Benjamin Paz

Association of reactive oxygen species levels and radioresistance in cancer stem cells.

The metabolism of oxygen, although central to life, produces reactive oxygen species (ROS) that have been implicated in processes as diverse as cancer, cardiovascular disease and ageing. It has recently been shown that central nervous system stem cells and haematopoietic stem cells and early progenitors contain lower levels of ROS than their more mature progeny, and that these differences are critical for maintaining stem cell function. We proposed that epithelial tissue stem cells and their cancer stem cell (CSC) counterparts may also share this property. Here we show that normal mammary epithelial stem cells contain lower concentrations of ROS than their more mature progeny cells. Notably, subsets of CSCs in some human and murine breast tumours contain lower ROS levels than corresponding non-tumorigenic cells (NTCs). Consistent with ROS being critical mediators of ionizing-radiation-induced cell killing, CSCs in these tumours develop less DNA damage and are preferentially spared after irradiation compared to NTCs. Lower ROS levels in CSCs are associated with increased expression of free radical scavenging systems. Pharmacological depletion of ROS scavengers in CSCs markedly decreases their clonogenicity and results in radiosensitization. These results indicate that, similar to normal tissue stem cells, subsets of CSCs in some tumours contain lower ROS levels and enhanced ROS defences compared to their non-tumorigenic progeny, which may contribute to tumour radioresistance.

Short-Term Outcomes After Robotic-Assisted Total Mesorectal Excision for Rectal Cancer

BackgroundLaparoscopic total mesorectal excision for rectal cancer remains a difficult procedure with high conversion rates. We have sought to improve on some of the pitfalls of laparoscopy by using the DaVinci robotic system. Here we report our two-year experience with robotic-assisted laparoscopic surgery for primary rectal cancer.MethodsA prospectively maintained database of all rectal cancer cases starting in November 2004 was created. A series of 39 consecutive unselected patients with primary rectal cancer was analyzed. Clinical and pathologic outcomes were reviewed retrospectively.Results22 patients had low anterior, 11 intersphincteric and six abdominoperineal resections. Postoperative mortality and morbidity were % and 12.8%, respectively. The median operative time was 285 minutes (range 180–540 mins). The conversion rate was 2.6%. A total mesorectal excision with negative circumferential and distal margins was accomplished in all patients, and a median of 13 (range 7–28) lymph nodes was removed. The anastomotic leak rate was 12.1%. The median hospital stay was 4 days. There have been no local recurrences at a median follow-up of 13 months.ConclusionsRobotic-assisted surgery for rectal cancer can be carried out safely and according to oncological principles. This approach shows promising short-term outcomes and may facilitate the adoption of minimally invasive rectal surgery.

Diagnostic and therapeutic delays among a multiethnic sample of breast and cervical cancer survivors

Several publications reporting on health disparities document that ethnic minorities disproportionately experience delays in healthcare access, delivery, and treatment. However, few studies examine factors underlying access and receipt of healthcare among cancer survivors from the patient perspective. This study explores diagnostic and therapeutic care delays among a multiethnic sample of breast and cervical cancer survivors and examines contextual factors influencing diagnostic and therapeutic care delays.

Papillary Carcinoma of the Breast: An Overview

Papillary carcinoma of the breast represents ~0.5% of all newly diagnosed cases of breast cancer. The prevalence of both invasive and in situ papillary carcinoma seems to be greater in older postmenopausal women and, in relative terms, in males. Histologic features of the tumor include cellular proliferations surrounding fibrovascular cores, with or without invasion. In this review, characteristics of both in situ and invasive disease are outlined. Immunohistochemical analyses of papillary carcinoma suggest the utility of markers such as smooth muscle myosin heavy chain, calponin, p63, and high molecular weight keratins, which can characterize the myoepithelial cell layer. With respect to radiographic evaluation of papillary carcinoma, ultrasonography is the most extensively studied imaging modality, though magnetic resonance mammography has potential utility. Available data suggest improved outcome for papillary carcinoma as compared to invasive ductal carcinoma. Treatment-related information for patients with papillary carcinoma is limited, and patterns noted in available series suggest a variable approach to this disease. The scarcity of information underscores the need for further treatment- and outcome-related studies in papillary carcinoma of the breast.

Phase I trial of intraperitoneal gemcitabine in the treatment of advanced malignancies primarily confined to the peritoneal cavity

Purpose: To determine the maximally tolerated dose, toxicity, and pharmacokinetics of i.p. gemcitabine. Experimental Design: Patients had peritoneal carcinomatosis. Gemcitabine (40, 80, 120, or 160 mg/m2) was administered into the peritoneal cavity in 2 L of warmed saline on days 1, 4, 8, and 12 of a 28-day cycle. Results: Thirty patients received 63 (median, 2; range, 0-6) courses. Tumors included ovary (14), uterus (2), colon (6), pancreas (3), and others (5). Dose-limiting toxicity included nausea, vomiting, diarrhea, dyspnea, fatal respiratory failure, and grade 3 elevation of alanine aminotransferase in three patients. Hematologic toxicity and pain were ≤grade 2. Three patients had decreased or resolved ascites. Of 19 patients evaluable for response, 10 had stable disease (median, 3.5 courses) and 9 had progressive disease. The median peak peritoneal concentration was 1,116-fold (range, 456-1,886) higher than the peak plasma level. Plasma and peritoneal levels were undetectable within 8 to 12 h. At 120 mg/m2, the median peritoneal area under the concentration versus time curve (AUC) was 82,612 ng/mL × h (range, 53,296-199,830) and the plasma AUC was 231 ng/mL × h (range, 47.6-259.5). The mean peritoneal advantage (AUCperitoneal/AUCplasma) was 847 (range, 356-1,385). Conclusions: I.p. administration of gemcitabine is tolerated within the tested dosage range. Technical problems with the Porta-Cath device and i.p. therapy per se may have been exacerbated by the enrollment of many patients with a variety of advanced i.p. diseases. Given the significant increase in local dose intensity and the documented activity of this drug, this agent may be an excellent candidate for i.p. therapy in optimally debulked ovarian cancer, either alone or in combination.

Towards developing a bilingual treatment summary and survivorship care plan responsive to Spanish language preferred breast cancer survivors

BackgroundTreatment summary and survivorship care plan studies are at the forefront of research priorities with precedence for ethnic minority inclusion. This preliminary study joined the advocacy, scientific, and medical communities to inform the development and evaluation of the Treatment Summary and Survivorship Care Plan (TSSCP-S) template targeted for Latino breast cancer patients (LCA).MethodsThe development of the TSSCP-S began as modifications to the American Society of Cancer Oncology (ASCO) (TSSCP-ASCO) template via a transcreation process informed by 12 LCA survivors/advocates, and evaluated by 10 survivor/advocates and health professionals. The TSSCP-S template development was guided by the Shared Care, Psychooncology Models, and Contextual Model of Health Related Quality of Life.ResultsThe bilingual TSSCP-S was independently evaluated by bilingual, survivor/advocates, and health professionals (n = 10). Preliminary analyses indicate that the TSSCP-S template was rated more favorably than the TSSCP-ASCO on the following domains: content (p = 0.02), clarity (p = 0.02), utility (p = 0.04), cultural and linguistic responsiveness (p = 0.03), and socioecological responsiveness (p = 0.01). Evaluators noted that the TSSCP-S template was more patient-centered, and endorsed the acceptability as well as the potential utility and applicability of the bilingual TSSCP-S template to appropriately guide surveillance and follow-up care.ConclusionsOur findings indicate that the TSSCP-S achieved clinical, cultural, and linguistic responsiveness relevant to Latinos. Patient-centered TSSCP that are presented in a bilingual format are necessary to achieve the intended goals of TSSCP including appropriate patient information, education, and resources pertaining to their treatment, potential side effects, and recommended surveillance and follow-up care for English language limited patients. Additionally, our culturally responsive TSSCP-S development framework offers a model for TSSCP template development for targeted and underserved populations, including ethnic and linguistic minority cancer survivors.Implications for Cancer SurvivorsThese data support the development and evaluation of a TSSCP targeted to an underserved, high-risk population, LCAs. Identifying methods to improve surveillance and follow-up guideline adherence may lead to improved clinical cancer outcomes and quality of life.

Enhanced Recovery after Surgery for Gastric Cancer Patients Improves Clinical Outcomes at a US Cancer Center

Purpose Enhanced recovery after surgery (ERAS) protocols for gastric cancer patients have shown improved outcomes in Asia. However, data on gastric cancer ERAS (GC-ERAS) programs in the United States are sparse. The purpose of this study was to compare perioperative outcomes before and after implementation of an GC-ERAS protocol at a National Comprehensive Cancer Center in the United States. Materials and Methods We reviewed medical records of patients surgically treated for gastric cancer with curative intent from January 2012 to October 2016 and compared the GC-ERAS group (November 1, 2015–October 1, 2016) with the historical control (HC) group (January 1, 2012–October 31, 2015). Propensity score matching was used to adjust for age, sex, number of comorbidities, body mass index, stage of disease, and distal versus total gastrectomy. Results Of a total of 95 identified patients, matching analysis resulted in 20 and 40 patients in the GC-ERAS and HC groups, respectively. Lower rates of nasogastric tube (35% vs. 100%, P<0.001) and intraabdominal drain placement (25% vs. 85%, P<0.001), faster advancement of diet (P<0.001), and shorter length of hospital stay (5.5 vs. 7.8 days, P=0.01) were observed in the GC-ERAS group than in the HC group. The GC-ERAS group showed a trend toward increased use of minimally invasive surgery (P=0.06). There were similar complication and 30-day readmission rates between the two groups (P=0.57 and P=0.66, respectively). Conclusions The implementation of a GC-ERAS protocol significantly improved perioperative outcomes in a western cancer center. This finding warrants further prospective investigation.

Abstract P4-21-35: Phase II trial of pertuzumab, trastuzumab, and nab-paclitaxel in patients (pts) with HER2 overexpressing (HER2+) locally advanced or inflammatory breast cancer (LABC) or untreated stage IV metastatic breast cancer (MBC)

Background: Pathologic complete response (pCR) to HER2-targeting neoadjuvant therapy (NT) predicts for improved survival (Cortazar et al, Lancet, 2014). The addition of pertuzumab to trastuzumab and docetaxel increased pCR rates, and, as first line treatment for MBC led to longer overall survival ([OS] Swain et al, NEJM 2015). Avoidance of anthracyclines in the adjuvant setting for HER2+ BC reduced the risk of secondary hematologic malignancies without a detriment to OS (Slamon et al, NEJM, 20111). Finally, nab-paclitaxel (nab) might provide an advantage over other taxanes via decreased use of steroids and may lead to increased response rates (RR). We designed a study of pertuzumab (pert), trastuzumab (trast), and nab, testing the feasibility and efficacy of this regimen in the LABC and metastatic breast cancer settings. Materials and Methods: Pts with Stages II-III LABC received six cycles of NT with pert (day 1 q 21 days), trast, and nab 100 mg/m2 (both given IV, weekly). Pts with untreated MBC received the same regimen until progression, toxicities, or patient or physician preference led to stopping therapy. Primary endpoints included pCR (LABC) and RR and progression-free survival (PFS) in MBC. Forty pts with LABC and 25 pts with MBC were to be accrued. The study was designed to test whether the pCR rate of Neosphere (Gianni et al, Lancet Oncol, 2012, > 45.8%) and the PFS rate of CLEOPATRA (median of > 18.5 months) can be matched or exceeded. Procurement of serial samples for assessment of tumor gene expression, circulating tumor cells, miRNA, and serum DNA profiling for exploratory biomarker analysis was carried out. Results:Twenty-two of 28 already enrolled pts with LABC (clinical stage II:15, stage III: 7) completed NT. The median age was 53 (34-77). The pCR rate was 86% (6/7) for hormone receptor negative (HR-) and 40% (6/15) for HR+ pts, with an overall pCR of 55%. Three pts without pCR following NT had residual BC with a HER2 negative phenotype. Eighteen of 22 pts required nab dose modifications. The most frequent toxicities following NT included elevated liver function tests:27%, peripheral neuropathy:23%, hematological toxicities:17%, diarrhea:18%, infusion reactions:18%. In the MBC cohort there were 13 of 16 enrolled pts with > 2 months of follow-up. The median age was 47 (31-65), 62% had HR+ disease. A CR rate of 4/13 (31%) and confirmed RR of 77% were observed. The median number of cycles with pert, trast, nab was 9 (3+ to 41); 11 of 13 pts required dose modifications or delays (3 of the delays were due to primary breast surgery performed upon response to treatment). At a median follow-up of 19 months, PFS and OS estimates are 63% (95% CI 0.09-0.93), and 89% (95% CI 0.61-1.0). Conclusion: The non-anthracycline-containing regimen of pertuzumab, trastuzumab, and nab-paclitaxel induced a high pCR rate in HER2+ BC. PFS is encouraging in MBC. Outcome of the fully accrued cohorts inclusive of residual cancer burden scores in the LABC cohort, and correlative data with exploratory biomarker analysis will be presented. Citation Format: Somlo G, Frankel P, Yeon C, Yuan Y, Yim J, Kruper L, Taylor L, Mortimer J, Waisman J, Jones V, Vito C, Paz B, Huria A, Li D, Gaal C, Tong T, Tumyan L. Phase II trial of pertuzumab, trastuzumab, and nab-paclitaxel in patients (pts) with HER2 overexpressing (HER2+) locally advanced or inflammatory breast cancer (LABC) or untreated stage IV metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-35.

Abstract P1-14-10: Phase II trial of neoadjuvant chemotherapy with carboplatin and nab-paclitaxel in patients with triple negative locally advanced and inflammatory breast cancer

Background: Pathologic complete response (pCR) and residual cancer burden (RCB scores of 0 [pCR] or 1[near CR]) after neoadjuvant chemotherapy (NCT) may predict for improved survival (Symmans et al. J Clin Oncol 25:4414-22, 2007). We set out to test the pCR rate with an anthracycline-free regimen of carboplatin (carb) and nab-paclitaxel (nab) in patients (pts) with triple negative breast cancer (TNBC). Materials and Methods: Forty-nine pts with stages II-III BC were to receive carb (AUC 6) on day 1 of a 28 day cycle, and nab 80 mg/m2 weekly, for a total of 4 cycles. Core biopsies were performed prior to NCT. Blood procurement for circulating tumor cell (CTC) analysis using the CellSearch platform was carried out pre-treatment, mid-treatment, and at surgery. We set out to assess the predictive value of Mammaprint (poor vs. good), BluePrint (basal, vs. luminal, vs. HER2) molecular subtype as well as microarray RNA and miRNA profiling, for pCR. Responses were also dichotomized as complete or near complete response (Symmans RCB scores of 0-1) vs. suboptimal response (RCB score > 1). Results: The median age was 53 (28-75). Pts presented with clinical stages II (63%) and III (37%). So far, 38 of the 49 pts accrued between 2/2012 and 6/2015, have undergone surgery, 68% of whom underwent modified radical mastectomy. The pCR rate (breast and lymph nodes in CR) was 53%, and RCB 0 and 1 were seen in 68% of pts. Toxicites included grade ¾ anemia (45%), thrombocytopenia (13%) and neutropenia (53%,1 pt with neutropenic fever). Dose adjustments were needed in over 80% of pts. Grades 2 or 3 peripheral neuropathy were seen in 8% each, and grades 3-4 fatigue (13%), hypokalemia (3%), and hyponatremia (3%) were observed. The median number of CTCs (pre-NCT) observed in 7 CTC positive pts of the first 27 pts who completed surgery was 1 (0-7), and 2 of the 7 pts continued to have CTCs at the time of surgery (1 CTC each), while 2 pts without CTCs pre-NCT had CTCs (1 each) detected at surgery. The final pt enrolled is expected to complete surgery by 10/2015. Results of sequential CTC assessments, MammaPrint/Blueprint and RNA/miRNA analysis of pre- and post-treatment specimens and their correlation with pCR will be presented. Conclusion: The non-anthracycline-containing regimen of carb and nab-paclitaxel induced a high pCR rate in TNBC, in preliminary analysis. Ongoing profiling may allow for future subset-specific modification of this regimen to increase pCR across all molecular subtypes of TNBC. Citation Format: Somlo G, Chung S, Frankel P, Hurria A, Koehler S, Kruper L, Mortimer JE, Paz B, Robinson K, Taylor L, Vito C, Waisman J, Yeon C, Yim J, Yuan Y, Tong T. Phase II trial of neoadjuvant chemotherapy with carboplatin and nab-paclitaxel in patients with triple negative locally advanced and inflammatory breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-10.

A phase II trial of neoadjuvant chemotherapy (NCT), organ-sparing surgery, and radiation in squamous cell head and neck cancer (SCHNC): Results of neoadjuvant chemotherapy

5617 Background: NCT with radiation has facilitated organ-sparing treatment in locally advanced SCHNC. We conducted a phase II study of patients (pts) with SCHNC to evaluate a combination of NCT, radiation, and surgery to evaluate response to NCT as well as evaluate overall survival and recurrence patterns. METHODS Pts had resectable untreated stage III, IV SCHNC of the oral cavity, oropharynx, hyopharynx, or larynryx, and stage II cancer of the base of tongue, hypopharynx, and larynx. An ANC ≥ 1500/μl, platelet ≥ 100K/μl, serum creatinine ≤ 1.5mg/dl, bilirubin ≤ 1.5 mg/dl, liver function tests < 2.5 ULN, Karnofsky Performance Status (KPS) ≥ 60%, and signed informed consent were required. NCT consisted of docetaxel 60 mg/m2, then a 96-hour infusion of cisplatin 25mg/m2/d, 5-fluorouracil 700 mg/m2/d, and leucovorin 500 mg/m2/d. After 2 courses (C), those with at least a partial response received a third C. Pts with clinical complete response (CCR) or tumors < T1 were received radiation or chemoradiation and, as needed, surgery including modified lymph node dissection. RESULTS A total of 31 pts (1 with tonsillar lymphoepithelioma) were enrolled with response data for NCT in the first 25 pts presented. Pts had stage III (9), IVa (13), IVb (2), and stage II (1) disease. Median age was 63 yrs and 84% had a KPS ≥ 80%. After 2 Cs, 23/25 pts were in response, 6 in clinical complete response (CCR) in both neck and primary site. After a third cycle, 11/22 were in CCR with 16/22 in CCR at the primary site. Biopsies and/or surgical resection were performed in 18 of these pts; 11 pathologic complete responses (PCR) were seen. PCR was seen in 15/18 primary sites, and no pt required laryngectomy or base of tongue resection. Hemiglossectomy was performed in 2 pts and tonsillectomy in 3 pts (with 2/3 in PCR). C 2 dose reductions were needed in 12/24 pts and most required growth factor support. C 3 included 7/23 pts without dose reductions. CONCLUSIONS NCT using a multi-agent regimen induces promising response rates allowing organ-sparing surgery in a high percentage of pts with SCHNC. Supported in part by grants from Aventis and CA 33572. [Table: see text].