Brittany Anne Davidson

Benefits and Harms of Breast Cancer Screening A Systematic Review

IMPORTANCE Patients need to consider both benefits and harms of breast cancer screening. OBJECTIVE To systematically synthesize available evidence on the association of mammographic screening and clinical breast examination (CBE) at different ages and intervals with breast cancer mortality, overdiagnosis, false-positive biopsy findings, life expectancy, and quality-adjusted life expectancy. EVIDENCE REVIEW We searched PubMed (to March 6, 2014), CINAHL (to September 10, 2013), and PsycINFO (to September 10, 2013) for systematic reviews, randomized clinical trials (RCTs) (with no limit to publication date), and observational and modeling studies published after January 1, 2000, as well as systematic reviews of all study designs. Included studies (7 reviews, 10 RCTs, 72 observational, 1 modeling) provided evidence on the association between screening with mammography, CBE, or both and prespecified critical outcomes among women at average risk of breast cancer (no known genetic susceptibility, family history, previous breast neoplasia, or chest irradiation). We used summary estimates from existing reviews, supplemented by qualitative synthesis of studies not included in those reviews. FINDINGS Across all ages of women at average risk, pooled estimates of association between mammography screening and mortality reduction after 13 years of follow-up were similar for 3 meta-analyses of clinical trials (UK Independent Panel: relative risk [RR], 0.80 [95% CI, 0.73-0.89]; Canadian Task Force: RR, 0.82 [95% CI, 0.74-0.94]; Cochrane: RR, 0.81 [95% CI, 0.74-0.87]); were greater in a meta-analysis of cohort studies (RR, 0.75 [95% CI, 0.69 to 0.81]); and were comparable in a modeling study (CISNET; median RR equivalent among 7 models, 0.85 [range, 0.77-0.93]). Uncertainty remains about the magnitude of associated mortality reduction in the entire US population, among women 40 to 49 years, and with annual screening compared with biennial screening. There is uncertainty about the magnitude of overdiagnosis associated with different screening strategies, attributable in part to lack of consensus on methods of estimation and the importance of ductal carcinoma in situ in overdiagnosis. For women with a first mammography screening at age 40 years, estimated 10-year cumulative risk of a false-positive biopsy result was higher (7.0% [95% CI, 6.1%-7.8%]) for annual compared with biennial (4.8% [95% CI, 4.4%-5.2%]) screening. Although 10-year probabilities of false-positive biopsy results were similar for women beginning screening at age 50 years, indirect estimates of lifetime probability of false-positive results were lower. Evidence for the relationship between screening and life expectancy and quality-adjusted life expectancy was low in quality. There was no direct evidence for any additional mortality benefit associated with the addition of CBE to mammography, but observational evidence from the United States and Canada suggested an increase in false-positive findings compared with mammography alone, with both studies finding an estimated 55 additional false-positive findings per extra breast cancer detected with the addition of CBE. CONCLUSIONS AND RELEVANCE For women of all ages at average risk, screening was associated with a reduction in breast cancer mortality of approximately 20%, although there was uncertainty about quantitative estimates of outcomes for different breast cancer screening strategies in the United States. These findings and the related uncertainty should be considered when making recommendations based on judgments about the balance of benefits and harms of breast cancer screening.

Profile of pazopanib and its potential in the treatment of epithelial ovarian cancer

Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. Recently, clinical trials have focused on novel antiangiogenic agents in combination with chemotherapy or alone in women with primary and recurrent ovarian cancer. Antiangiogenic agents include monoclonal antibodies, tyrosine-kinase inhibitors, and peptibodies. Many of these agents, including bevacizumab, pazopanib, nintedanib, cediranib, and trebananib, have been evaluated in randomized Phase III clinical trials, and all have demonstrated a progression-free survival (PFS) benefit. Specifically, maintenance pazopanib was shown to improve PFS in women with newly diagnosed EOC. Pazopanib, an oral TKI, inhibits several kinase receptors, including those for vascular endothelial growth factor (-1,-2,-3), platelet-derived growth factor (-α and -β), and fibroblast growth factor. It also targets stem cell-factor receptor (c-kit), interleukin 2-inducible T-cell kinase, lymphocyte-specific protein tyrosine kinase, and colony-stimulating factor 1 receptor. Pazopanib has been investigated in several Phase II and III clinical trials, with results indicating a potential role in the management of EOC. This article provides an overview of pazopanib in the treatment of EOC.

New therapies for advanced, recurrent, and metastatic endometrial cancers

Endometrial cancer is the most common gynecologic malignancy in the United States, accounting for 6% of cancers in women. In 2017, an estimated 61,380 women were diagnosed with endometrial cancer, and approximately 11,000 died from this disease. From 1987 to 2008, there was a 50% increase in the incidence of endometrial cancer, with an approximate 300% increase in the number of associated deaths. Although there are many chemotherapeutic and targeted therapy agents approved for ovarian, fallopian tube and primary peritoneal cancers, since the 1971 approval of megestrol acetate for the palliative treatment of advanced endometrial cancer, only pembrolizumab has been Food and Drug Administration (FDA)-approved for high microsatellite instability (MSI-H) or mismatch repair deficient (dMMR) endometrial cancer; this highlights the need for new therapies to treat advanced, recurrent, metastatic endometrial cancer. In this review, we discuss current and emerging treatment options for endometrial cancer, including chemotherapy, targeted therapy, and immunotherapy. The National Cancer Institute (NCI) and others are now focusing their efforts on the design of scientifically rational targeted therapy and immunotherapy trials for specific molecular phenotypes of endometrial cancer. This is essential for the advancement of cancer care for women, which is threatened by a severe enrollment decline of approximately 80% for gynecologic oncology clinical trials.

Differential Angiogenic Gene Expression in TP53 Wild-Type and Mutant Ovarian Cancer Cell Lines

Objectives: Underlying mechanisms regulating angiogenesis in ovarian cancer have not been completely elucidated. Evidence suggests that the TP53 tumor suppressor pathway and tumor microenvironment play integral roles. We utilized microarray technology to study the interaction between TP53 mutational status and hypoxia on angiogenic gene expression. Methods: Affymetrix U133A arrays were analyzed for angiogenic gene expression in 19 ovarian cancer cell lines stratified both by TP53 mutation status and A2780 wild-type (wt) TP53 vs. mutated (m) TP53 cell lines after treatment under hypoxic conditions or with ionizing radiation. Results: Twenty-eight differentially expressed angiogenic genes were identified in the mTP53 cell lines compared to wtTP53 lines. Five genes were upregulated in mTP53 cells: 40% involved in extracellular matrix (ECM) degradation [matrix metalloproteinase 10 (MMP10)/15] and 60% in angiogenesis (fibroblast growth factor receptor 3/VEGFA/ephrin receptor-B4). Twenty-three genes were upregulated in wtTP53: nearly 22% were ECM constituents or involved in ECM degradation; over 40% were growth factors or mediators of angiogenesis. Five genes were upregulated in the A2780mTP53 cells: 40% involved in ECM remodeling (MMP10, ADAMTS1), 40% with pro-angiogenic activity (EFNB2, factor 2 receptor), and 20% with anti-angiogenic properties (ADAMTS1). Three genes were upregulated in hypoxia treated cells compared to controls: one with anti-angiogenic activity (angiopoietin-like 4) and two with pro-angiogenic activity (VEGFA, EFNA3). No significant gene fold changes were noted after exposure to radiation. Four genes continued to demonstrate significant differential expression (p ≤ 0.05) after adjusting for multiple comparisons. These genes included endoglin upregulation in wt lines (pro-angiogenesis) and upregulation of FGF20 (growth factor), ADAMTS1 (anti-angiogenesis) and MMP10 (ECM degradation) in mTP53 cell lines. Conclusion: Our exploratory findings indicate that non-overlapping angiogenic pathways may be altered by TP53 mutations and hypoxic conditions in the tumor microenvironment. Further evaluation is needed for confirmation.

Risk-benefit assessment of the combined oral contraceptive pill in women with a family history of female cancer.

Introduction: Oral contraceptive pills (OCPs) are the most frequently used form of effective, reversible contraception among women of childbearing potential. In the average risk population, OCPs may offer a protective benefit against ovarian, endometrial and colorectal malignancies. In women at high risk for breast, ovarian, endometrial or colorectal malignancies, the risk–benefit profile is less well studied. Areas covered: In this article, we review pertinent literature on the use of OCPs in patients with genetic susceptibilities due to mutations in BRCA1, BRCA2 or mismatch repair genes implicated in hereditary nonpolyposis colorectal cancer as well as those with a strong family history of malignancies associated with these syndromes. Expert opinion: For women at high risk for ovarian, endometrial and/or colorectal malignancies due to genetic susceptibilities or a strong family history, the possibility of chemoprevention with OCPs may be an attractive option; however, the potential increase in breast cancer, although small, must be considered in clinical decision-making. The ultimate decision to use OCPs in a high-risk woman should be based on a consideration of her specific genetic risk, her age, her reproductive plans and her willingness to consider surgical prophylaxis options.

Disparities in the surgical staging of high-grade endometrial cancer in the United States.

BackgroundThe National Comprehensive Cancer Network (NCCN) and the Society of Gynecologic Oncology (SGO) recommend lymph node sampling (LNS) as a key component in the surgical staging of high-grade endometrial cancer. Our goal was to examine surgical staging patterns for high-grade endometrial cancer in the United States.MethodsThe National Cancer Data Base (NCDB) was searched for patients who underwent surgery for serous, clear cell, or grade 3 endometrioid endometrial cancer. Outcomes were receipt of LNS and overall survival (OS). Multivariate logistic regression was used to examine receipt of LNS in Stage I–III disease based on race (White vs. Black), income, surgical volume, and distance traveled to care. Multivariate Cox proportional hazards regression modeling was used to assess OS based on stage, race, income, LNS, surgical volume, and distance traveled.ResultsForty-two thousand nine hundred seventy-three patients were identified: 76% White, 53% insured by Medicare/Medicaid, 24% traveled >30 miles, and 33% stage III disease. LNS was similar among White and Black women (81% vs 82%). LNS was more common among >30 miles traveled (84% vs 81%, p < 0.001), higher surgical volume (83% vs 80%, p < 0.001), and academic centers (84% vs 80%, p < 0.001). In multivariate analysis, higher income, higher surgical volume, Charlson-Deyo score, and distance traveled were predictors of LNS. Stage III disease (HR 3.39, 95% CI 3.28–3.50), age (10-year increase; HR 1.63, 95% CI 1.61–1.66), lack of LNS (HR 1.64, 95% CI 1.56–1.69), and low income (HR 1.20, 95% CI 1.14–1.27) were predictors of lower survival.ConclusionsSurgical care for high-grade endometrial cancer in the United States is not uniform. Improved access to high quality care at high volume centers is needed to improve rates of recommended LNS.

Tumor grade and chemotherapy response in endometrioid endometrial cancer

The objective of this study is to evaluate the association between tumor grade and response to chemotherapy in patients with endometrioid endometrial adenocarcinoma. Patients with advanced or recurrent endometrioid endometrial adenocarcinoma of known tumor grade who received at least 3 cycles of chemotherapy were retrospectively identified at three institutions. RECIST 1.1 criteria were used to assess response to neoadjuvant, postoperative or salvage chemotherapy. Chi-square testing was used to evaluate the association between tumor grade and chemotherapy response. Ninety-one patients met inclusion criteria: 13 with grade 1, 29 with grade 2 and 49 with grade 3 tumors. Eighty-four percent of patients received chemotherapy for recurrence, 12% for postoperative residual disease, and 4% in the neoadjuvant setting. The majority (85%) received carboplatin and paclitaxel. Forty-six percent (6/13) of grade 1, 72% (21/29) of grade 2 and 43% (21/49) of grade 3 tumors achieved an objective response. Grade 2 tumors were more likely to respond to chemotherapy compared to grade 3 tumors (72% vs. 43%, p = 0.02; Table 2), and specifically more likely to respond to carboplatin/paclitaxel (72% vs. 41%, p = 0.016). Median progression-free survival for patients receiving chemotherapy for recurrence or progression was 9 months for grade 1, 8 months for grade 2, and 5 months for grade 3 tumors. Similar results between grade and treatment response were apparent in the subset of 37 patients with a recently re-assigned tumor grade (G2 88% vs. G3 44%, p = 0.032). In this series of endometrioid endometrial cancers, grade 2 tumors had the best measurable response to chemotherapy.

Quality of life is significantly associated with survival in women with advanced epithelial ovarian cancer: An ancillary data analysis of the NRG Oncology/Gynecologic Oncology Group (GOG-0218) study

OBJECTIVE Evaluate association between baseline quality of life (QOL) and changes in QOL measured by FACT-O TOI with progression-free disease (PFS) and overall survival (OS) in advanced epithelial ovarian cancer (EOC). METHODS Patients enrolled in GOG-0218 with completed FACT-O TOI assessments at baseline and at least one follow-up assessment were eligible. Baseline FACT-O TOI scores were sorted by quartiles (Q1-4) and outcomes compared between Q1 and Q2-4 with log-rank statistic and multivariate Cox regression adjusting for age, stage, post-surgical residual disease size, and performance status (PS). Trends in FACT-O TOI scores from baseline to the latest follow-up assessment were evaluated for impact on intragroup (Q1 or Q2-4) outcome by log-rank analysis. RESULTS Of 1152 eligible patients, 283 formed Q1 and 869 formed Q2-4. Mean baseline FACT-O TOI scores were 47.5 for Q1 vs. 74.7 for Q2-4 (P<0.001). Q1 compared to Q2-4 had worse median OS (37.5 vs. 45.6months, P=0.001) and worse median PFS (12.5 vs. 13.1months, P=0.096). Q2-4 patients had decreased risks of disease progression (HR 0.974, 95% CI 0.953-0.995, P=0.018), and death (HR 0.963, 95% CI 0.939-0.987, P=0.003) for each five-point increase in baseline FACT-O TOI. Improving versus worsening trends in FACT-O TOI scores were associated with longer median PFS (Q1: 12.7 vs. 8.6months, P=0.001; Q2-4: 16.7 vs. 11.1months, P<0.001) and median OS (Q1: 40.8 vs. 16months, P<0.001; Q2-4: 54.4 vs. 33.6months, P<0.001). CONCLUSIONS Baseline FACT-O TOI scores were independently prognostic of PFS and OS while improving compared to worsening QOL was associated with significantly better PFS and OS in women with EOC.

Skin Metastases to Cesarean Scar at Diagnosis of Carcinoma of Cervix in aPostpartum Female

Objective: The authors describe the first report of a cesarean scar metastasis at time of diagnosis of cervical cancer in a postpartum female. Results: We describe the case of a 23 year old multiparous female who is diagnosed with stage IVB cervical cancer 5 months after an emergent cesarean delivery for preterm premature rupture of membranes. At time of diagnosis, she presented with a large cutaneous metastasis at the site of her Pfannenstiel incision. She completed a course of radiation and chemotherapy, however opted for hospice when disease progression was noted after 6 cycles of cisplatin and paclitaxel. Conclusion: The patient’s disease was likely present at the time of her cesarean section. We recommend thorough pelvic exams in women who present late in pregnancy without prior prenatal care. Though cesarean section is thought to decrease the likelihood of cervical cancer recurrence, it does not completely obviate the risk.

Hysterectomy with sentinel lymph node biopsy in the setting of pre-operative diagnosis of endometrial intraepithelial neoplasia: A cost-effectiveness analysis

OBJECTIVES Sentinel lymph node biopsy (SLNB) may be considered in the setting of a pre-operative diagnosis of endometrial intraepithelial neoplasia (EIN) due to high rates of concurrent invasive cancer. The aim of this study is to compare the cost-effectiveness of different surgical management strategies for a pre-operative diagnosis of EIN. METHODS A decision model was developed from a third party payer perspective to compare four surgical strategies for the management of EIN: (1) hysterectomy; (2) hysterectomy with frozen section (hysterectomy + frozen); (3) hysterectomy with SLNB (hysterectomy + SLNB); (4) hysterectomy with frozen section and SLNB (hysterectomy + frozen + SLNB). The probability that frozen section identifies high- or low-risk cancer, final pathology distribution, adjuvant treatments, and surgery/imaging costs were abstracted from the literature, Medicare reimbursement data, and the financial department of a private academic hospital. Adjuvant treatments were determined through NCCN guidelines and published studies. Effectiveness was quantified as percentage of patients who received the guideline-based treatment that aligned with their true stage. RESULTS The base case cost and effectiveness of each strategy was: hysterectomy-