Marcus Q. Bernardini

Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study

BACKGROUND Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated with subtype-specific survival. METHODS 12 studies participating in the Ovarian Tumor Tissue Analysis consortium contributed tissue microarray sections and clinical data to our study. Participants included in our analysis had been diagnosed with invasive serous, mucinous, endometrioid, or clear-cell carcinomas of the ovary. For a patient to be eligible, tissue microarrays, clinical follow-up data, age at diagnosis, and tumour grade and stage had to be available. Clinical data were obtained from medical records, cancer registries, death certificates, pathology reports, and review of histological slides. PR and ER statuses were assessed by central immunohistochemistry analysis done by masked pathologists. PR and ER staining was defined as negative (<1% tumour cell nuclei), weak (1 to <50%), or strong (≥50%). Associations with disease-specific survival were assessed. FINDINGS 2933 women with invasive epithelial ovarian cancer were included: 1742 with high-grade serous carcinoma, 110 with low-grade serous carcinoma, 207 with mucinous carcinoma, 484 with endometrioid carcinoma, and 390 with clear-cell carcinoma. PR expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001) and high-grade serous carcinoma (log-rank p=0·0006), and ER expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001). We recorded no significant associations for mucinous, clear-cell, or low-grade serous carcinoma. Positive hormone-receptor expression (weak or strong staining for PR or ER, or both) was associated with significantly improved disease-specific survival in endometrioid carcinoma compared with negative hormone-receptor expression, independent of study site, age, stage, and grade (hazard ratio 0·33, 95% CI 0·21-0·51; p<0·0001). Strong PR expression was independently associated with improved disease-specific survival in high-grade serous carcinoma (0·71, 0·55-0·91; p=0·0080), but weak PR expression was not (1·02, 0·89-1·18; p=0·74). INTERPRETATION PR and ER are prognostic biomarkers for endometrioid and high-grade serous ovarian cancers. Clinical trials, stratified by subtype and biomarker status, are needed to establish whether hormone-receptor status predicts response to endocrine treatment, and whether it could guide personalised treatment for ovarian cancer. FUNDING Carraresi Foundation and others.

Pregnancy outcomes in patients after radical trachelectomy.

OBJECTIVES This study was undertaken to review and analyze the fertility and pregnancy outcomes in patients who have undergone radical trachelectomy as the method of management of invasive carcinoma of the cervix. STUDY DESIGN All preoperative, operative, and follow-up data were collected prospectively. Perinatal information was completed by chart reviews and patient questionnaires. RESULTS Of 80 patients having undergone the above procedure, 39 have attempted to conceive for a median of 11 months (range 1-85). There have been a total of 22 pregnancies in 18 patients (4 patients pregnant twice). Of the 22 pregnancies, 18 were viable, with 12 progressing to term and delivering by caesarean section. Preterm premature rupture of membranes was the primary cause of preterm delivery. CONCLUSION This series confirms that pregnancy is a safe and realistic outcome for women undergoing radical trachelectomy for invasive carcinoma of the cervix. Given the apparently high incidence of preterm premature rupture of membranes, these pregnancies should be managed as high risk.

Phenotypic heterogeneity and instability of human ovarian tumor-initiating cells

The cancer stem cell (CSC) model proposes that tumors have a hierarchical organization in which only some cells indefinitely self-renew and thereby sustain tumor growth. In addition, the CSC model requires that tumor-initiating cells (TICs) be prospectively isolatable on the basis of their phenotype. Previous studies have suggested that serous ovarian cancer (SOC) conforms to the CSC model, but these used arguably nonfidelitous immortalized cell lines, cultured primary cells, or passaged xenografts as the source of tumor cells. We developed a robust assay for quantifying TICs from primary SOC. Using this assay, we find that TICs are rare when assayed in either NOD/SCID or NOD/SCID/IL2Rγ−/− (NSG) mice. TIC frequency (TICf) varies substantially between patients, although it is similar in primary ovarian masses and omental metastases, suggesting that TICf is an intrinsic property of ovarian tumors. CD133 marks all TICs from several primary SOC cases. However, in other cases, substantial TIC activity is found in both the CD133+ and CD133− fractions, whereas still other cases have exclusively CD133− TICs. Furthermore, the TIC phenotype can change in xenografts: primary tumors in which all TICs are CD133+ can give rise to xenografts that contain substantial numbers of CD133− TICs. Our results highlight the need for quantitative rigor in the evaluation of TICs and for caution when using passaged xenografts for such studies. Furthermore, although our data suggest that SOC conforms to the CSC hypothesis, the heterogeneity of the TIC phenotype may complicate its clinical application.

Adenomyosis is associated with myometrial invasion by FIGO 1 endometrial adenocarcinoma

Summary: Adenomyosis is commonly seen in hysterectomy specimens for endometrial adenocarcinoma where it could be involved with the tumor. When adenocarcinoma involves adenomyosis, the tumor may remain limited to the adenomyosis or proceeds to invade the adjacent myometrium. The purpose of this study was to investigate whether the risk of myometrial invasion by grade 1 endometrioid adenocarcinoma in cases with cancer-positive adenomyosis is different from that of cases where cancer occurs in the absence of adenomyosis. Forty-six consecutive hysterectomy specimens with International Federation of Gynecology and Obstetrics (FIGO) grade 1 endometrial endometrioid adenocarcinoma involving adenomyosis and 49 consecutive specimens with the same tumor occurring in the absence of adenomyosis were retrospectively studied by 4 experienced gynecologic pathologists. In cases with adenomyosis, myometrial invasion was confirmed by CD10-negative staining around glands with irregular outline surrounded by inflamed desmoplastic stroma. Myometrial invasion was found in significantly more adenomyosis cases (n = 42, 91.3%) than in cases without adenomyosis (n = 38, 77.5%) (&khgr;2 = 4.79, P = 0.03). In 16 cases of the former group, the invasion only occurred from the foci of adenomyosis. Although myometrial invasion in the outer half was more common in the adenomyosis group (n = 16, 34.8%) than in cases without adenomyosis (n = 9, 18.4%), the difference was not statistically significant (&khgr;2 = 3.29, P = 0.07). By involving coexistent adenomyosis, FIGO grade 1 endometrial endometrioid adenocarcinoma is associated with myometrial invasion, probably through increasing the surface area of its interface with the adjacent myometrium. When compared with their counterparts that occur in the absence of adenomyosis, these tumors are significantly more likely to invade the myometrium.

ARID1A loss correlates with mismatch repair deficiency and intact p53 expression in high-grade endometrial carcinomas

BAF250a (ARID1A) loss is a frequent event in high-grade endometrial cancers. It has been proposed that ARID1A is a driver gene, with ARID1A mutations occurring secondary to deregulated mismatch repair mechanism in gastric cancers, representing an alternative oncogenic pathway to p53 alteration. The prognostic significance of ARID1A loss is controversial. In this study, we investigated the frequency of BAF250a immunohistochemical loss in a cohort of high-grade endometrial cancers (n=190) and correlated it with mismatch repair (hMLH1, hMSH2, hMSH6, and hPMS2) and p53 protein expression. The 190 cases consisted of 82 high-grade endometrioid, 88 serous, 10 clear cell, and 10 mixed (carcinosarcomas and mixed histology). There was BAF250a loss in 55/190 (29%) cancers, most commonly in high-grade endometrioid carcinomas (46 vs 9% in serous carcinomas, P<0.0001). Loss of any mismatch repair proteins was observed in 63/190 (33%) cancers, most commonly in high-grade endometrioid carcinomas (57 vs 10% in serous carcinomas, P<0.0001). Aberrant p53 expression was found in 86/190 (45%) cancers, more commonly in serous carcinomas (77 vs 18% in high-grade endometrioid carcinomas, P<0.0001). BAF250a loss was associated with mismatch repair loss (P<0.0001) and normal p53 expression (P<0.0001). These associations were maintained in the subset analysis within the high-grade endometrioid (P=0.026 and P=0.0083, respectively) and serous carcinoma cases (P=0.0031 and P<0.0001, respectively). Survival analysis revealed a superior progression-free survival (P=0.017) for patients with BAF250a loss within the entire cohort but not within the high-grade endometrioid and serous subtypes. Additionally, data from The Cancer Genome Atlas were extracted to correlate mutations in ARID1A, TP53, and MMR genes; we found that ARID1A mutations were negatively associated with TP53 mutations but were unrelated to mismatch repair gene mutations. In conclusion, BAF250a loss is more common in high-grade endometrioid carcinomas than in other high-grade endometrial cancers and is associated with mismatch repair deficiency and normal p53 expression.

The impacts of neoadjuvant chemotherapy and of debulking surgery on survival from advanced ovarian cancer

OBJECTIVES Women with advanced ovarian cancer are treated with chemotherapy either before (neoadjuvant) or after surgery (primary debulking). The goal is to leave no residual disease post-surgery; for women treated with primary debulking surgery this has been associated with an improvement in survival. It has not been shown that the survival advantage conferred by having no residual disease post-surgery is present for women who receive neoadjuvant chemotherapy. METHODS We reviewed the records of 326 women with stage IIIc or IV serous ovarian cancer. We determined if they received neoadjuvant chemotherapy or primary debulking surgery and we measured the extent of residual disease post-surgery. We estimated seven-year survival rates for women after various treatments. RESULTS Women who had neoadjuvant chemotherapy were more likely to have no residual disease than women who had primary debulking surgery (50.1% versus 41.5%; p=0.03) but they experienced inferior seven-year survival (8.6% versus 41%; p<0.0001). Among women who had primary debulking surgery, those with no residual disease had much better seven-year survival than women who had any residual disease (73.6% versus 21.0%; p<0.0001). Women who had no residual disease after debulking surgery and who received intraperitoneal chemotherapy had a seven-year survival of 90%. CONCLUSIONS Neoadjuvant chemotherapy should be reserved for ovarian cancer patients who are not candidates for primary debulking surgery. Among women with no residual disease after primary debulking surgery, intraperitoneal chemotherapy extends survival.

Kinesin family member 14: An independent prognostic marker and potential therapeutic target for ovarian cancer

The novel oncogene KIF14 (kinesin family member 14) shows genomic gain and overexpression in many cancers including OvCa (ovarian cancer). We discovered that expression of the mitotic kinesin KIF14 is predictive of poor outcome in breast and lung cancers. We now determine the prognostic significance of KIF14 expression in primary OvCa tumors, and evaluate KIF14 action on OvCa cell tumorigenicity in vitro. Gene‐specific multiplex PCR and real‐time QPCR were used to measure KIF14 genomic (109 samples) and mRNA levels (122 samples) in OvCa tumors. Association of KIF14 with clinical variables was studied using Kaplan–Meier survival and Cox regression analyses. Cellular effects of KIF14 overexpression (stable transfection) and inhibition (stable shRNA knockdown) were studied by proliferation (cell counts), survival (Annexin V immunocytochemistry) and colony formation (soft‐agar growth). KIF14 genomic gain (>2.6 copies) was present in 30% of serous OvCas, and KIF14 mRNA was elevated in 91% of tumors versus normal epithelium. High KIF14 in tumors independently predicted for worse outcome (p = 0.03) with loss of correlation with proliferation marker expression and increased rates of recurrence. Overexpression of KIF14 in OvCa cell lines increased proliferation and colony formation (p < 0.01), whereas KIF14 knockdown induced apoptosis and dramatically reduced colony formation (p < 0.05). Our findings indicate that KIF14 mRNA is an independent prognostic marker in serous OvCa. Dependence of OvCa cells on KIF14 for maintenance of in vitro colony formation suggests a role of KIF14 in promoting a tumorigenic phenotype, beyond its known role in proliferation.

Surgical outcome of robotic surgery in morbidly obese patient with endometrial cancer compared to laparotomy.

Introduction Before the introduction of robotic surgery at our institution, most obese women of class 2 or greater (body mass index [BMI] >35) underwent a laparotomy for the management of endometrial cancer. Since November 2008, we have performed most of these cases in a robotic fashion. This manuscript presents the outcome of these women in comparison with a historical cohort of women treated with laparotomy. Methods Women with clinical stage I or II endometrial cancer and a BMI greater than 35 kg/m2 treated with robotic surgery at our institution between November 2008 and November 2010 were compared with a historical cohort of similar patients who underwent laparotomy. Patients’ characteristics, operating room time, type of surgery, length of hospital stay, and incidence of perioperative complications were compared between the 2 groups. Results A total of 86 women were analyzed in this study (robotic surgery, 45; laparotomy, 41). The overall intraoperative complication rate is 5.8%. There is no statistical difference in age, number of comorbidities, BMI, prior abdominal surgery, and operative complications between the women who underwent robotic surgery versus laparotomy. Postoperative complication rates are higher in the laparotomy group (44% vs 17.7%; P = 0.007), and hospital length of stay is also higher in the laparotomy group (4 vs 2 days; P < 0.001). There is no difference in rates of (pelvic) lymph node dissection; however, para-aortic node dissection is more common in the robotic surgery group. Conclusion Robotic surgery for the surgical management of the morbidly obese patient is shown to be safe and have less perioperative complications compared with open surgery.

Performance characteristics of screening strategies for Lynch syndrome in unselected women with newly diagnosed endometrial cancer who have undergone universal germline mutation testing

Immunohistochemistry (IHC) for mismatch repair protein expression, microsatellite instability (MSI) testing, tumor morphology, and family history were compared to determine which screening strategy is superior in identifying Lynch syndrome (LS) in unselected women with newly diagnosed endometrial cancer (EC) who have undergone universal germline mutation testing.

The role of lymphadenectomy in the management of preoperative grade 1 endometrial carcinoma

OBJECTIVE We sought to assess the accuracy of a preoperative grade 1 designation and role of lymphadenectomy in women with preoperative grade 1 endometrial cancer. METHODS A retrospective analysis of patients diagnosed with preoperative grade 1 endometrial cancer from 1970 to 2006 was conducted. Inclusion criteria were preoperative grade 1 disease and hysterectomy with or without surgical staging. RESULTS 581 patients who underwent surgery for preoperative grade 1 cancer were identified. Lymphadenectomy was performed in 46%. Pelvic and aortic node metastases were identified in 5.4% and 3.2% patients who underwent lymphadenectomy. 9.7% were upgraded intraoperatively and 25% were upgraded on final pathology with 22% having grade 2 and 3% grade 3 disease. 22.5% with grade 1 disease intraoperatively were upgraded on final pathology, with 21.1% having grade 2 and 1.4% grade 3 disease. 9% had advanced stage disease. 20% of patients with disease limited to the uterus had adverse features including high risk histologic variants, grade 3 disease, myometrial invasion >1/2, and/or cervical involvement. After adjusting for risk factors there was no significant difference in OS (HR 1.00, p=0.992) or PFS (HR 0.96, p=0.815) between the patients who did or did not undergo surgical staging. CONCLUSION A substantial number of patients with grade 1 endometrial cancer based on preoperative and intraoperative assessments have higher grade disease on final pathology. Although lymphadenectomy does not affect survival in this group it may identify patients with advanced disease and assist in tailoring adjuvant therapy for those with adverse risk factors.