19.4% of patients aged <55 years (p = 0.0007), and 23.4% of high-grade serous ovarian cancer (HGSOC) patients. In contrast, the BRCA1 mutation was detected in 24% of the OC patients, 27.4% of patients aged ≥55 years, and 26.7% of the HGSOC patients. However, MGMT methylation was detected in 10% of the controls and 17.4% of the BC patients (p = 0.0003). This epimutation was linked to 26.4% of the late-onset BC patients (p = 0.0001) and 11% of the TNBC patients. MGMT methylation was also found in 15.2% of the OC patients (p = 0.034) and 19.1% of HGSOC patients (p = 0.054). Furthermore, 36% of the BRCA1-methylated patients and 34.5% of the MGMT-methylated patients had a family history of cancer, including breast and ovarian cancer. Notably, BRCA1 and MGMT mRNA levels were greater in the WBC RNA of the BC patients and cancer-free methylation carriers than in that of the OC patients. Our data indicate that BRCA1 and MGMT epimutations significantly contribute to the development of breast cancer and ovarian cancer in Saudi cancer patients. These blood-based biomarkers could help identify female patients at high risk of developing TNBC and HGSOC at an early age.

An Unexpected Diagnosis of Second Primary Malignancy in a Breast Cancer Survivor: A Case Report.

BACKGROUND: Breast cancer survival rates are increasing more than ever with the development of better diagnostic and therapeutic techniques. Survivors of breast cancer have an increased risk of developing second primary malignancies, which may be mistaken for breast cancer recurrence and lead to delayed diagnosis and poor prognosis. CASE REPORT: We report a case of a 62-year-old female who presented with shortness of breath and bone pain. She had a history of left triple-positive invasive ductal carcinoma (T1N0M0) treated with bilateral skin-sparing mastectomy, adjuvant Taxotere, and trastuzumab-based therapy and then continued on trastuzumab and letrozole. She underwent imaging to explore the source of her symptoms at which new pulmonary nodules were discovered. During workup, she was found to have elevated tumor markers. They were initially suspected to be breast cancer recurrence metastases based on elevated tumor markers; however, further investigations confirmed that the nodules were a second primary lung adenocarcinoma with a different molecular profile. The patient had disease progression despite chemotherapy and eventually succumbed to her disease. CONCLUSION: This case highlights the importance of considering second primary malignancies in breast cancer survivors and utilizing advanced diagnostic modalities to efficiently diagnose such cases.

Consensus Recommendations for the Diagnosis, Biomarker Testing, and Clinical Management of Advanced or Metastatic Non-small Cell Lung Cancer With Mesenchymal-Epithelial Transition Exon 14 Skipping Mutations in the Middle East, Africa, and Russia.

Mesenchymal-epithelial transition exon 14 (METex14) skipping mutations occur in about 3%-4% of patients with non-small cell lung cancer (NSCLC). This is an aggressive subtype associated with poor prognosis. METex14 skipping is a potentially targetable mutation. Targeted therapy is a promising treatment modality for patients with advanced/metastatic METex14-mutant NSCLC. Performing systematic molecular testing to detect the driver mutation is essential for initiating targeted therapy. However, there is a lack of guidelines on molecular testing for assessing the eligibility of patients for targeted therapy. Therefore, a multidisciplinary panel consisting of experts from the Middle East, Africa, and Russia convened via a virtual advisory board meeting to provide their insights on various molecular testing techniques for the diagnosis of METex14 skipping mutation, management of patients with targeted therapies, and developing consensus recommendations for improving the processes. The expert panel emphasized performing molecular testing and liquid biopsy before treatment initiation and tissue re-biopsy for patients with failed molecular testing. Liquid biopsy was recommended as complementary to tissue biopsy for disease monitoring and prognosis. Selective MET inhibitors were recommended as the first and subsequent lines of therapy. These consensus recommendations will facilitate the management of METex14 skipping NSCLC in routine practice and warrant optimum outcomes for these patients.

Adult-Type Ovarian Granulosa Cell Tumour: Treatment Outcomes From a Single-Institution Experience.

OBJECTIVES:  Ovarian granulosa cell tumour is rare. This study aims to report the clinical characteristics and long-term outcomes of adult-type ovarian granulosa cell tumour (AOGCT) at King Faisal Specialist Hospital and Research Centre (KFSH&RC) and to determine the prognostic factors affecting relapse and survival. METHODS: We retrospectively reviewed patients with AOGCT, from 1988 to 2014, who were treated at our institution. Baseline characteristics, pathological findings, and outcomes were analysed and reported. RESULTS: Sixty-one patients with AOGCT were identified with a median age of 49 years. Median follow-up was 5.0 years (range 2.1-8.2 years). 74% of patients were FIGO (International Federation of Gynecology and Obstetrics) stage I, whereas 7% were stage II, 5% were stage III, and unknown in 14% of the cases. The most common presenting symptoms included abdominal pain (43%) and vaginal bleeding (43%). The majority of patients (38 patients, 62%) were treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy. Five (8%) patients received adjuvant chemotherapy. Sixteen patients (26%) relapsed with a median time to relapse of 5.5 years (0.7-8.1 years). Half of the recurrences (eight patients, 50%) occurred after five years of diagnosis. Five-year overall survival and disease-free survival (DFS) were 93% and 84%, respectively. Factors associated with a high risk of recurrence were the presence of ascites (p=0.000) and elevated preoperative CA 125 level (p=0.048). The overall survival was significantly influenced by the menopausal status (premenopausal 100% vs. postmenopausal 84%; p=0.02), preoperative CA 125 (normal 100% vs. elevated 64%; p=0.005), ascites (present 33% vs. absent 100%; p=0.000), and age (<55 years 100% vs. ≥ 55 years 77%; p= 0.002). CONCLUSION:  This study confirms a good outcome for patients with AOGCT. They require long-term follow-up as late recurrences can occur many years post definitive therapy. The presence of ascites and elevated preoperative CA 125 levels were associated with a higher risk of recurrence and poor prognosis. Outcomes appear unaffected by fertility-sparing surgery or adjuvant chemotherapy.

Lynch Syndrome Identification in Saudi Cohort of Endometrial Cancer Patients Screened by Universal Approach.

Lynch syndrome (LS) is the most common cause of inherited endometrial cancer (EC). The prevalence and molecular characteristic of LS in Middle Eastern women with EC have been underexplored. To evaluate the frequency of LS in a cohort of EC patients from Saudi Arabia, a total of 436 EC cases were screened utilizing immunohistochemistry (IHC), MLH1 promoter methylation analysis and next-generation sequencing technology. A total of 53 of 436 (12.2%) ECs were classified as DNA mismatch repair-deficient (dMMR). MLH1 promoter hypermethylation was detected in 30 ECs (6.9%). Three ECs (0.7%) were found to be LS harboring germline pathogenic variants (PVs)/likely pathogenic variants (LPVs): two in the MSH2 gene and one in the MSH6 gene. Three ECs (0.7%) were Lynch-like syndrome (LLS) carrying double somatic MSH2 PVs/LPVs. Seven cases were found to have variants of uncertain significance in cancer-related genes other than MMR genes. Our results indicate that LS prevalence is low among Saudi EC patients and LLS is as common as LS in this ethnicity. Our findings could help in better understanding of the prevalence and mutational spectrum of this syndrome in Saudi Arabia, which may help in defining best strategies for LS identification, prevention and genetic counseling for EC patients.

MicroRNA-126 expression in the peripheral white blood cells of patients with breast and ovarian cancer is a potential biomarker for the early prediction of cancer risk in the carriers of methylated BRCA1.

Constitutive breast cancer type 1 gene (BRCA1) promoter methylation is associated with increased cancer risk, but its role in cancer-free (CF) female carriers is incompletely understood. MicroRNA (miR) is modulated during early tumorigenesis. The present study assessed the modulation of miR-126 expression in the peripheral white blood cells (WBC) of patients with breast cancer (BC) and ovarian cancer (OC) as a biomarker of cancer risk in BRCA1 methylation carriers. A total of 1,114 female subjects [502 patients with BC, 187 patients with OC and 425 CF volunteers] were involved. Screening for BRCA1 promoter methylation in WBC was performed using the methylation-specific polymerase chain reaction (PCR) assay, BRCA1 mRNA was analyzed using a reverse transcription-quantitative PCR assay and miR-126 expression was analyzed using a stem-loop RT-qPCR assay. WBC BRCA1 promoter methylation status was significantly associated with OC (P=0.0266), early-onset BC (P=0.0003) and triple-negative BC (P=0.0066). Notably, 9.4% of the CF group exhibited WBC BRCA1 promoter methylation. In addition, high levels of miR-126 in WBCs were detected in all three groups. The increased level of miR-126 was significantly associated with a lower risk of distant metastasis (P=0.045) in BC, but a higher risk of disease progression and death (P=0.0029) in OC. There was a positive correlation between BRCA1 mRNA and miR-126 levels in the WBCs of all three groups, regardless of BRCA1 promoter methylation status. Notably, circulating miR-126 level was decreased in the BC and OC groups, but not in the CF group. Together, these results suggest the likely involvement of miR-126 in the constitutional methylation of BRCA1 promoter-related malignancies. Therefore, miR-126 may be a candidate biomarker for the early prediction of BC and OC risk in CF BRCA1 methylation carriers.

Assessing frequency and clinical outcomes of BRCA mutated ovarian cancer in Saudi women.

PURPOSE: BRCA gene mutations (BRCAm) have an impact on patients' characteristics and clinical outcomes of ovarian cancer (OC). The frequency and patterns of BRCAm vary among countries and ethnicities. There are limited data from Saudi Arabia (SA); thus, this study aims to determine the frequency, pattern, and impact on patient characteristics and outcomes of BRCAm OC compared to wild-type BRCA (BRCAw) in Saudi women. METHODS: This retrospective study evaluated women diagnosed with non-mucinous OC, fallopian tube, or peritoneal carcinoma who had BRCA status tested in an accredited lab between January 2016 and December 2017. The associations between various parameters and BRCAm were estimated using logistic regression. Statistical analysis performed with SPSS (Version 27). RESULT: Sixty-one women with a median age of 52 at diagnosis were analyzed. Germline BRCA mutations were found in 41% of cases (25/61). The most common deleterious germline BRCA1 mutation was c.1140dupG (39%). Most women (72%) had no family history of cancers and 82% had advanced stage. Regardless of BRCA mutations, an optimal overall response rate (ORR) to first-line treatment has been achieved although most cases relapsed (84%) and the majority were platinum-sensitive relapse (85%). Higher ORR to subsequent lines and better survival were obtained in women with BRCA-mutation. CONCLUSION: The prevalence of BRCAm of OC was higher in Saudi women compared to regional and most of the international figures. The better clinical outcomes of BRCAm women agreed with the reported evidence. Further studies on BRCA mutations of OC and genetic counseling are highly recommended. TRIAL REGISTRATION: Trial approved by the Institutional Review Board of King Faisal Specialist Hospital and Research Center (RAC # 2171137) and conducted at King Faisal Specialist Hospital and Research Center, PO Box 3354, Riyadh 11,211, Saudi Arabia.

Management guidelines for stage III non-small cell lung cancer.

Management of stage III non- small cell lung cancer (NSCLC) is very challenging due to being a group of widely heterogeneous diseases that require multidisciplinary approaches with timely and coordinated care. The standards of care had significant changes over the last couple of years because of the introduction of consolidation therapy with checkpoint inhibitor following concurrent chemo-radiotherapy and the evolving new role of tyrosine kinase inhibitors in the adjuvant setting. The manuscript presents evidence-based recommendations for the workup, staging, treatment and follow up of the various subtypes of stage III NSCLC. The guidelines were developed by experts in various fields of thoracic oncology and guidelines development. The guidelines consider the sequence of interventions and the role of each discipline in the management of the disease taking into account the recent development and included required resources to help physicians provide better care.

Genetic heterogeneity and evolutionary history of high-grade ovarian carcinoma and matched distant metastases.

BACKGROUND: High-grade serous ovarian carcinoma (HGSOC) is the most frequent type of ovarian carcinoma, associated with poor clinical outcome and metastatic disease. Although metastatic processes are becoming more understandable, the genomic landscape and metastatic progression in HGSOC has not been elucidated. METHODS: Multi-region whole-exome sequencing was performed on HGSOC primary tumours and their metastases (n = 33 tumour regions) from six patients. The resulting somatic variants were analysed to delineate tumour evolution and metastatic dissemination, and to compare the repertoire of events between primary HGSOC and metastasis. RESULTS: All cases presented branching evolution patterns in primary HGSOC, with three cases further showing parallel evolution in which different mutations on separate branches of a phylogenetic tree converge on the same gene. Furthermore, linear metastatic progression was observed in 67% of cases with late dissemination, in which the metastatic tumour mostly acquires the same mutational process active in primary tumour, and parallel metastatic progression, with early dissemination in the remaining 33.3% of cases. Metastatic-specific SNVs were further confirmed as late dissemination events. We also found the involvement of metastatic-specific driver events in the Wnt/ß-catenin pathway, and identified potential clinically actionable events in individual patients of the metastatic HGSOC cohort. CONCLUSIONS: This study provides deeper insights into clonal evolution and mutational processes that can pave the way to new therapeutic targets.

Patterns of diagnostic procedures for lung cancer pathology in the Middle East and North Africa.

BACKGROUND: Accurate pathological diagnosis is the first critical step in the management of lung cancer. This step is important to determine the histological subtype of the cancer and to identify any actionable targets. Our study aimed at evaluating the patterns of procedures used to obtain pathological diagnosis of lung cancer in the Middle East and North Africa (MENA) Region. METHODS: Data of consecutive patients with the diagnosis of non-small cell lung cancer (NSCLC) were collected from participating centers from different countries in the MENA Region. Methods of obtaining tissue diagnosis and workup were analyzed to determine the practice patterns of obtaining tissue diagnosis of lung cancer. RESULTS: A total of 566 patients were recruited from 10 centers in 5 countries including Saudi Arabia, United Arab Emirates (UAE), Qatar, Lebanon and Algeria. Majority of patients were males (78.1%) with a median age of 61 years (range, 22-89 years). Obtaining tissue diagnosis was successful in the first attempt in 72.3% of patients, while 16.4% and 6.3% of patients required 2nd and 3rd attempt, respectively. The success in first attempt was as follows: image guided biopsy (91%), surgical biopsy (88%), endobronchial biopsy (79%) and cytology (30%). The success in the second attempt was as follows; surgical biopsy (100%), image guided biopsy (95%), endobronchial biopsy (65%), cytology (25%). CONCLUSIONS: More than quarter of the patients required repeated biopsy in the MENA Region. Image guided biopsy has the highest initial yield. Implementing clear process and multidisciplinary guidelines about the selection of diagnostic procedures is needed.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for management of recurrent/relapsed ovarian granulosa cell tumor: a single-center experience.

AIM: The aim of this study was to retrospectively report our experience (efficacy/morbidity) with cytoreductive surgery+hyperthermic intraperitoneal chemotherapy (CRS+HIPEC) for the management of recurrent/relapsed ovarian granulosa cell tumors (OGCT). MATERIAL AND METHODS: From 2010 to 2013, six patients underwent CRS+HIPEC. CRS was performed with standard peritonectomy procedures and visceral resections directed towards complete elimination of tumors from the abdominopelvic cavity. HIPEC was performed with cisplatin (50 mg/m²) and doxorubicin (15 mg/m²) and allowed to circulate in the abdominopelvic cavity for 90 min at 41.0-42.2°C. RESULTS: Cytoreduction completeness (CC-0) was achieved in all except one patient (CC-1). Five patients had OGCT recurrences in abdomen+pelvis and one patient in abdomen only. No grade V morbidity (Clavien-Dindo classification) occurred. Two patients developed lung atelectasis, which was managed by mere chest physiotherapy (grade I). One patient developed urinary tract infection (grade II) and another patient developed pneumonia (grade II) - both of which were managed by antibiotics. One patient developed splenic bed and anterior abdominal wall collections requiring ultrasound-guided aspiration without general anesthesia (grade III). One patient developed pulmonary embolism requiring intensive care-unit management (grade IV). Four chemo-naïve patients received adjuvant chemotherapy whereas the remaining two previously chemo-exposed patients received no adjuvant therapy. All patients were alive and disease-free without proof of recurrence/relapse at 40, 32, 27, 24, 20 and 16 months. The average interval of follow-up after CRS+HIPEC was roughly 27 months (range: 16-40 months). CONCLUSION: CRS+HIPEC appears to be an efficacious and morbidly well-tolerated therapeutic modality for recurrent/relapsed OGCT. Long-term follow-up data and further research are needed.

Improved survival with combined chemo-radiotherapy in primary central nervous system lymphoma.

BACKGROUND: Primary CNS lymphoma (PCNSL) is an aggressive primary brain tumor. Cranial irradiation alone rarely results in long-term disease control or prolonged survival. We retrospectively analyzed data on the effect of adding high-dose methotrexate (HDMTX) prior to whole brain irradiation (WBI). METHODS: All patients with PCNSL diagnosed and managed during 1991-2004 were identified and demographic characteristics, prognostic factors, treatment and outcome were reviewed. Of 62 patients, 10 were excluded (4 had WBI<40 Gy and 6 had no treatment). Radiation alone was considered curative with a dose>40 Gy. Combined modality therapy included 3-4 cycles of HDMTX (3 g/m2) followed by WBI. RESULT: Of 52 patients analyzed for outcome, 36 had WBI (dose>40 Gy), 16 received 3-4 cycles of HDMTX followed by WBI (combined modality therapy [CMT]). Median age was 48.2 years; 42 years in the CMT group, 51 years in WBI. Patient characteristics were comparable between two groups except for higher multifocal tumor in the CMT group (92% vs. x22%, p=.029). Median follow up was 12.83±6.4 months. The hazard ratio for an event was 0.64 (95% CI, 0.52-0.98) and for death 0.58 (95% CI, 0.48-0.92), both in favor of CMT. Univariate regression analysis using one-way analyses of variance (ANOVA) and multivariate Cox regression analysis for prognostic factors including age (<60 vs. >60 years), ECOG PS (0-2 vs. 3-4), extent of surgery (biopsy vs. debulking), solitary vs multifocal tumor and dose of radiation therapy (<50 Gy vs. >50 Gy) failed to identify any prognostic factor. CONCLUSION: This retrospective comparison supports phase II trial results that indicate that high-dose methotrexate followed by WBI in PCNSL improves outcome.