Heidi J. Gray

Antibody Immunity to the p53 Oncogenic Protein Is a Prognostic Indicator in Ovarian Cancer

PURPOSE Presence of intratumoral T-cell infiltration has been linked to improved survival in ovarian cancer patients. We questioned whether antibody immunity specific for ovarian cancer tumor antigens would predict disease outcome. We evaluated humoral immune responses against ovarian cancer antigens p53, HER-2/neu, and topoisomerase IIalpha. PATIENTS AND METHODS Serum was collected from 104 women (median age, 59 years; range, 34 to 89 years) at the time of their initial definitive surgery for ovarian cancer. Serum was analyzed by enzyme-linked immunosorbent assay for antibodies to p53, HER-2/neu, and topoisomerase IIalpha proteins. Antibody immunity to tetanus toxoid was assessed as a control. The incidence of humoral immunity at the time of diagnosis to any of these three antigens was tabulated. For patients with advanced-stage disease (III/IV), correlation was made between the presence of tumor-specific immunity at the time of diagnosis and overall survival. Patients were followed for a median of 1.8 years. RESULTS Multivariate analysis showed the presence of p53 antibodies to be an independent variable for prediction of overall survival in advanced-stage patients. Overall survival was significantly higher for patients with antibodies to p53 when compared with patients without p53 antibodies (P = .01). The median survival for p53 antibody-positive patients was 51 months (95% CI, 23.5 to 60.5 months) compared with 24 months (95% CI, 19.4 to 28.6 months) for patients without antibodies to p53. CONCLUSION Data presented here demonstrate that advanced stage ovarian cancer patients can have detectable tumor-specific antibody immunity and that immunity to p53 may predict improved overall survival in patients with advanced-stage disease.

Intratumoral T cells, tumor-associated macrophages, and regulatory T cells: Association with p53 mutations, circulating tumor DNA and survival in women with ovarian cancer

OBJECTIVES Forty percent of women with ovarian cancer have circulating free tumor DNA. We sought to determine if the tumor immune infiltrate varied based on tumor p53 mutation status or presence of circulating tumor DNA. METHODS We performed immunohistochemistry on 119 ovarian cancer specimens with CD3 and CD8 (Intratumoral T cells (TILs)), CD68 (tumor-associated macrophages (TAMs)), and FoxP3 (T regulatory cells (Tregs)). Tumors had been previously sequenced for mutations in exons 4-10 of p53, and plasma from women characterized for free tumor DNA. RESULTS TIL and TAM levels were positively correlated (P<0.0001). High levels of TILs were identified in 54 of 119 tumors (45.4%). No survival difference was identified according to the presence of TILs or TAMs. Patients with greater TILs were more likely to be optimally cytoreduced (P=0.005). p53 mutations were associated with more TILs (P=0.008). The presence of circulating tumor DNA did not correlate with TILs, TAMs, or Tregs. In the subgroup with a low host antitumor immune response, the intermediate response Tregs group did have a survival advantage (P=0.049). CONCLUSIONS p53 mutations are associated with higher levels of TILs. The ratio of Tregs to TILS may be more important than absolute levels. A brisk T cell response within the tumor predicts adequacy of cytoreduction, suggesting successful cytoreduction may be partially due to underlying tumor biology and host response.

Lapatinib and potential prognostic value of EGFR mutations in a Gynecologic Oncology Group phase II trial of persistent or recurrent endometrial cancer

OBJECTIVE A phase II trial was performed to evaluate the efficacy and safety of the tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and HER2, lapatinib, and to explore EGFR, HER2 (EGFR2), phosphorylated ERK MAP kinase (pERK), and Ki67 expression, as well as EGFR mutations in persistent/recurrent endometrial cancer (EC). METHODS Women with histologically-confirmed, measurable, persistent/recurrent EC following one or two prior regimens were eligible and treated with 1500 mg oral lapatinib daily until progression or severe toxicity. A 2-stage group sequential design was used to evaluate the regimen with 6 month PFS as the primary endpoint. The trial had a 10% type I error rate with 90% power. EGFR, HER2, pERK, and Ki67 were evaluated by immunohistochemistry (IHC) from hysterectomy specimens, pre-treatment biopsies, and post-treatment biopsies (when available). Exons 18-21 of EGFR were sequenced. RESULTS Three patients of 30 evaluable had PFS ≥6 months, one had a partial response, seven had stable disease, 21 had progressive disease and one was indeterminate. Three mutations in EGFR were identified. Two of these, L688F and K754E, were not associated with response or PFS. However, a newly identified mutation in exon 18, E690K, occurred in the patient with a partial response and progression-free survival extending past six months. CONCLUSION While lapatinib has limited activity in unselected cases, the identification of a previously unreported mutation in EGFR (E690K) with a response suggests that lapatinib may be beneficial in some cases of EC.

Thirty-day mortality after primary cytoreductive surgery for advanced ovarian cancer in the elderly

OBJECTIVE: To identify factors associated with increased 30-day mortality after advanced ovarian cancer debulking among elderly women. METHODS: A database linking Medicare records with the Surveillance, Epidemiology, and End Results (SEER) data was used to identify a cohort of 5,475 women aged 65 and older who had primary debulking surgery for stage III or IV epithelial ovarian cancer (diagnosed 1995–2005). Women were stratified by acuity of hospital admission. Multivariable analysis was performed to identify patient-related and treatment-related variables associated with 30-day mortality. RESULTS: Five thousand four hundred seventy-five women had surgery for advanced ovarian cancer, and the overall 30-day mortality was 8.2%. Women admitted electively had a 30-day mortality of 5.6% (251 of 4,517), and those admitted emergently had a 30-day mortality of 20.1% (168 of 835). Advancing age, increasing stage, and increasing comorbidity score were all associated with an increase in 30-day mortality (all P<.05) among elective admissions. A group of women at high risk admitted electively included those aged 75 or older with stage IV disease and women aged 75 or older with stage III disease and a comorbidity score of 1 or more. This group had an observed 30-day mortality of 12.7% (95% confidence interval 10.7%–14.9%). CONCLUSION: Age, cancer stage, and comorbidity scores may be helpful to stratify electively admitted patients based on predicted postoperative mortality. If validated in a prospective cohort, then these factors may help identify women who may benefit from alternative treatment strategies. LEVEL OF EVIDENCE: II

Combined Weekly Topotecan and Biweekly Bevacizumab in Women With Platinum- Resistant Ovarian, Peritoneal, or Fallopian Tube Cancer

A phase 2 trial was conducted to determine the toxicity and efficacy of combined weekly topotecan and biweekly bevacizumab in patients with primary or secondary platinum‐resistant ovarian, peritoneal, or fallopian tube cancer (OC).

Trends in treatment of advanced epithelial ovarian cancer in the Medicare population

OBJECTIVE Optimal care for most patients with advanced ovarian cancer generally includes both surgery and chemotherapy. Little is known about the proportion of women in the US who receive combination care or the sequence in which this care is delivered. This study evaluated patterns of care, frequency of completion of recommended therapy and factors associated with sequencing of therapy. METHODS Using the Surveillance, Epidemiology and End-Results data we identified a cohort of 8211 women aged 65 and above with stage III/IV epithelial ovarian cancer diagnosed between 1995 and 2005. Receipt of chemotherapy or surgery was identified using Medicare claims. Logistic regression was used to evaluate factors associated with sequencing of treatment and the receipt of surgery. RESULTS 3241 (39.1%) had surgery and at least 6 cycles of chemotherapy in either order. Surgery was performed initially in 4827 (58.8%) women and 3658/4827 (75.8%) had subsequent chemotherapy. 2017 (24.6%) had primary chemotherapy and 649/2017 (32.2%) of these women had subsequent surgery. Advanced age, African American race, stage IV disease, non-married status and increasing medical comorbidity were all associated with the failure to receive both surgery and at least 6 cycles of chemotherapy (all p<0.01). CONCLUSIONS The majority of women with advanced ovarian cancer in the Medicare population do not receive both combination therapy with surgery and at least 6 cycles of chemotherapy. A large proportion of women are receiving chemotherapy as primary treatment for advanced ovarian cancer, and the majority of these patients do not have cancer-directed surgery.

Common polymorphisms in TP53 and MDM2 and the relationship to TP53 mutations and clinical outcomes in women with ovarian and peritoneal carcinomas.

The importance of somatic TP53 mutations and germline TP53 codon 72 genotype in the survival of women with epithelial ovarian cancer is controversial. Recent data suggest that a promoter polymorphism in the MDM2 gene may influence age of cancer onset in a gender‐specific fashion. We sought to determine the relationship between somatic TP53 mutations, germline genotypes at TP53 codon 72 and MDM2 SNP309, and overall survival and response to chemotherapy in a large series of patients with ovarian and peritoneal carcinomas. Of the 188 cancers, 103 (54.8%) had a TP53 mutation, of which 71% were missense mutations and 29% were null mutations. TP53 mutation status and mutation type (null vs. missense) did not influence response to therapy or overall survival. Women with the codon 72 Pro/Pro had a decreased overall survival (median, 29 months) compared with women with one or two arginine alleles (median, 49 months; P = 0.04). Somatic mutation or deletion was equally common for either codon 72 allele. Age of diagnosis was not influenced by codon 72 but showed a trend for younger age in women with somatic TP53 mutations and the MDM2 G/G genotype.

Ovarian cancer in the elderly: Outcomes with neoadjuvant chemotherapy or primary cytoreduction

BACKGROUND Recent studies have suggested inferior outcomes for elderly women with ovarian cancer. Our goal was to evaluate neoadjuvant chemotherapy versus primary cytoreduction in elderly women. METHODS A retrospective chart review was performed for women aged 65+ diagnosed with ovarian cancer at our institution between 1997 and 2007. Univariate and multivariate logistic regression models were used to evaluate complication rates. Survival was evaluated with Cox regression and the Kaplan-Meier method. RESULTS One hundred seventy-five patients were identified, 34 (19%) of whom were aged 80+. Those aged 65-79 and those 80+ received neoadjuvant chemotherapy with equal frequency (19% vs. 21%, p=0.92). Treatment with neoadjuvant chemotherapy was associated with odds ratios of 0.80 (95% CI 0.37-1.75) for surgical complications and 0.79 (95% CI 0.33-1.90) for chemotherapeutic complications. In those aged 80+, the frequency of surgical complications (OR 1.01, p=0.62) and chemotherapeutic complications (OR 1.04, p=0.78) did not differ compared to younger patients. Overall survival did not differ based on initial treatment regimen, with 34 months in the primary surgery group and 29 months in the neoadjuvant chemotherapy group (p=0.65). The median disease specific survival for those aged 65-79 was 35 months, and 24 months in those aged 80+ (p=0.15). Post-operative mortality for patients aged 80+ was zero. CONCLUSIONS In our patient population, those aged 80+ have similar surgical and chemotherapy-related complication rates and comparable survival to those aged 65-79. The choice of initial treatment modality does not appear to impact survival when the decision is made in a selective fashion.

Pelvic exenteration in the age of modern chemoradiation.

BACKGROUND To examine outcomes after pelvic exenteration in women treated with modern chemoradiation and surgical techniques. METHODS All patients at our institution with a diagnosis of gynecologic malignancy who underwent pelvic exenteration after treatment with chemoradiation between 1/90 and 6/08 were evaluated with a retrospective chart review. RESULTS 44 women were identified, of whom 29 (66%) had cervical, 6 (14%) had uterine, 5 (11%) had vaginal, and 4 (9%) had vulvar cancer. The majority of patients (82%) were initially treated with external beam whole-pelvic radiation with concurrent cisplatin. 38 patients (86%) underwent exenteration for a central pelvic recurrence, and the remaining 6 patients (14%) for radiation necrosis. The most common surgical complication was transfusion requirement in 36 patients (82%), followed by wound infection in 15 (34%), small bowel obstruction in 8 (18%), and sepsis in 6 (14%). The median time spent in the ICU post-operatively was 2 days. One patient (2%) died during her post-operative hospital stay. The mean EBL overall was 2497 cc and the mean operative time was 544 min. Use of electrothermal bipolar coagulation, which was used in 64% of the exenterations, significantly reduced blood loss (3679 cc vs. 1836 cc, p=0.014). After exenteration, 21 patients (48%) were diagnosed with a recurrence of cancer, and the mean progression free survival was 31 months. Patients who received exenteration less than 2 years after their initial chemoradiation had a significantly shorter overall survival time (8 months vs. 33 months, p=0.016). CONCLUSIONS Approximately 50% of women develop recurrence following exenterations done after chemoradiation. Survival is significantly longer in patients who necessitate exenteration greater than 2 years out from initial treatment. Electrothermal bipolar coagulation appears to significantly reduce blood loss during these surgeries.

Neoadjuvant Chemotherapy in the Medicare Cohort with Advanced Ovarian Cancer

OBJECTIVE The value of neoadjuvant chemotherapy (NAC) for the treatment of advanced ovarian cancer has yet to be determined. While NAC may facilitate and simplify complete cytoreduction and reduce the risk of surgery, the delay of surgery related to NAC needs to be balanced against any potential benefit. METHODS Surveillance, Epidemiology and End-Results (SEER) data linked to Medicare claims were used to identify 6844 women with treated stage III/IV epithelial ovarian cancer (1995-2005). Patients were classified by primary treatment (surgery (PDS) or chemotherapy), and the primary chemotherapy group was characterized as having NAC or palliative chemotherapy (PC) based on whether there was documentation that surgery was recommended. We compared surgical complications and survival between the groups. RESULTS 4827 (71%) of women were treated with PDS, 958 received NAC (14%) and 1059 (15%) had PC. Only 577 (60%) of women with NAC underwent surgery and they had fewer ostomies (8.5% vs. 19.2%, p<0.001) and fewer infections, gastrointestinal and pulmonary complications than PDS (all p<0.01). Comparing NAC to PDS there was a 16% increase in the risk of death at 2years (RR 1.16, 95%CI 1.01-1.34) for women with stage III disease and a 15% reduction in the risk for women with stage IV disease (RR 0.85, 95%CI 0.73-0.99). CONCLUSIONS NAC followed by surgery was associated with fewer surgical complications than PDS. The direction and magnitude of the difference in survival between women receiving NAC and those receiving PDS differed according to the stage of disease and follow up time.