Therapeutic applications of germline testing for cancer predisposition genes in Asia in the real world.

BACKGROUND: Germline genetic testing is traditionally carried out in patients suspected with hereditary cancer syndrome for enhanced cancer surveillance and/or preventive strategies, but is increasingly carried out for therapeutic indications. MATERIALS AND METHODS: We conducted a retrospective review of patients who underwent germline genetic testing at our centre to determine the prevalence of actionable pathogenic germline variants (PGV) and their clinical utility. RESULTS: From 2000 to 2022, 1154 cancer patients underwent germline testing, with the majority (945/1154) tested with multi-gene panels. Four hundred and eleven (35.6%) patients harboured a PGV and 334 (81%) were clinically actionable. BRCA1/2 accounted for 62.3% of actionable mutations, followed by mismatch repair (18%), and other homologous recombination repair (HRR) genes (19.7%). One hundred and fifty-two germline-positive patients have advanced cancers, and 79 received germline-directed therapies (poly ADP ribose polymerase inhibitors = 75; immunotherapy = 4). Median duration of immunotherapy and poly ADP ribose polymerase were 20.5 months (range 5-40 months) and 8 months (range 1-76 months), respectively. Among BRCA/HRR mutation carriers who received platinum-based chemotherapy, pathological complete response rate in the neoadjuvant setting was 53% (n = 17 breast cancers) and objective response rate was >80% in the advanced setting (n = 71). CONCLUSIONS: One-third of cancer patients tested carried a PGV and ∼80% were clinically actionable. Three-quarters of germline-positive advanced cancer patients received germline-directed therapies in the real world, underscoring the practical utility of germline testing to guide cancer therapeutics.

An EMT spectrum defines an anoikis-resistant and spheroidogenic intermediate mesenchymal state that is sensitive to e-cadherin restoration by a src-kinase inhibitor, saracatinib (AZD0530).

The phenotypic transformation of well-differentiated epithelial carcinoma into a mesenchymal-like state provides cancer cells with the ability to disseminate locally and to metastasise. Different degrees of epithelial-mesenchymal transition (EMT) have been found to occur in carcinomas from breast, colon and ovarian carcinoma (OC), among others. Numerous studies have focused on bona fide epithelial and mesenchymal states but rarely on intermediate states. In this study, we describe a model system for appraising the spectrum of EMT using 43 well-characterised OC cell lines. Phenotypic EMT characterisation reveals four subgroups: Epithelial, Intermediate E, Intermediate M and Mesenchymal, which represent different epithelial-mesenchymal compositions along the EMT spectrum. In cell-based EMT-related functional studies, OC cells harbouring an Intermediate M phenotype are characterised by high N-cadherin and ZEB1 expression and low E-cadherin and ERBB3/HER3 expression and are more anoikis-resistant and spheroidogenic. A specific Src-kinase inhibitor, Saracatinib (AZD0530), restores E-cadherin expression in Intermediate M cells in in vitro and in vivo models and abrogates spheroidogenesis. We show how a 33-gene EMT Signature can sub-classify an OC cohort into four EMT States correlating with progression-free survival (PFS). We conclude that the characterisation of intermediate EMT states provides a new approach to better define EMT. The concept of the EMT Spectrum allows the utilisation of EMT genes as predictive markers and the design and application of therapeutic targets for reversing EMT in a selective subgroup of patients.

Ovarian tumors of borderline malignancy: a review of 247 patients from 1991 to 2004.

Borderline ovarian tumors account for 15% of epithelial ovarian cancers and are different from invasive malignant carcinoma. Majority are early stage, occurring in women in the reproductive age group, where fertility is important. We reviewed retrospectively 247 such cases treated at the Gynaecological-Oncology Unit, KK Women's and Children's Hospital, between January 1991 and December 2004. The mean age was 38 years (16-89 years). Majority of the cases (92%) were FIGO stage I (Ia, 75%; Ib, 1%; and Ic, 16%). Seven (3.5%) patients were diagnosed as having stage II disease, six (2.5%) as stage IIIa, two (1%) as stage IIIb, and four (2%) as stage IIIc. Histological origin was as follows: mucinous (68%), serous (26%), endometrioid (2.6%), and clear cell (1.2%). Primary surgical procedures undertaken were as follows: hysterectomy with bilateral salpingo-oophorectomy (52%), unilateral salpingo-oophorectomy (33%), or ovarian cystectomy (15%). Adjuvant chemotherapy was administered in 13 patients (5.2% of cases), of which 4 patients were given chemotherapy only because of synchronous malignancies. There were six recurrences (2.4% of cases). Overall mean time to recurrence was 59 months. Recurrence rate for patients who underwent a primary pelvic clearance was 1.6% compared to fertility-sparing conservative surgery (3.3%; although P= 0.683). No significant difference was noted in recurrence and mortality between staged versus unstaged procedures. The overall survival rate was 98.0%. There were a total of five deaths (2.8%): three (1.5%) from invasive ovarian/peritoneal carcinoma and two from synchronous uterine malignancies. It appears that surgical resection is the mainstay of treatment, with conservative surgery where fertility is desired or pelvic clearance if the family is complete. Surgical staging is important to identify invasive extraovarian implants that portend an adverse prognosis. The role of adjuvant chemotherapy is not established.

A rare case of metastatic ovarian carcinoma originating from primary intrahepatic cholangiocarcinoma. Case report.

BACKGROUND: A rare case of metastatic ovarian carcinoma arising from intrahepatic cholangiocarcinoma is reported and the literature reviewed. CASE: A 49-year-old woman presented with ascites and a left pelvic mass. Optimal debulking surgery was carried out including a segmental resection of segment 5/6 of the liver. Histopathology confirmed an intrahepatic cholangiocarcinoma metastatic to the ovaries and omentum. CONCLUSION: Distinguishing a metastatic tumor from a primary ovarian tumoris critical for appropriate management. A high index of suspicion intraoperatively and subsequent expert pathological review are essential in making the correct diagnosis.

Malignant ovarian germ cell tumors: the KK Hospital experience.

Ovarian germ cell malignancies pose a therapeutic challenge especially amongst young patients. This is a retrospective review of 49 patients treated for such malignancies at KK Women's and Children's Hospital over a 13-year period. The relative proportion of such tumors was 6.2%. Age at presentation ranged from 14 to 51 years (mean 25.4 years). Forty-nine percent of tumors were immature teratomas and 81.6% had stage I disease. All patients had surgery initially and 67.3% required postoperative adjuvant chemotherapy. The patients were followed-up for one to 145 months (mean 51.6 months). All the 87.8% of patients on follow-up are alive and disease-free. There was one recurrence. Five patients had eight successful pregnancies, with no congenital anomalies. Mean duration when menstruation was resumed and regular was 2.5 and 3.5 months, respectively. With combination chemotherapy and conservative surgery, the outlook for patients is excellent, with emphasis on preservation of ovarian function and fertility.