Neoadjuvant weekly paclitaxel and carboplatin with trastuzumab and pertuzumab in HER2-positive breast cancer: a Brown University Oncology Research Group (BrUOG) study.

PURPOSE: In HER2-positive breast cancer (HER2+ BC), neoadjuvant chemotherapy (NACT) with dual HER2-targeted therapy achieves high pathologic complete response (pCR) rates. Anthracycline-free NACT regimens avoid toxicities associated with anthracyclines, but every 3-week TCHP also has substantial side effects. We hypothesized that a weekly regimen might have equivalent efficacy with less toxicity; we also investigated whether poorly responding patients would benefit from switching to AC. METHODS: Patients with clinical stage II-III HER2+ BC received weekly paclitaxel 80 mg/m2 and carboplatin AUC2 with every 3-week trastuzumab and pertuzumab (wPCbTP), with the option of splitting the pertuzumab loading dose. After 12 weeks, responding patients continued wPCbTP for another 6 weeks, while non-responders switched to AC. Dose modifications and post-op therapy were at investigator discretion. RESULTS: In 30 evaluable patients, the pCR rate was 77% (95% CI 58-90%); 12/14 (86%) in ER-negative and 11/16 (69%) in ER-positive. Only two patients transitioned to AC for non-response, of which one achieved pCR. There were no episodes of febrile neutropenia or grade ≥ 3 peripheral neuropathy, though several patients who continued wPCbTP stopped before week 18. Split-dose pertuzumab was associated with less grade ≥ 2 diarrhea (40%) than the standard loading dose (60%). CONCLUSION: pCR rates with our regimen were as high as reported with TCHP with fewer grade ≥ 3 toxicities, though diarrhea remains a concern. Too few patients had a suboptimal response to adequately test switching to AC. The wPCbTP regimen should be considered an alternative to TCHP as neoadjuvant therapy for HER2+ BC. TRAIL REGISTRATION: ClinicalTrials.gov identifier: NCT02789657.

Final report on serial phase II trials of all-intraperitoneal chemotherapy with or without bevacizumab for women with newly diagnosed, optimally cytoreduced carcinoma of Müllerian origin.

BACKGROUND: Intraperitoneal (IP) chemotherapy can improve outcomes for women with optimally cytoreduced epithelial ovarian cancer but toxicities are a concern. We conducted 2 phase 2 trials of an IV/IP regimen using carboplatin and paclitaxel without (Trial A) and with bevacizumab (Trial B). METHODS: Both trials consisted of carboplatin AUC 6 day 1, and paclitaxel 60 mg/m2 on days 1,8, 15 of a 21-day cycle; in Trial B, patients received IV bevacizumab 15 mg/kg every cycle starting cycle 2. Chemotherapy was administered IV for cycle 1 and then IP for all subsequent cycles. Primary objectives included safety and tolerability, pathologic CR rate (Trial A), and the rate of completion of IP cycles of therapy (Trial B). Progression-free (PFS), overall survival (OS), and pharmacokinetic analysis were secondary endpoints. RESULTS: 81 patients were treated on both trials (n = 40 and 41 in trials A and B, respectively). Median age for trials A and B was 59 (range, 36-76) and 55 (range, 19-69) years, respectively. 68% and 85% of patients, respectively for A and B, completed at least 4 cycles of treatment in both trials. Treatment with bevacizumab resulted in higher rates of grade 3 fatigue (37 versus 33%) and grade 3-4 diarrhea (22 versus 8%). Median PFS was 23.5 (95%CI 16.2-35.3) and 25 (95%CI 16.4-42.7) months, respectively; median OS was 68 (95%CI 49.5-NR) and 79.7 (95%CI 59.0-79.7) months, respectively for Trial A and B. CONCLUSIONS: Weekly administered IP carboplatin and IP paclitaxel is tolerable and safe with similar activity with and without concommittant bevacizumab in these 2 trials.

A phase I trial of paclitaxel, cisplatin, and veliparib in the treatment of persistent or recurrent carcinoma of the cervix: an NRG Oncology Study (NCT#01281852).

Background: Preclinical studies demonstrate poly(ADP-ribose) polymerase (PARP) inhibition augments apoptotic response and sensitizes cervical cancer cells to the effects of cisplatin. Given the use of cisplatin and paclitaxel as first-line treatment for persistent or recurrent cervical cancer, we aimed to estimate the maximum tolerated dose (MTD) of the PARP inhibitor veliparib when added to chemotherapy. Patients and methods: Women with persistent or recurrent cervical carcinoma not amenable to curative therapy were enrolled. Patients had to have received concurrent chemotherapy and radiation as well as possible consolidation chemotherapy; have adequate organ function. The trial utilized a standard 3 + 3 phase I dose escalation with patients receiving paclitaxel 175 mg/m2 on day 1, cisplatin 50 mg/m2 on day 2, and escalating doses of veliparib ranging from 50 to 400 mg orally two times daily on days 1-7. Cycles occurred every 21 days until progression. Dose-limiting toxicities (DLTs) were assessed at first cycle. Fanconi anemia complementation group D2 (FANCD2) foci was evaluated in tissue specimens as a biomarker of response. Results: Thirty-four patients received treatment. DLTs (n = 1) were a grade 4 dyspnea, a grade 3 neutropenia lasting ≥3 weeks, and febrile neutropenia. At 400 mg dose level (DL), one of the six patients had a DLT, so the MTD was not reached. Across DLs, the objective response rate (RR) for 29 patients with measurable disease was 34% [95% confidence interval (CI), 20%-53%]; at 400 mg DL, the RR was 60% (n = 3/5; 95% CI, 23%-88%). Median progression-free survival was 6.2 months (95% CI, 2.9-10.1), and overall survival was 14.5 months (95% CI, 8.2-19.4). FANCD2 foci was negative or heterogeneous in 31% of patients and present in 69%. Objective RR were not associated with FANCD2 foci (P = 0.53). Conclusions: Combining veliparib with paclitaxel and cisplatin as first-line treatment for persistent or recurrent cervical cancer patients is safe and feasible. Clinical trial information: NCT01281852.

Epithelial ovarian cancer: the molecular genetics of epithelial ovarian cancer.

BACKGROUND: Epithelial ovarian cancer (EOC) remains one of the leading causes of cancer-related deaths among women worldwide, despite gains in diagnostics and treatments made over the last three decades. Existing markers of ovarian cancer possess very limited clinical relevance highlighting the emerging need for identification of novel prognostic biomarkers as well as better predictive factors that might allow the stratification of patients who could benefit from a more targeted approach. PATIENTS AND METHODS: A summary of molecular genetics of EOC. RESULTS: Large-scale high-throughput genomic technologies appear to be powerful tools for investigations into the genetic abnormalities in ovarian tumors, including studies on dysregulated genes and aberrantly activated signaling pathways. Such technologies can complement well-established clinical histopathology analysis and tumor grading and will hope to result in better, more tailored treatments in the future. Genomic signatures obtained by gene expression profiling of EOC may be able to predict survival outcomes and other important clinical outcomes, such as the success of surgical treatment. Finally, genomic analyses may allow for the identification of novel predictive biomarkers for purposes of treatment planning. These data combined suggest a pathway to progress in the treatment of advanced ovarian cancer and the promise of fulfilling the objective of providing personalized medicine to women with ovarian cancer. CONCLUSIONS: The understanding of basic molecular events in the tumorigenesis and chemoresistance of EOC together with discovery of potential biomarkers may be greatly enhanced through large-scale genomic studies. In order to maximize the impact of these technologies, however, extensive validation studies are required.

A SNaPshot of potentially personalized care: Molecular diagnostics in gynecologic cancer.

BACKGROUND: Genetic abnormalities underlie the development and progression of cancer, and represent potential opportunities for personalized cancer therapy in Gyn malignancies. METHODS: We identified Gyn oncology patients at the MGH Cancer Center with tumors genotyped for a panel of mutations by SNaPshot, a CLIA approved assay, validated in lung cancer, that uses SNP genotyping in degraded DNA from FFPE tissue to identify 160 described mutations across 15 cancer genes (AKT1, APC, BRAF, CTNNB1, EGFR, ERBB2, IDH1, KIT, KRAS, MAP2KI, NOTCH1, NRAS, PIK3CA, PTEN, TP53). RESULTS: Between 5/17/10 and 8/8/13, 249 pts consented to SNaPshot analysis. Median age 60 (29-84) yrs. Tumors were ovarian 123 (49%), uterine 74(30%), cervical 14(6%), fallopian 9(4%), primary peritoneal 13(5%), or rare 16(6%) with the incidence of testing high grade serous ovarian cancer (HGSOC) halving over time. SNaPshot was positive in 75 (30%), with 18 of these (24%) having 2 or 3 (n=5) mutations identified. TP53 mutations are most common in high-grade serous cancers yet a low detection rate (17%) was likely related to the assay. However, 4 of the 7 purely endometrioid ovarian tumors (57%) harbored a p53 mutation. Of the 38 endometrioid uterine tumors, 18 mutations (47%) in the PI3Kinase pathway were identified. Only 9 of 122 purely serous (7%) tumors across all tumor types harbored a 'drugable' mutation, compared with 20 of 45 (44%) of endometrioid tumors (p<0.0001). 17 pts subsequently enrolled on a clinical trial; all but 4 of whom had PIK3CA pathway mutations. Eight of 14 (47%) cervical tumors harbored a 'drugable' mutation. CONCLUSION: Although SNaPshot can identify potentially important therapeutic targets, the incidence of 'drugable' targets in ovarian cancer is low. In this cohort, only 7% of subjects eventually were treated on a relevant clinical trial. Geneotyping should be used judiciously and reflect histologic subtype and available platform.

Management and outcomes for elderly women with vulvar cancer over time.

OBJECTIVE: To examine changes over time in survival and treatment for women diagnosed with vulvar squamous cell carcinoma included in the Surveillance, Epidemiology, and End Results (SEER) Program. DESIGN: Retrospective analysis. SETTING: USA, data obtained from the SEER Program for 1988-2009. POPULATION: Women with vulvar squamous cell carcinoma. METHODS: Women were stratified by age: <50, 50-64, 65-79, and ≥80 years. Differences in survival and treatment patterns were analysed between age groups. Multivariate logistic regression models were constructed to examine treatment patterns. Kaplan-Meier and Cox proportional hazards survival methods were used to assess survival. MAIN OUTCOME MEASURES: Vital status from the date of diagnosis until death, censoring or last follow-up. RESULTS: The final study group consisted of 8553 women, 1806 (21.12%) <50 years, 2141 (25.03%) 50-64 years, 2585 (30.22%) 65-79 years, and 2021 (23.63%) >80 years old. After adjusting for patient and tumour characteristics, older women were less likely to have surgery and more likely to receive radiotherapy. Compared with women under 50 years, women 50-64 had a two-fold higher risk of death (HR 1.91, 95% CI 1.55-2.34); those 65-79 years had a four-fold higher risk of death (HR 4.01, 95% CI 3.32-4.82), and those ≥80 years had a seven-fold higher risk of death (HR 6.98, 95% CI 5.77-8.46). These trends stayed relatively constant over the time periods studied. CONCLUSIONS: Women over 50 years are at a higher risk of vulvar cancer-specific mortality, which increases with age. These trends stayed relatively constant over the time periods studied.

Ovarian cancer: genomic analysis.

OBJECTIVES: Despite improvements in the management of ovarian cancer patients over the last 30 years, there has been only a minimal improvement in overall survival. While targeted therapeutic approaches for the treatment of cancer have evolved, major challenges in ovarian cancer research persist, including the identification of predictive biomarkers with clinical relevance, so that empirical drug selection can be avoided. In this article, we review published genomic analysis studies including data generated in our laboratory and how they have been incorporated into modern clinical trials in a rational and effective way. METHODS: Multiple published genomic analysis studies were collected for review and discussion with emphasis on their potential clinical applicability. RESULTS: Genomic analysis has been shown to be a powerful tool to identify dysregulated genes, aberrantly activated pathways and to uncover uniqueness of subclasses of ovarian tumors. The application of this technology has provided a solid molecular basis for different clinical behaviors associated with tumor histology and grade. Genomic signatures have been obtained to predict clinical end points for patients with cancer, including response rates, progression-free survival, and overall survival. In addition, genomic analysis has provided opportunities to identify biomarkers, which either result in a modification of existing clinical management or to stratification of patients to novel therapeutic approaches designed as clinical trials. CONCLUSIONS: Genomic analyses have accelerated the identification of relevant biomarkers and extended our understanding of the molecular biology of ovarian cancer. This in turn, will hopefully lead to a paradigm shift from empirical, uniform treatment to a more rational, personalized treatment of ovarian cancers. However, validation of potential biomarkers on both the statistical and biological levels is needed to confirm they are of clinical relevance, in order to increase the likelihood that the desired outcome can be predicted and achieved.

Phase II trial of erlotinib in women with squamous cell carcinoma of the vulva.

OBJECTIVE: To evaluate the efficacy and toxicity of erlotinib in the management of squamous cell carcinoma (SCC) of the vulva. METHODS: Patients with vulvar lesions amenable to surgery or chemoradiation (cohort 1) or those with metastatic measurable disease (cohort 2) received erlotinib 150 mg daily. Patients were monitored for toxicity. Responses were determined by digital photography or RECIST 1.1. Cohort 1 underwent pre and post treatment biopsies. EGFR immunohistochemistry (IHC), fluorescence in-situ hybridization (FISH), and mutational analysis were performed. RESULTS: 41 patients were enrolled: 17 in cohort 1 and 24 in cohort 2. Notable grade 3 or 4 toxicities included allergic reaction (1), diarrhea/electrolyte abnormalities (3), ischemic colitis (1), and renal failure (3) and electrolyte abnormalities (n=2). Mean number of cycles for cohort 2 was 3.3. Overall clinical benefit rate was 67.5% with 11 (27.5%) partial responses (PR), 16 (40.0%) stable disease (SD), and 7 (17.5%) progressive disease. Responses were of short duration. All pre and post treatment biopsies exhibited 2-3+ EGFR staining. 5 of 14 patients (35%) were found to have EGFR amplification (n=3) or high polysomy/trisomy (n=2). These five patients had either a PR (n=3) or SD (n=2). Gain of function mutations were not been identified. CONCLUSIONS: This is the first reported controlled trial evaluating erlotinib for the management of vulvar carcinoma. Toxicities were acceptable given the lack of treatment options for these patients. Given the observed clinical benefits erlotinib may represent one of the most active agents available to treat vulvar SCC.

Digitizing clinical trials.

Clinical trials are a fundamental tool used to evaluate the efficacy and safety of new drugs and medical devices and other health system interventions. The traditional clinical trials system acts as a quality funnel for the development and implementation of new drugs, devices and health system interventions. The concept of a "digital clinical trial" involves leveraging digital technology to improve participant access, engagement, trial-related measurements, and/or interventions, enable concealed randomized intervention allocation, and has the potential to transform clinical trials and to lower their cost. In April 2019, the US National Institutes of Health (NIH) and the National Science Foundation (NSF) held a workshop bringing together experts in clinical trials, digital technology, and digital analytics to discuss strategies to implement the use of digital technologies in clinical trials while considering potential challenges. This position paper builds on this workshop to describe the current state of the art for digital clinical trials including (1) defining and outlining the composition and elements of digital trials; (2) describing recruitment and retention using digital technology; (3) outlining data collection elements including mobile health, wearable technologies, application programming interfaces (APIs), digital transmission of data, and consideration of regulatory oversight and guidance for data security, privacy, and remotely provided informed consent; (4) elucidating digital analytics and data science approaches leveraging artificial intelligence and machine learning algorithms; and (5) setting future priorities and strategies that should be addressed to successfully harness digital methods and the myriad benefits of such technologies for clinical research.

Phenotypic evaluation of ESBL- and carbapenemaseproducing Escherichia coli and Klebsiella pneumoniae from a teaching hospital in the Philippines.

Antimicrobial resistance is a worldwide public health concern. Rise in the number of antimicrobial resistant organisms, such as extended spectrum ß-lactamase- (ESBL) and carbapenemase-producing Escherichia coli and Klebsiella pneumoniae, continue to burden millions of people worldwide. E. coli and K. pneumoniae were isolated and collected for four months from a teaching hospital in the Philippines. All isolates were subjected to ESBL and carbapenemase testing using the double disk synergy test and modified Hodge test, respectively. Their pattern of resistance among different classes of antimicrobial agents was also investigated using the Kirby-Bauer disk diffusion test. Among the 32 clinical isolates tested, 28.1% were positive for ESBL production and 6.3% were positive for carbapenemase production. Species-specific classification showed that E. coli (44.4%) has the highest rate of ESBL production whereas both E. coli (5.6%) and K. pneumoniae (7.1%) showed almost similar rates of carbapenemase production. Antimicrobial resistance pattern of drug resistant isolates showed that all organisms were resistant to ampicillin, and majority showed resistance towards ciprofloxacin, cefotaxime, ceftriaxone, and sulfamethoxazole/trimethoprim. ESBL production is seen highest among E. coli isolates while similar rates of carbapenemase production was observed to both E. coli and K. pneumoniae isolates. Overall, antimicrobial resistance continues to rise and poses a huge threat in public health worldwide. Efforts should be made in developing rapid tests for antimicrobial resistance and to search for effective treatment from infections caused by multidrug resistant organisms.

Phase I trial of bortezomib and carboplatin in recurrent ovarian or primary peritoneal cancer.

PURPOSE: To determine the maximum-tolerated dose, pharmacodynamics, and safety of the combination of bortezomib and carboplatin in recurrent ovarian cancer. PATIENTS AND METHODS: Fifteen patients were treated with a fixed dose of carboplatin (area under the curve [AUC] 5) and increasing doses of bortezomib (0.75, 1, 1.3, and 1.5 mg/m2/dose). Patients must have received upfront chemotherapy and up to two prior chemotherapy regimens for recurrent disease. Neurologic evaluation was performed at baseline and after every two cycles by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group neurotoxicity questionnaire and examination by an attending neurologist. All patients received carboplatin alone in cycle 1 to establish baseline pharmacodynamics for nuclear factor-kappa B (NF-kB). Starting with cycle 2, patients were treated with carboplatin on day 1 and bortezomib on days 1, 4, 8, and 11. RESULTS: Diarrhea, rash, neuropathy, and constipation (with colonic wall thickening on computed tomography) were dose-limiting toxicities, occurring in the two patients treated at the 1.5 mg/m2/dose level. The Functional Assessment of Cancer Therapy/Gynecologic Oncology Group neurotoxicity questionnaire was helpful in guiding the need for dose reductions. Neurotoxicity was manageable through six cycles, with appropriate dose reductions. Carboplatin had no effect on bortezomib pharmacodynamics as measured by percent inhibition of the 20S proteasome. Bortezomib decreased carboplatin-induced NF-kB. The overall response rate to this combination was 47%, with two complete responses (CR) and five partial responses, including one CR in a patient with platinum-resistant disease. CONCLUSION: The recommended phase II dose of bortezomib administered in combination with carboplatin (AUC 5) is 1.3 mg/m2/dose.

Methods for Chemoprotection and Chemosensitization : MDR-1 For Chemoprotection Using Retroviruses to Modify Hematopoietic Cells and Cytosine Deaminase for Chemosensitization Using Adenoviral Vectors to Modify Epithelian Neoplastic Cells.

Surgery, radiation therapy, and chemotherapy have been applied to the curative therapy of 50% of cancer patients in the United States during the past 100 years. It is clear that the chemotherapeutic agents used to develop curative therapy for leukemias, lymphomas, gestational malignancy, and testicular cancer are not as active in the more numerous epithelial neoplasms, perhaps because of the complexity of genetic change in these latter neoplasms.

The Grainyhead transcription factor Grhl3/Get1 suppresses miR-21 expression and tumorigenesis in skin: modulation of the miR-21 target MSH2 by RNA-binding protein DND1.

Epidermal differentiation and stratification, crucial for barrier formation, are regulated by a complex interplay of transcription factors, including the evolutionarily conserved Grainyhead-like 3 (Grhl3/Get1); Grhl3-deleted mice exhibit impaired epidermal differentiation and decreased expression of multiple differentiation genes. To test whether Grhl3 regulates epidermal genes indirectly by controlling the expression of specific microRNAs (miRs), we performed miR profiling and identified 11 miRs that are differentially regulated in Grhl3(-/-) skin, one of which is miR-21, previously shown to be upregulated in diseased skin, including in psoriasis and squamous cell skin cancer. We found that miR-21 is normally expressed in the post-mitotic suprabasal layers of the epidermis, overlapping with Grhl3. The miR-21 promoter is bound and repressed by Grhl3 indicating that these two factors are involved in a regulatory loop maintaining homeostasis in the epidermis. Although miR-21 overexpression in normal keratinocytes had mild effects on the expression of several known miR-21 targets, an enhanced downregulation of the miR-21 tumor-related targets, including MSH2, was observed in Ras-transformed keratinocytes. The increased sensitivity of transformed keratinocytes to miR-21's effects occurs in part through downregulation of the RNA-binding protein DND1 during the transformation process. Additionally, we observed increased tumorigenesis in mice subcutaneously injected with transformed keratinocytes lacking Grhl3. These findings indicate that decreased Grhl3 expression contributes to tumor progression and upregulation of the oncomir miR-21 in squamous cell carcinoma of the skin.

Simple procedure for detection of Mycobacterium gordonae in water causing false-positive acid-fast smears.

A simple procedure for detecting a few cells of Mycobacterium gordonae in laboratory water that yielded spurious smear results is described.