Mariana Steiner

Olaparib Monotherapy in Patients With Advanced Cancer and a Germline BRCA1/2 Mutation

PURPOSE Olaparib is an oral poly (ADP-ribose) polymerase inhibitor with activity in germline BRCA1 and BRCA2 (BRCA1/2) -associated breast and ovarian cancers. We evaluated the efficacy and safety of olaparib in a spectrum of BRCA1/2-associated cancers. PATIENTS AND METHODS This multicenter phase II study enrolled individuals with a germline BRCA1/2 mutation and recurrent cancer. Eligibility included ovarian cancer resistant to prior platinum; breast cancer with ≥ three chemotherapy regimens for metastatic disease; pancreatic cancer with prior gemcitabine treatment; or prostate cancer with progression on hormonal and one systemic therapy. Olaparib was administered at 400 mg twice per day. The primary efficacy end point was tumor response rate. RESULTS A total of 298 patients received treatment and were evaluable. The tumor response rate was 26.2% (78 of 298; 95% CI, 21.3 to 31.6) overall and 31.1% (60 of 193; 95% CI, 24.6 to 38.1), 12.9% (eight of 62; 95% CI, 5.7 to 23.9), 21.7% (five of 23; 95% CI, 7.5 to 43.7), and 50.0% (four of eight; 95% CI, 15.7 to 84.3) in ovarian, breast, pancreatic, and prostate cancers, respectively. Stable disease ≥ 8 weeks was observed in 42% of patients (95% CI, 36.0 to 47.4), including 40% (95% CI, 33.4 to 47.7), 47% (95% CI, 34.0 to 59.9), 35% (95% CI, 16.4 to 57.3), and 25% (95% CI, 3.2 to 65.1) of those with ovarian, breast, pancreatic, or prostate cancer, respectively. The most common adverse events (AEs) were fatigue, nausea, and vomiting. Grade ≥ 3 AEs were reported for 54% of patients; anemia was the most common (17%). CONCLUSION Responses to olaparib were observed across different tumor types associated with germline BRCA1/2 mutations. Olaparib warrants further investigation in confirmatory studies.

Integrative oncology in the Middle East: from traditional herbal knowledge to contemporary cancer care

BACKGROUND Based on traditional, historical, ethnobotanical, laboratory, and clinical findings, we present research framework aiming to identify Middle Eastern herbs that are worthy of further research for their anticancer potential. METHODS A comprehensive research project was developed by a multinational team comprising family physicians, medicine specialists, oncologists, an Islamic medicine history specialist, a traditional medicine ethnobotanist, and a basic research scientist. The project followed two consecutive phases: (i) historical and ethnobotanical search for cancer-related keywords and (ii) Medline search for in vitro and in vivo studies. RESULTS This search yielded 44 herbs associated with cancer care. The Medline search yielded 34 herbs of which 9 herbs were reported in various clinical studies. CONCLUSIONS This multidisciplinary survey was found to be a valuable way to identify herbs with potential clinical significance in cancer care. Based on this pilot study, it is suggested that the Middle East can serve as a valuable region for future multicultural-oriented cancer research.BACKGROUND Based on traditional, historical, ethnobotanical, laboratory, and clinical findings, we present research framework aiming to identify Middle Eastern herbs that are worthy of further research for their anticancer potential. METHODS A comprehensive research project was developed by a multinational team comprising family physicians, medicine specialists, oncologists, an Islamic medicine history specialist, a traditional medicine ethnobotanist, and a basic research scientist. The project followed two consecutive phases: (i) historical and ethnobotanical search for cancer-related keywords and (ii) Medline search for in vitro and in vivo studies. RESULTS This search yielded 44 herbs associated with cancer care. The Medline search yielded 34 herbs of which 9 herbs were reported in various clinical studies. CONCLUSIONS This multidisciplinary survey was found to be a valuable way to identify herbs with potential clinical significance in cancer care. Based on this pilot study, it is suggested that the Middle East can serve as a valuable region for future multicultural-oriented cancer research.

Attitudes of patients with gynecological and breast cancer toward integration of complementary medicine in cancer care.

Objective The purpose of this study was to explore prospectively the perspectives of patients with breast and gynecological cancers regarding integration of complementary and alternative medicine (CAM) in conventional oncology settings. Methods We developed a 27-item questionnaire that was administered to convenient sample of patients with breast cancer and another with gynecological cancer who were attending a community-based oncology service in northern Israel. Results Of the 275 respondents, 109 (39.6%) had gynecological cancers and 166 (60.4%) had breast cancer. Current and/or previous year CAM use for oncology treatment was significantly higher among the patients with gynecological cancer (73/166 [44%] vs 67/106 [63%], P = 0.03). A logistic regression model indicated that CAM use was associated with gynecological cancer (EXP [B], 2.51; 95% confidence interval for EXP [B], 1.29–4.88; P = 0.007], younger age, Jewish religion, and lesser degree of religiosity. The patients highly expected their gynecologist-oncologist and family doctor to refer them to CAM counseling. Moreover, they expected their gynecologist-oncologist to participate in building a CAM treatment plan if CAM were to be integrated into the oncology service. The patients expected the CAM consultant to inform them of the safety and efficacy of CAM treatments, emphasizing expectations to strengthen their general ability to cope with the disease, reduce chemotherapy side effects, and provide emotional and spiritual support. Conclusion Although patients with gynecological malignancies use CAM significantly more than patients with breast cancer, both groups share similar conceptions regarding the active role of their gynecologist oncologists in the process of CAM integration within supportive care and expect CAM consultation to focus on improving their well-being.

Abstract P5-08-02: Real-life analysis evaluating 1594 N0/Nmic breast cancer patients for whom treatment decisions incorporated the 21-gene recurrence score result: 5-year KM estimate for breast cancer specific survival with recurrence score results ≤30 is >98%

Background: The 21-Gene Recurrence Score® Assay (Oncotype DX®) has been validated as a prognostic and predictive tool in estrogen receptor (ER)+ breast cancer in multiple studies using archival specimens of clinical trials with long term follow up. Prospective outcome data from patients where treatment decisions incorporated the Recurrence Score results have not been reported. We evaluated treatments and clinical outcomes in patients undergoing Recurrence Score testing in 9 medical centers within Clalit Health Services (CHS), the largest HMO in Israel. Methods: Medical records of patients with N0/Nmic ER+ HER2-negative disease undergoing testing from 12/2004 to 12/2010 in 9 medical centers (Rabin, Lin, Soroka, Meir, Kaplan, Hadassah, Ha9emek, Rambam, and Shaare Zedek) within CHS were individually reviewed to verify treatments given, recurrence, and survival status. 5-year Kaplan-Meier (KM) and standard error estimates for distant recurrence and breast cancer specific survival were determined. Results: 1594 patients were evaluated with 5.9 years median follow-up. Median age, 61 (25-85) years; N0/Nmic (90%/10%); Grade I (16%), II (48%), III (16%), N/A (19%); histology, IDC (80%), lobular (13%), other (7%). Distribution of Recurrence Score risk groups (Recurrence Score results of Conclusions: These are the first prospective long term clinical outcome data from approximately 1600 patients for whom the 21-gene Recurrence Score assay has been incorporated in real-life clinical decision making. The documented use of CT was appropriately based on the Recurrence Score result, and the outcomes for recurrence and survival are consistent with previously reported prospective-retrospective studies of the 21-gene assay. The 5 year KM estimates for distant recurrence rate in patients with low and intermediate Recurrence Score results who were treated based upon their Recurrence Score results were very low (0.5% and 1.2%, respectively). Citation Format: Stemmer SM, Steiner M, Rizel S, Soussan-Gutman L, Geffen DB, Nisenbaum B, Ben-Baruch N, Isaacs K, Fried G, Rosengarten O, Uziely B, Svedman C, Rothney M, Klang SH, Ryvo L, Kaufman B, Evron E, Zidan J, Shak S, Liebermann N. Real-life analysis evaluating 1594 N0/Nmic breast cancer patients for whom treatment decisions incorporated the 21-gene recurrence score result: 5-year KM estimate for breast cancer specific survival with recurrence score results ≤30 is >98%. [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 P5-08-02.

Wheatgrass in Afifi's Garden: Sprouting Integrative Oncology Collaborations in the Middle East

We suggest that bridging traditional and modern medicine can in many cases empower patients and enable them to better cope with cancer treatment. Our experiences in the Middle East might be applicable to other areas of the world facing a similar need to integrate evidence-based medicine with narrative-based, ethics-based, and ethnic medicine in the practice of oncology. In addition,we hope that our common efforts will encourage future collaboration among scientists and clinicians in the Middle East, which in turn might promote understanding, tolerance, and mutual respect among professionals in an area of the world troubled by ongoing geopolitical conflict.

Oral bisphosphonates and improved survival of breast cancer.

Purpose: Bisphosphonates are used for treatment or prevention of osteoporosis and of bone metastases. The use of oral bisphosphonates was suggested to be associated with reduced risk of developing breast cancer, and their positive influence on breast cancer survival was only demonstrated with third-generation bisphosphonates. We studied the association of use of oral bisphosphonates after breast cancer diagnosis on overall and breast cancer survival. Experimental Design: A nested case–control analysis was performed using data from the population-based Breast Cancer in Northern Israel Study (BCINIS). Participants were postmenopausal women with newly diagnosed breast cancer insured by Clalit. Use of second-generation bisphosphonates (alendronate and/or risedronate) was identified using computerized prescription records. The analysis was restricted to women who did not use bisphosphonates prior to diagnosis. Results: In a cohort of 3,731 postmenopausal women with breast cancer, followed up for an average of 70 months, there were 799 cases of death which were matched to 15,915 control periods of living breast cancer cases. Use of bisphosphonates after diagnosis for at least 18 months was significantly more common among survivors than among their matched controls who died, adjusted for tumor stage/grade (overall survival: OR = 0.63, 0.41–0.96, P = 0.03; breast cancer–specific survival: OR = 0.28, 0.09–0.91, P = 0.035). A similar advantageous effect, but statistically underpowered, was found in estrogen receptor (ER)-positive, ER-negative, and HER2neu-positive tumors. Conclusions: The use of oral bisphosphonates, by postmenopausal, probably osteoporotic, women initiated after diagnosis of breast cancer was associated with a significant improvement in overall and breast-specific odds of survival. Clin Cancer Res; 23(7); 1684–9. ©2016 AACR.

Clinical outcomes in patients with node-negative breast cancer treated based on the recurrence score results: evidence from a large prospectively designed registry

The 21-gene Recurrence Score® (RS) assay is a validated prognostic/predictive tool in ER + early-stage breast cancer. However, clinical outcome data from prospective studies in RS ≥ 11 patients are lacking, as are relevant real-life clinical practice data. In this retrospective analysis of a prospectively designed registry, we evaluated treatments/clinical outcomes in patients undergoing RS-testing through Clalit Health Services. The analysis included N0 ER + HER2-negative breast cancer patients who were RS-tested from 1/2006 through 12/2010. Medical records were reviewed to verify treatments/recurrences/survival. The cohort included 1801 patients (median follow-up, 6.2 years). Median age was 60 years, 50.4% were grade 2 and 81.1% had invasive ductal carcinoma; 48.9% had RS < 18, 40.7% RS 18–30, and 10.4% RS ≥ 31, with chemotherapy use of 1.4, 23.7, and 87.2%, respectively. The 5-year Kaplan–Meier estimates for distant recurrence were 0.8, 3.0, and 8.6%, for patients with RS < 18, RS 18–30 and RS ≥ 31, respectively; the corresponding 5-year Kaplan–Meier estimates for breast cancer death were 0.0, 0.9, and 6.2%. Chemotherapy-untreated patients with RS < 11 (n = 304) and 11–25 (n = 1037) (TAILORx categorization) had 5-year Kaplan–Meier estimates for distant recurrence risk/breast cancer death of 1.0%/0.0% and 1.3%/0.4%, respectively. Our results extend those of the prospective TAILORx trial: the 5-year Kaplan–Meier estimates for distant recurrence and breast cancer death rate for the RS < 18 patients were very low supporting the use of endocrine therapy alone. Furthermore, in chemotherapy-untreated patients with RS 11–25 (where TAILORx patients were randomized to chemoendocrine or endocrine therapy alone), 5-year distant recurrence rates were also very low, suggesting that chemotherapy would not have conferred clinically meaningful benefit.Genetic testing: Diagnostic shows which node-negative patients need chemoPatients with early breast cancer that hasn’t spread to lymph nodes can likely forgo chemotherapy if they score under 25 on Oncotype DX. That’s the finding of a retrospective analysis led by Salomon Stemmer from Rabin Medical Center in Petah Tikvah, Israel, that looked at 1801 women with node-negative, ER-positive, HER2-negative disease who received the diagnostic test, which measures the expression levels of 21 genes within tumor cells. Rates of disease recurrence and death were low for patients who received only anti-hormone treatment and had low-to-intermediate Oncotype DX results, suggesting no need for additional chemotherapy (which carries an appreciable risk of toxicity). Previously, a prospective US study called TAILORx established that women with scores under 11 could be spared chemotherapy. The Israeli trial validates and extends the results to include women with scores up to 25.

Short-term complications of intra-operative radiotherapy for early breast cancer

IORT is becoming an accepted radiotherapy technique for treatment of early breast cancer. Data regarding the early complications of breast IORT are lacking.

Paclitaxel, carboplatin, and oral etoposide in advanced gastric adenocarcinoma: association with severe myelotoxicity.

The prognosis of locally advanced or metastatic adenocarcinoma of the stomach is poor. In an attempt to improve therapeutic results, we undertook a phase II trial to investigate a combination of paclitaxel, carboplatin, and oral etoposide, all active drugs in this malignancy and with a synergistic effect in combination. Fourteen patients with advanced gastric adenocarcinoma were treated with paclitaxel 200 mg/m2 iv, carboplatin AUC-6 iv on d 1, and oral etoposide 50 mg/d alternating with 100 mg/d on d 1–10. Cycles were repeated every 3 wk. Of the 14 patients treated, partial response was observed in 3/12 (25%) evaluable patients. Median survival for the entire group was 7 mo. The treatment was associated with severe myelotoxicity. Neutropenic fever that required hospitalization developed in 7/14 (50%) of patients, and symptomatic anemia that required red blood cell transfusion was noted in 8/14 (57%). There was one drug-related death associated with neutropenic fever, Gram negative sepsis, grade 4 thrombocytopenia, and gastrointestinal bleeding. Nonhematological toxicity was moderate. We conclude that the current regimen of paclitaxel, carboplatin, and oral etoposide is not recommended in advanced gastric carcinoma owing to unacceptable myelotoxicity.

Clinical outcomes in ER+ HER2 -node-positive breast cancer patients who were treated according to the Recurrence Score results: evidence from a large prospectively designed registry

The Recurrence Score® is increasingly used in node-positive ER+ HER2-negative breast cancer. This retrospective analysis of a prospectively designed registry evaluated treatments/outcomes in node-positive breast cancer patients who were Recurrence Score-tested through Clalit Health Services from 1/2006 through 12/2011 (N = 709). Medical records were reviewed to verify treatments/recurrences/survival. Median follow-up, 5.9 years; median age, 62 years; 53.9% grade 2; 69.8% tumors ≤ 2 cm; 84.5% invasive ductal carcinoma; 42.0% N1mi, and 37.2%/15.5%/5.2% with 1/2/3 positive nodes; 53.4% Recurrence Score < 18, 36.4% Recurrence Score 18–30, and 10.2% Recurrence Score ≥ 31. Overall, 26.9% received adjuvant chemotherapy: 7.1%, 39.5%, and 86.1% in the Recurrence Score < 18, 18–30, and ≥ 31 group, respectively. The 5-year Kaplan–Meier estimates for distant recurrence were 3.2%, 6.3%, and 16.9% for these respective groups and the corresponding 5-year breast cancer death estimates were 0.5%, 3.4%, and 5.7%. In Recurrence Score < 18 patients, 5-year distant-recurrence rates for N1mi/1 positive node/2–3 positive nodes were 1.2%/4.4%/5.4%. As patients were not randomized to treatment and treatment decision is heavily influenced by Recurrence Score, analysis of 5-year distant recurrence by chemotherapy use was exploratory and should be interpreted cautiously: In Recurrence Score < 18, recurrence rate was 7.7% in chemotherapy-treated (n = 27) and 2.9% in chemotherapy-untreated patients (n = 352); P = 0.245. In Recurrence Score 18–30, recurrence rate in chemotherapy-treated patients (n = 102) was significantly lower than in untreated patients (n = 156) (1.0% vs. 9.7% P = 0.019); in Recurrence Score ≤ 25 (the RxPONDER study cutoff), recurrence rate was 2.3% in chemotherapy-treated (n = 89) and 4.4% in chemotherapy-untreated patients (n = 488); P = 0.521. In conclusion, our findings support using endocrine therapy alone in ER+ HER2-negative breast cancer patients with micrometastases/1–3 positive nodes and Recurrence Score < 18.Genetic testing: Gene panel guides treatment for node-positive patientsWomen with breast cancer that has spread to the lymph nodes do well on anti-hormone treatment alone if they score under 18 on OncotypeDX. Salomon Stemmer from Rabin Medical Center in Petah Tikvah, Israel, and colleagues conducted the first analysis of a large prospectively designed registry in which patients with breast cancer cells in the underarm lymph nodes have taken the 21-gene expression analysis known as OncotypeDX to guide their treatment. Among the 709 women with node-positive, ER-positive, HER-negative disease, patients with test scores under 18 did just as well if they received chemotherapy or not in addition to anti-hormone treatment, whereas those with scores of 18 to 30 had significantly lower recurrence rates if they received both therapies. The findings suggest that only women with OncotypeDX scores under 18 can safely forgo chemotherapy.