Delphine Topart

Frequent expression of PD-L1 on circulating breast cancer cells.

Immune checkpoint regulators such as PD‐L1 have become exciting new therapeutic targets leading to long lasting remissions in patients with advanced malignancies. However, in view of the remarkable costs and the toxicity profiles of these therapies, predictive biomarkers able to discriminate responders from non‐responders are urgently needed. In the present paper, we provide evidence that PD‐L1 is frequently expressed on metastatic cells circulating in the blood of hormone receptor‐positive, HER2‐negative breast cancer patients. We performed western blot, flow cytometry and immunocytochemical analyses to demonstrate the specificity of the PDL1 antibody used in our study and established immunoscores for PDL1 expression on single tumor cells. We then selected sixteen patients with circulating tumor cells (CTCs) using the CellSearch® system and found PD‐L1(+) CTCs in 11 patients (68.8%). The fraction of PD‐L1(+) CTCs varied from 0.2 to 100% in individual patients. This is the first report demonstrating the expression of PD‐L1 on CTCs. The established CTC/PD‐L1 assay can be used for liquid biopsy in future clinical trials for stratification and monitoring of cancer patients undergoing immune checkpoint blockade.

An ambispective observational study in the safety and efficacy of abiraterone acetate in the French temporary authorizations for use (ATU): Predictive parameters of response.

149 Background: The Temporary Authorizations for Use (ATU) procedure is an exceptional measure making available medicinal products that have not yet been granted a Marketing Authorisation. Abiraterone acetate (AA) was available for ATU since December 2010 in France. We then decided to evaluate the tolerance and efficacy of this treatment and identify predictive factors of response. METHODS 82 centers were contacted and clinical data were reported in two months (15th July-19th September 2011). Patients were defined as non-responders in case of interruption of AA due to disease progression or death. PSA values were recorded at each medical visit. Reported toxicities were also recorded. Statistical analyses were descriptive and predictive factors were determined. RESULTS A total of 18 centers accepted to participate in this study including 381 patients. Median age at diagnosis was 63 years. The Gleason score (n=320) were 4-6, 7, and 8-10 in 13.4%, 36.9% and 49.7%, respectively. Before AA, the type of metastasis was bone only, organs only, and bone+organs in 45.4%, 7.9% and 46.7%, respectively. Median PSA before CT and before AA was 58.1 and 137.5 ng/ml, respectively. Median duration of hormonotherapy (HT) before any CT was 34 months. Median duration of CT before AA was 6.1 months with a median number of CT lines of one. Median duration of AA was 117 days. In the non-responders group (n=114), median duration of AA was significantly shorter than in the responders group (n=267), 87 days vs 147 days, respectively (p<0.0001). One third of the patients in the responders group presented a PSA increase over time but continued AA as they clinically improved. Only 13 patients stopped AA for grade 3-4 toxicities. GIeason 8-10 and the number of CT lines (>1) before AA were identified as independent predictive factors of non response. CONCLUSIONS This report is the largest ambispective observational study of AA in an ATU process. PSA values during AA treatment were used as a good indicator of progression. GIeason 8-10 and the number of CT lines (>1) before AA were identified as independent predictive factors and therefore could be used for further strategies in this setting.

Bevacizumab-Related Surgical Site Complication Despite Primary Tumor Resection in Colorectal Cancer Patients

BackgroundCombining conventional systemic chemotherapy with the angiogenesis inhibitor bevacizumab is now recommended as a first treatment for metastatic colorectal neoplasms. The risk for short-term postoperative complications related to bevacizumab has been assessed. Late postoperative complications related to bevacizumab have also been suggested by preliminary reports.MethodsWe reviewed a cohort of 142 patients with previous surgery for primary colonic or rectal tumor and without evidence of local recurrence, receiving bevacizumab for metastatic disease.ResultsFour patients experienced a late surgical site complication related to bevacizumab. Common features were rectal location, low anastomosis, and preoperative irradiation. Combining these three factors, the risk of a bevacizumab-related complication was 4 in 27 (14.8%); if previous history of postoperative leakage was reported, the risk was raised to 2 in 4. No complications occurred in colonic location or the non-irradiated patients. The mechanism of these complications could be ischemic lesion in post-irradiated tissues involving anastomoses.ConclusionWe conclude that angiogenesis inhibitors should be carefully considered for patients having low colorectal anastomosis and previous irradiation.

Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma-Results of the REchallenge with SUnitinib in MEtastatic RCC (RESUME) Study.

AIM To assess the efficacy and tolerability of sunitinib rechallenge in the third-line or later setting in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS This observational study comprised 61 mRCC patients at 19 centres in France who received sunitinib rechallenge between January 2006 and May 2013. Patients received first-line sunitinib, ≥1 different targeted therapies, and then sunitinib rechallenge. Patient/disease characteristics, tolerability, treatment modalities, and outcomes of therapeutic lines were recorded. The primary end-point was progression-free survival (PFS) in sunitinib rechallenge. RESULTS Analyses included 52 patients; median age was 59 years, 75% were male, and 98% had clear-cell mRCC and prior nephrectomy. At sunitinib rechallenge versus first-line, patients had poorer performance (Karnofsky performance status 90-100: 30% versus 81%) and Memorial Sloan Kettering Cancer Centre prognostic risk (poor risk: 18% versus 3%). Overall, 20%, 65%, 12%, and 4% received sunitinib rechallenge as third-, fourth-, fifth-, and sixth-line therapy, respectively, at 14.6 months (median) after stopping initial treatment. With first-line sunitinib and rechallenge, median PFS was 18.4 and 7.9 months, respectively; objective response rate was 54% and 15%. Two of eight rechallenge responders had not achieved first-line response. Median overall survival was 55.9 months. The sunitinib rechallenge safety profile was as expected, with no new adverse events reported. CONCLUSIONS Sunitinib rechallenge is a feasible treatment option with potential clinical benefit for mRCC patients. Disease progression with first-line sunitinib may not be associated with complete or irreversible resistance to therapy.

Comparative Study of Neoadjuvant Chemotherapy With and Without Zometa for Management of Locally Advanced Breast Cancer With Serum VEGF as Primary Endpoint: The NEOZOL Study

Introduction: Neoadjuvant chemotherapy has become the treatment of choice for locally advanced breast cancer. Zoledronic acid (ZA) is a bisphosphonate initially used in the treatment of bone metastases because of its antibone resorption effect. Antitumor effects of ZA, including the inhibition of cell adhesion to mineralized bone or the antiangiogenic effect, have been demonstrated. However, the clinical significance of these effects remains to be determined. Materials and Methods: We undertook a multicenter open‐label randomized trial to analyze the value of adding ZA to neoadjuvant chemotherapy for TNM clinical stage T2/T3 breast cancer. The primary endpoint was the evolution of serum VEGF. Results: The data from 24 patients were included in the ZA group and 26 in the control group. The evolution of serum VEGF was slightly in favor of ZA at 5.5 months (−0.7% vs. +7.5%), without reaching statistical significance (P = .52). The secondary endpoints were the breast conservation rate (higher with ZA; 83.3% vs. 65.4%; P = NS), pathologic complete response (no effect), and circulating tumor cells (odds ratio, 0.68 in favor of ZA; 95% confidence interval, 0.02‐24.36). No cases of jaw necrosis or severe renal failure were observed in either group. Conclusion: ZA is an antitumor drug of interest because of its multiple effects on tumor biology. Larger trials with longer follow‐up that include additional endpoints such as relapse and survival rates would be of interest.

Abstract P5-21-02: Final results of the VitaCal randomized phase III study evaluating the impact of a tailored oral vitamin D supplementation regimen on serum 25-hydroxyvitamin D levels in early breast cancer patients

Purpose: Only a minority of patients with early breast cancer (EBC) treated with adjuvant or neoadjuvant chemotherapy have sufficient baseline vitamin D. The current recommendations regarding daily vitamin D supplementation appears too low to correct this deficiency in this population. Optimal vitamin D dosing has yet to be determined in this setting. The current randomized phase III study address the issue of the effectiveness and safety of a tailored high dose oral vitamin D supplementation as a means for restoring normal 25-hydroxy vitamin D (25OHD) levels in a large population of chemotherapy-treated EBC patients. Methods: Chemotherapy-treated EBC patients were stratified according to the degree of Vitamin D deficiency, time between chemotherapy initiation and inclusion (0 to 6 months versus 6 to 12 months), hormone receptors status and menopausal status. Participants were randomly assigned to receive a 6-months conventional (C) vitamin D and calcium supplementation or a 6-months high dose oral vitamin D regimen tailored on the degree of deficiency (T) associated with a conventional calcium supplementation. Primary endpoint was the efficacy (6-months percentage of 25OHD serum levels normalization) in the T arm compared with the C arm. Patients without vitamin D normalization from the C arm were allowed to switch to the T arm after 6 months. Statistical analyses were performed on an intent to treat basis. Results: The trial accrued 215 patients, among which 197 patients presented with vitamin D deficiency, and randomized 195 patients (T, 100; C, 95) from July 2011 to January 2013. The groups were well balanced in regard to the stratification characteristics, as well as in regard of median weight and neoadjuvant or adjuvant chemotherapy status. Compliance to the daily oral supplementation was low in both arms, 64% of the patients in both arms taking less than 80% of the planned oral supplementation dose. Compliance to the tailored high dose vitamin D schedule appeared better (78%). After 6 months of treatment, at the primary endpoint analysis time, significantly more patients in the T arm presented with normalized serum vitamin D levels compared to the C arm (30% vs . 12.6%; p =0.003). Vitamino-calcic supplementation was well tolerated, with no difference in the treatment-related toxicity between the 2 arms. 52 patients without vitamin D normalization from the C arm switched to the T arm after 6 months. At the 12 months endpoint, 44% of these patients achieved vitamin D normalization. Conclusion: In this randomized phase III study, a tailored high dose oral vitamin D supplementation allowed a statistically higher percentage of serum 25OHD levels normalization compared to a conventional regimen, without any increase in side effects, in a large population of chemotherapy-treated EBC patients. Observance of a daily oral supplementation remains poor in this setting, advocating for an adaptation of the schedule and dosage of this supplementation in a population of patients subject to chemotherapy-induced emesis. Clinical trial number NCT01480869. Citation Format: William Jacot, Nelly Firmin, Lise Roca, Delphine Topart, Sophie Gallet, Anna Durigova, Simone Mirr, Stephane Pouderoux, Jean-Pierre Bleuse, Pierre-Jean Lamy, Gilles Romieu. Final results of the VitaCal randomized phase III study evaluating the impact of a tailored oral vitamin D supplementation regimen on serum 25-hydroxyvitamin D levels in early breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-21-02.