Genome-matched treatments and patient outcomes in the Maine Cancer Genomics Initiative (MCGI).

Genomic tumor testing (GTT) is an emerging technology aimed at identifying variants in tumors that can be targeted with genomically matched drugs. Due to limited resources, rural patients receiving care in community oncology settings may be less likely to benefit from GTT. We analyzed GTT results and observational clinical outcomes data from patients enrolled in the Maine Cancer Genomics Initiative (MCGI), which provided access to GTTs; clinician educational resources; and genomic tumor boards in community practices in a predominantly rural state. 1603 adult cancer patients completed enrollment; 1258 had at least one potentially actionable variant identified. 206 (16.4%) patients received a total of 240 genome matched treatments, of those treatments, 64% were FDA-approved in the tumor type, 27% FDA-approved in a different tumor type and 9% were given on a clinical trial. Using Inverse Probability of Treatment Weighting to adjust for baseline characteristics, a Cox proportional hazards model demonstrated that patients who received genome matched treatment were 31% less likely to die within 1 year compared to those who did not receive genome matched treatment (HR: 0.69; 95% CI: 0.52-0.90; p-value: 0.006). Overall, GTT through this initiative resulted in levels of genome matched treatment that were similar to other initiatives, however, clinical trials represented a smaller share of treatments than previously reported, and "off-label" treatments represented a greater share. Although this was an observational study, we found evidence for a potential 1-year survival benefit for patients who received genome matched treatments. These findings suggest that when disseminated and implemented with a supportive infrastructure, GTT may benefit cancer patients in rural community oncology settings, with further work remaining on providing genome-matched clinical trials.

A Peer-Based Strategy to Overcome HPV Vaccination Inequities in Rural Communities: A Physical Distancing-Compliant Approach.

The human papilloma virus (HPV) vaccine is the world's first proven and effective vaccine to prevent cancers in males and females when administered pre-exposure. Like most of the US, barely half of Vermont teens are up-to-date with the vaccination, with comparable deficits in New Hampshire and Maine. The rates for HPV vaccine initiation and completion are as low as 33% in rural New England. Consequently, there is a compelling responsibility to communicate its importance to unvaccinated teenagers before their risk for infection increases. Messaging in rural areas promoting HPV vaccination is compromised by community-based characteristics that include access to appropriate medical care, poor media coverage, parental and peer influence, and skepticism of science and medicine. Current strategies are predominantly passive access to literature and Internet-based information. Evidence indicates that performance-based messaging can clarify the importance of HPV vaccination to teenagers and their parents in rural areas. Increased HPV vaccination will significantly contribute to the prevention of a broadening spectrum of cancers. Reducing rurality-based inequities is a public health priority. Development of a performance-based peer-communication intervention can capture a window of opportunity to provide increasingly effective and sustained HPV protection. An effective approach can be partnering rural schools and regional health teams with a program that is nimble and scalable to respond to public health policies and practices compliant with COVID-19 pandemic-related modifications on physical distancing and interacting in the foreseeable future.

Prevalence, Predictors, and Same Day Treatment of Positive VIA Enhanced by Digital Cervicography and Histopathology Results in a Cervical Cancer Prevention Program in Cameroon.

BACKGROUND: In 2007, the Cameroon Baptist Convention Health Services (CBCHS) implemented a screen-and-treat cervical cancer prevention program using visual inspection with acetic acid enhanced by digital cervicography (VIA-DC). METHODS: We retrospectively analyzed 46,048 medical records of women who received care through the CBCHS Women's Health Program from 2007 through 2014 to determine the prevalence and predictors of positive VIA-DC, rates of same day treatment, and cohort prevalence of invasive cervical cancer (ICC). RESULTS: Of the 44,979 women who were screened for cervical cancer, 9.0% were VIA-DC-positive, 66.8% were VIA-DC-negative, 22.0% were VIA-DC-inadequate (normal ectocervix, but portions of the transformation zone were obscured), and 2.2% were VIA-DC-uncertain (cervical abnormalities confounding VIA-DC interpretation). Risk factors significantly associated with VIA-DC-positive screen were HIV-positivity, young age at sexual debut, higher lifetime number of sexual partners, low education status and higher gravidity. In 2014, 31.1% of women eligible for cryotherapy underwent same day treatment. Among the 32,788 women screened from 2007 through 2013, 201 cases of ICC were identified corresponding to a cohort prevalence of 613 per 100,000. CONCLUSIONS: High rate of VIA-DC-positive screens suggests a significant burden of potential cervical cancer cases and highlights the need for expansion of cervical cancer screening and prevention throughout the 10 regions of Cameroon. VIA-DC-inadequate rates were also high, especially in older women, and additional screening methods are needed to confirm whether these results are truly negative. In comparison to similar screening programs in sub-Saharan Africa there was low utilization of same day cryotherapy treatment. Further studies are required to characterize possible program specific barriers to treatment, for example cultural demands, health system challenges and cost of procedure. The prevalence of ICC among women who presented for screening was high and requires further investigation.

Assessing Residents' Frozen Section Skills for Endometrial Cancer.

Intraoperative frozen section (IFS) on endometrial cancer is an invaluable skill for pathologists-in-training to master. Within limited time constraints, pathologists are expected to determine tumor type, grade, and depth of myometrial invasion. During their training, pathology residents gradually gain experience in handling the majority of cases. However, significant errors can still be seen among senior level trainees. We aimed to improve training effectiveness by evaluating our trainees' performance, identifying common errors, and recommending focused curriculum. Twenty-two residents [postgraduate year (PGY)-1-PGY-4] performed 260 IFS during a 4-yr period. We compared their independent IFS diagnoses with final diagnoses. Overall resident IFS accuracy was 73%. Accuracy for tumor type and depth of myometrial invasion was 80% and 93%, respectively. Two thirds of errors were due to sampling with the rest because of interpretation. Major deficiencies lay in recognizing high-risk histologic types (serous, clear cell, sarcoma) and unconventional myometrial invasion patterns (MELF, adenoma malignum, and adenomyosis-like). Resident IFS errors would theoretically result in suboptimal staging for 32 (12%) patients and unnecessary staging for 1 (0.4%). Overall IFS performance improved as training level increased (76% accuracy for PGY-1 accompanied by PGY-5; 59% for PGY-2; 74% for PGY-3; and 86% for PGY-4). We recommend a dedicated curriculum targeting these difficult yet clinically important entities through review literature and a collection of classic cases demonstrating the diverse morphology variations. Implementing such focused training would greatly improve our trainees' competence on IFS, preparing them to handle a wide variety of cases and situations in future practice.

Mucinous Adenocarcinoma of the Endometrium Compared With Endometrioid Endometrial Cancer: A SEER Analysis.

OBJECTIVE: Mucinous endometrial cancer (MEC) is a rare histologic subtype of endometrial cancers. The purpose of this study is to compare the outcomes of patients with MEC with patients with endometrioid endometrial cancers (EEC), and to determine whether there are significant clinicopathologic differences between these tumors. METHODS: Surveillance, Epidemiology, and End Results (SEER) Program data for 1988 to 2009 was reviewed. Demographic and clinical data were compared. The impact of histology on survival was analyzed using the Kaplan-Meier method. Factors predictive of outcome were compared using the Cox proportional hazards model. RESULTS: The study group consisted of 104,659 women, 103,097 (98.5%) had EEC and 1562 (1.5%) MEC. The mean age at diagnosis for EEC and MEC was 62 and 63.4, respectively (P<0.001). MEC tumors were more frequently classified as grade 1 (51.3% vs. 44%; P<0.001). In patients with MEC, a higher rate of pelvic lymph node metastasis (16.3% vs. 10.4%; P<0.001) was noted, but not para-aortic lymph node metastasis (5.1% vs. 4%; P=0.1). After adjusting for race, period of diagnosis, SEER registry, marital status, stage, age, surgery, radiotherapy, grade, histology, and lymph node dissection, there was no difference in survival between MEC and EEC (hazard ratio 0.90; 95% confidence interval, 0.78-1.05). CONCLUSIONS: Mucinous histology does not significantly affect survival when compared with endometrioid histology in endometrial cancer. Patients with MEC were more likely to have positive pelvic lymph nodes at the time of surgery.

Advances in the management of recurrent endometrial cancer.

OBJECTIVE: Endometrial carcinoma is the most common malignancy of the female reproductive tract. Although most cases are diagnosed at an early stage, endometrial carcinoma carries a poor prognosis when it recurs after previous definitive treatment or when diagnosed at an advanced stage. The purpose of this review is to summarize the contemporary management of recurrent endometrial carcinoma. METHODS: A literature review was conducted on the management of advanced, recurrent, or metastatic endometrial cancer to determine the best evidence to support the roles of surgery, radiation, and medical therapy. RESULTS: Radiation therapy (RT) has a role in the treatment of a local or regional recurrence, especially in the patient who has not had prior RT. For selected patients who experience a loco-regional recurrence and who have been treated with RT, pelvic exenteration may be an option. Those patients with metastatic disease are not curable and should be considered for palliative chemotherapy. The data support the use of carboplatin and paclitaxel as an acceptable alternative to cisplatin-based regimens. For women who progress after first-line treatment, the options are limited. Current clinical trials are evaluating the role of angiogenesis inhibitors and molecularly targeted therapy (including the mammalian target of rapamycin inhibitors and multitargeted tyrosine kinase inhibitors) with the aim of identifying other novel agents that can be exploited for treatment of advanced disease. CONCLUSIONS: The treatment of women with advanced, recurrent, or metastatic endometrial cancer represents an unmet need in oncology. Robust clinical trials are required to explore how to improve on therapy. The incorporation of molecularly targeted agents has the potential to improve outcomes for women who require treatment in both the first-line and second-line settings.

Assessing the efficacy of targeting the phosphatidylinositol 3-kinase/AKT/mTOR signaling pathway in endometrial cancer.

OBJECTIVE: Alterations in the PI3K pathway are prevalent in endometrial cancer due to PIK3CA mutation and loss of PTEN. We investigated the anti-tumor activity of the PI3K inhibitor NVP BKM-120 (BKM) as a single agent and in combination with standard cytotoxic chemotherapy in a human primary endometrial xenograft model. METHODS: NOD/SCID mice bearing xenografts of primary human tumors with and without PIK3CA gene mutations were divided into two and four arm cohorts with equivalent tumor volumes. BKM was administered alone and in combination with paclitaxel and carboplatin (P/C) and endometrial xenograft tumor volumes were assessed. Tumors from the BKM, P/C, P/C+BKM and vehicle treated mice were processed for determination of PI3K/AKT/mTOR pathway activation. RESULTS: In both single agent experiments, BKM resulted in significant tumor growth suppression starting at days 5-10 compared to the linear growth observed in vehicle treated tumors (p<0.04 in all experiments). Tumor resurgence manifested between days 14 and 25 (p<0.03). When BKM was combined with P/C, this resistance pattern failed to develop in three separate xenograft lines (p<0.05). Synergistic tumor growth suppression (p<0.05) of only one xenograft tumor with no detected PIK3CA mutation was observed. Acute treatment with BKM led to a decrease in pAKT levels. CONCLUSION: Independent of PIK3CA gene mutation, BKM mediated inhibition of the PI3K/AKT/mTOR pathway in endometrial tumors precludes tumor growth in a primary xenograft model. While a pattern of resistance emerges, this effect appears to be mitigated by the addition of conventional cytotoxic chemotherapy.

Laparoendoscopic single-site radical hysterectomy with pelvic lymphadenectomy: initial multi-institutional experience for treatment of invasive cervical cancer.

STUDY OBJECTIVE: To describe the feasibility, safety, and outcomes of women with stage I cervical cancer treated with laparoendoscopic single-site surgery radical hysterectomy (LESS-RH). DESIGN: A retrospective descriptive study (Canadian Task Force classification III). SETTING: Multiple academic teaching hospitals. PATIENTS: Women with Fédération Internationale de Gynécologie et d'Obstétrique FIGO stage IA1 to IB1 cervical cancer. INTERVENTIONS: LESS-RH as the primary therapy for cervical cancer performed by a gynecologic oncologist with expertise in LESS. A multichannel, single-port access device; a flexible-tipped 5-mm laparoscope; and a multifunctional instrument were used in all cases. Clinicopathologic, surgical, and perioperative outcomes were analyzed. MEASUREMENTS AND MAIN RESULTS: Twenty-two women were identified in whom a LESS-RH was attempted; 20 (91%) successfully underwent the procedure, including 19 in whom pelvic lymphadenectomy (PLND) was completed. Of the 2 converted procedures, 1 patient underwent 2-port laparoscopy secondary to truncal obesity, and 1 patient underwent conversion to laparotomy secondary to external iliac vein laceration during PLND. The median age and body mass index were 46 years and 23.3 kg/m(2), respectively. The median number of pelvic lymph nodes removed was 22. One patient experienced an intraoperative complication, and no patient required reoperation. The margins of excision were negative. One patient with 2 positive pelvic nodes and 1 patient with microscopic parametrial disease received adjuvant chemosensitized radiation; 3 additional patients received adjuvant radiation therapy secondary to an intermediate risk for recurrence. After a median follow up of 11 months, no recurrences were detected. CONCLUSION: LESS-RH/PLND is feasible and safe for select patients with stage I cervical cancer. Larger studies are needed to confirm whether the increased technical difficulty of this procedure justifies its use in routine gynecologic oncology practice.

Carcinosarcoma of the ovary compared to papillary serous ovarian carcinoma: a SEER analysis.

OBJECTIVE: The aims of this study are to determine if outcomes of patients with ovarian carcinosarcoma (OCS) differ from women with high grade papillary serous ovarian carcinoma when compared by stage as well as to identify any associated clinico-pathologic factors. METHODS: The Surveillance, Epidemiology, and End Results (SEER) Program data for all 18 registries from 1998 to 2009 was reviewed to identify women with OCS and high grade papillary serous carcinoma of the ovary. Demographic and clinical data were compared, and the impact of tumor histology on survival was analyzed using the Kaplan-Meier method. Factors predictive of outcome were compared using the Cox proportional hazard model. RESULTS: The final study group consisted of 14,753 women. 1334 (9.04%) had OCS and 13,419 (90.96%) had high grade papillary serous carcinoma of the ovary. Overall, women with OCS had a worse five-year, disease specific survival rate, 28.2% vs. 38.4% (P<0.001). This difference persisted for each FIGO disease stages I-IV, with five year survival consistently worse for women with OCS compared with papillary serous carcinoma. Over the entire study period, after adjusting for histology, age, period of diagnosis, SEER registry, marital status, stage, surgery, radiotherapy, lymph node dissection, and history of secondary malignancy after the diagnosis of ovarian cancer, carcinosarcoma histology was associated with decreased cancer-specific survival. CONCLUSIONS: OCS is associated with a poor prognosis compared to high grade papillary serous carcinoma of the ovary. This difference was noted across all FIGO stages.

Racial disparities in cervical cancer survival over time.

BACKGROUND: The purpose of this study is to examine changes over time in survival for African American (AA) and white women diagnosed with cervical cancer (CC). METHODS: Surveillance, Epidemiology, and End Results (SEER) Program data from 1985 to 2009 were used for this analysis. Racial differences in survival were evaluated between African American (AA) and white women. Kaplan-Meier and Cox proportional hazards survival methods were used to assess differences in survival by race at 5-year intervals. RESULTS: The study sample included 23,368 women, including 3886 (16.6%) who were AA and 19,482 (83.4%) who were white. AA women were older (51.4 versus 48.9 years; P<.001) and had a higher rate of regional (38.3% versus 31.8%; P<.001) and distant metastasis (10.7% versus 8.7%; P<.001). AA less frequently received cancer-directed surgery (32.4% versus 46%; P<.001), and more frequently radiotherapy (36.3% versus 26.4%; P<.001). Overall, AA women had a hazard ratio (HR) of 1.41 (95% confidence interval=1.32-1.51) of cervical cancer (CC) mortality compared with whites. Adjusting for SEER registry, marital status, stage, age, treatment, grade, and histology, AA women had an HR of 1.13 (95% confidence interval=1.05-1.22) of CC-related mortality. After adjusting for the same variables, there was a significant difference in CC-specific mortality between 1985 to 1989 and 1990 to 1994, but not after 1995. CONCLUSIONS: After adjusting for race, SEER registry, marital status, stage, age, treatment, grade, and histology, there was a significant difference in CC-specific mortality between 1985 to 1989 and 1990 to 1994, but not after 1995.

Laparoendoscopic single-site surgery in gynecology: a review of the literature, tools, and techniques.

UNLABELLED: Recent decades have witnessed a tremendous shift from laparotomy to laparoscopy as the surgical approach of choice in gynecology. Completion of increasingly complicated procedures has been facilitated by technical advances in instrumentation. Lately, increasing attention has been paid to reducing both the number and size of laparoscopic incisions, with the ultimate goal being the absence of any visible scar. Laparoendoscopic single-site surgery (LESS), or single-incision laparoscopy, describes the use of 1 small skin incision to complete laparoscopic surgical procedures where traditionally multiple incisions were created. In addition to examining the developing literature related to LESS in gynecology, the aims of this review were to describe the technical challenges encountered during performance of LESS and to provide practical solutions for instrumentation and surgical techniques that allow them to be overcome. TARGET AUDIENCE: Obstetricians and gynecologists, family physicians LEARNING OBJECTIVES: After completing this CME activity, physicians should be better able to identify potential benefits of LESS, and implement practical solutions for instrumentation and surgical techniques to overcome technical challenges faced during LESS.

Racial disparities and changes in clinical characteristics and survival for vulvar cancer over time.

OBJECTIVE: The purpose of this study was to examine changes over time in survival for African-American (AA) and white women diagnosed with squamous cell carcinoma of the vulva. STUDY DESIGN: The Surveillance, Epidemiology, and End Results (SEER) Program for 1973-2009 was used for this analysis. We evaluated racial differences in survival between AA and white women. Kaplan-Meier and Cox proportional hazards survival methods were used to assess differences in survival by race by decade of diagnosis. RESULTS: The study sample included 5867 women, including 5379 whites (91.6%) and 488 AA (8.3%). AA women were younger (57 vs 67 years; P < .001) and had a higher rate of distant metastasis (6.1% vs 3.7%; P < .001). AA women had surgery less frequently (84.2% vs 87.6%; P = .03) and more frequently radiotherapy (24.2% vs 20.6%; P < .001). AA women had a hazard ratio (HR) of 0.84 (95% confidence interval [CI], 0.74-0.95) of all-cause mortality and 0.66 (95% CI, 0.53-0.82) of vulvar cancer mortality compared with whites. Adjusting for SEER Registry, marital status, stage, age, surgery, radiotherapy, grade, lymph node status, and decade, AA women had an HR of 0.67 (95% CI, 0.53-0.84) of vulvar cancer-related mortality compared with whites. After adjusting for the same variables, there was a significant difference in survival between AA and whites in the periods of 1990-1999 (HR, 0.62; 95% CI, 0.41-0.95) and 2000-2009 (HR, 0.46; 95% CI, 0.30-0.72) but not earlier. CONCLUSION: AA presented at a significantly younger age compared with white women and had better survival compared with whites.

Platinum resistance after neoadjuvant chemotherapy compared to primary surgery in patients with advanced epithelial ovarian carcinoma.

OBJECTIVE: Primary debulking surgery (PDS) has historically been the standard treatment for advanced ovarian cancer. Recent data appear to support a paradigm shift toward neoadjuvant chemotherapy with interval debulking surgery (NACT-IDS) for a subset of women with advanced ovarian cancer. It remains unresolved whether NACT-IDS increases the risk of platinum resistance. We compared response to chemotherapy in patients that received NACT-IDS vs. PDS. METHODS: From our Cancer Registry database we identified patients with stages IIIC and IV epithelial ovarian cancer who underwent treatment from January, 2005 to December, 2010. Standard univariate analyses were performed, as were multivariable analysis with logistic regression. The Kaplan-Meier method was used to generate survival data. RESULTS: The study population consisted of 425 patients, 95 (22.3%) underwent NACT-IDS and 330 (77.6%) PDS. After the initial platinum-based chemotherapy, 42 (44.2%) women in the NACT-IDS group were considered to have platinum resistant disease, compared to 103 (31.2%) in the PDS group (P=0.01). When multivariate logistic regression was used to control for factors independently associated with platinum resistance, NACT-IDS was no longer associated with an initial increased risk. However, in women that had a recurrence and were retreated with platinum-based chemotherapy, 32 (88.8%) in the NACT-IDS group had developed a recurrence within six months and were considered platinum resistant, compared to 62 (55.3%) in the PDS (P<0.001). CONCLUSION: In women with EOC that have a recurrence and are treated again with platinum-based chemotherapy, NACT-IDS appears to increase the risk of platinum resistance.

Hypercalcemia associated with a malignant brenner tumor arising from a mature cystic teratoma.

A 60-year-old woman presented with abdominal pain and weight loss and was found to have serum calcium of 15.0 mg/dl. Serum parathyroid hormone-related peptide (PTHrP) returned elevated. Imaging suggested bilateral mature cystic teratomas. Her hypercalcemia was treated initially with intravenous saline, as well as intramuscular and subcutaneous calcitonin. She underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy, and final pathology revealed malignant Brenner tumor in association with a mature cystic teratoma. Her postoperative PTHrP returned less than assay, and her total and ionized calcium fell below normal, requiring supplemental calcium and vitamin D. At follow-up one month after discharge, her calcium had normalized. We present the first reported case of hypercalcemia occurring in association with a malignant Brenner tumor. Malignancy-associated hypercalcemia occurs via four principal mechanisms: (1) tumor production of PTHrP; (2) osteolytic bone involvement by primary tumor or metastasis; (3) ectopic activation of vitamin D to 1,25-(OH)(2) vitamin D, and (4) ectopic production of parathyroid hormone. PTHrP-mediated hypercalcemia is the most common mechanism and was responsible in this case. In patients with paraneoplastic hypercalcemia who undergo surgical treatment, close monitoring and management of serum calcium is necessary both pre- and postoperatively.

Primary cytoreductive surgery for advanced ovarian cancer: is it the past, present, or future?

Ovarian cancer accounts for more deaths in the United States than all other gynecologic malignancies combined. This is largely due to the fact that no effective screening test has been identified thus far to facilitate early detection. As a result, two-thirds of women continue to be diagnosed with advanced stage III or IV disease. Historically, the standard of care has consisted of primary cytoreductive surgery-with an operative goal of achieving an optimal result with minimal residual disease-followed by adjuvant, platinum-based chemotherapy. However, data suggesting comparable efficacy of neoadjuvant chemotherapy and interval debulking has recently challenged this conventional dogma. The current decision-making on how to initially treat women with newly diagnosed advanced ovarian cancer has become increasingly controversial. This article focuses on whether primary cytoreductive surgery should remain the preferred method of management, or whether it is time for it to be superseded by neoadjuvant chemotherapy.