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International audience; BACKGROUND:Two-stage hepatectomy of bilobar colorectal liver metastases is widely used and shows encouraging survival results. However, the risk of dropout after the first stage remains high and is associated with poor survival. The objective of our study was to evaluate the factors associated with long-term survival based on the pathologic response to preoperative systemic chemotherapy in colorectal liver metastases patients who underwent two-stage hepatectomy.METHODS:The pathologic response to preoperative chemotherapy and its effect on second-stage completion and survival were retrospectively evaluated in 67 patients treated between 2003 and 2013.RESULTS:A total of 56 patients underwent two-stage hepatectomy for initially nonresectable colorectal liver metastases. Chemotherapy was combined with a biotherapy in 32 cases. The tumor regression grade, modified tumor regression grade, and Blazer grade were used to classify patients as responders (tumor regression grade and modified tumor regression grade 1-3, Blazer 0-1) or nonresponders (tumor regression grade and modified tumor regression grade 4-5, Blazer 2) after the first stage. Tumor response in the three classifications was associated with second-stage completion (tumor regression grade 1-3: OR = 4.01, 95% CI: 1.12-14.36, P = .033; modified tumor regression grade 1-3: OR = 3.8, 95% CI: 1.13-12.6, P = .03; Blazer 0-1: OR = 5.45, 95% CI: 1.66-17.85, P = .005). Triple chemotherapy was also associated with responders. The median overall survival of responders was significantly higher (Blazer 0-1: 42.9 months versus Blazer 2: 20.1 months, P = .018; tumor regression grade 1-3: 42.9 months versus tumor regression grade 4-5: 25.1 months, P = .04).CONCLUSION:A pathologic response to chemotherapy is associated with second-stage completion and longer survival. Further studies are needed to achieve the early identification of patients for whom the benefit of the second surgical stage is less straightforward.

Summary Background The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to cytoreductive surgery has been associated with encouraging survival results in some patients with colorectal peritoneal metastases who were eligible for complete macroscopic resection. We aimed to assess the specific benefit of adding HIPEC to cytoreductive surgery compared with receiving cytoreductive surgery alone. Methods We did a randomised, open-label, phase 3 trial at 17 cancer centres in France. Eligible patients were aged 18–70 years and had histologically proven colorectal cancer with peritoneal metastases, WHO performance status of 0 or 1, a Peritoneal Cancer Index of 25 or less, and were eligible to receive systemic chemotherapy for 6 months (ie, they had adequate organ function and life expectancy of at least 12 weeks). Patients in whom complete macroscopic resection or surgical resection with less than 1 mm residual tumour tissue was completed were randomly assigned (1:1) to cytoreductive surgery with or without oxaliplatin-based HIPEC. Randomisation was done centrally using minimisation, and stratified by centre, completeness of cytoreduction, number of previous systemic chemotherapy lines, and timing of protocol-mandated systemic chemotherapy. Oxaliplatin HIPEC was administered by the closed (360 mg/m2) or open (460 mg/m2) abdomen techniques, and systemic chemotherapy (400 mg/m2 fluorouracil and 20 mg/m2 folinic acid) was delivered intravenously 20 min before HIPEC. All individuals received systemic chemotherapy (of investigators' choosing) with or without targeted therapy before or after surgery, or both. The primary endpoint was overall survival, which was analysed in the intention-to-treat population. Safety was assessed in all patients who received surgery. This trial is registed with ClinicalTrials.gov , NCT00769405 , and is now completed. Findings Between Feb 11, 2008, and Jan 6, 2014, 265 patients were included and randomly assigned, 133 to the cytoreductive surgery plus HIPEC group and 132 to the cytoreductive surgery alone group. After median follow-up of 63·8 months (IQR 53·0–77·1), median overall survival was 41·7 months (95% CI 36·2–53·8) in the cytoreductive surgery plus HIPEC group and 41·2 months (35·1–49·7) in the cytoreductive surgery group (hazard ratio 1·00 [95·37% CI 0·63–1·58]; stratified log-rank p=0·99). At 30 days, two (2%) treatment-related deaths had occurred in each group.. Grade 3 or worse adverse events at 30 days were similar in frequency between groups (56 [42%] of 133 patients in the cytoreductive surgery plus HIPEC group vs 42 [32%] of 132 patients in the cytoreductive surgery group; p=0·083); however, at 60 days, grade 3 or worse adverse events were more common in the cytoreductive surgery plus HIPEC group (34 [26%] of 131 vs 20 [15%] of 130; p=0·035). Interpretation Considering the absence of an overall survival benefit after adding HIPEC to cytoreductive surgery and more frequent postoperative late complications with this combination, our data suggest that cytoreductive surgery alone should be the cornerstone of therapeutic strategies with curative intent for colorectal peritoneal metastases. Funding Institut National du Cancer, Programme Hospitalier de Recherche Clinique du Cancer, Ligue Contre le Cancer.

Background The 21-gene Recurrence Score (RS) result predicts outcome and chemotherapy benefit in node-negative and node-positive (N+), estrogen receptor-positive (ER+) patients treated with endocrine therapy. The purpose of this study was to evaluate the prognostic impact of RS results in N+, hormone receptor-positive (HR+) patients treated with adjuvant chemotherapy (6 cycles of FEC100 vs. 3 cycles of FEC100 followed by 3 cycles of docetaxel 100 mg/m2) plus endocrine therapy (ET) in the PACS-01 trial (J Clin Oncol 2006;24:5664-5671). Methods The current study included 530 HR+/N+ patients from the PACS-01 parent trial for whom specimens were available. The primary objective was to evaluate the relationship between the RS result and distant recurrence (DR). Results There were 209 (39.4%) patients with low RS (

Purpose Optimal duration of adjuvant chemotherapy in the treatment of early-stage breast cancer remained to be investigated rigorously for the standard regimens in widespread use in North America (doxorubicin/cyclophosphamide, AC) and Europe (5-fluorouracil/epirubicin/cyclophosphamide, FEC). Whether six cycles of FEC 100 present an advantage, or not, compared with only four cycles was tested directly in a phase III prospective multicentre trial. Patients and methods Between 2002 and 2006, 1515 women between 18 and 65°years of age, with node negative N(−) high-risk early-stage breast cancer, were included in the study following breast surgery and axillary lymph node dissection or procedure by sentinel node technique. Inclusion in the study required tumour size T ≥ 1 cm and at least one of the high-risk factors: T > 2 cm, negative oestrogen receptor/progesterone receptor (ER– and PR–), Scarff-Bloom-Richardson (SBR) grade II or III and age ≤ 35°years. Patients were randomly assigned to either six FEC 100 (Arm A) or four FEC 100 (Arm B). The trial was powered to detect an absolute difference ≥6% in disease-free survival (DFS) at 5°years. Results At 6.1°years median follow-up, with 91 (12%) events recorded in Arm A versus 106 (14%) in Arm B, no statistically significant risk increase was associated with four versus six FEC 100: DFS (hazard ratio (HR) = 1.18; CI 95% [0.89–1.56], P = .24) and overall survival (OS) (HR = 1.39; CI 95% [0.91–2.13], P = .12). Conclusion Differences in chemotherapy duration did not induce notably different outcomes in our cohort of high-risk patients. Clinical trial registry number NCT00055679 , Agence National de Securite du Medicament (ANSM) – France.

Purpose We conducted a double-randomised phase III trial to evaluate a concomitant taxane-anthracycline regimen in node-positive breast cancer and the efficacy of trastuzumab in the human epidermal growth factor receptor 2 (HER2)–positive subpopulation. Methods A total of 3010 patients with node-positive breast cancer were randomly assigned to receive 6 cycles of 500 mg/m2 of fluorouracil, 100 mg/m2 of epirubicin and 500 mg/m2 of cyclophosphamide (FEC) or 75 mg/m2 of epirubicin and 75 mg/m2 of docetaxel (ED). Patients with HER2-positive tumours were secondary randomly assigned to either trastuzumab or observation. The primary end-point was disease-free survival (DFS) in the two chemotherapy arms. Results After a 115-month median follow-up, DFS was not significantly better in the ED arm (DFS: 70%, 95% confidence interval [CI]: 67–72) than in the FEC arm (DFS: 68%, 95% CI: 65–70; hazard ratio [HR] = 0.88, 95% CI: 0.77–1.01; p = 0.064). The OS was not different between FEC (OS: 80%, 95% CI: 78–83) and ED (OS: 81%, 95% CI: 79–83); HR = 0.97, 95% CI: 0.81–1.16; p = 0.729). ED appeared more toxic. In the 528 HER2-positive subset, there was trend for a higher DFS, in the intention-to-treat population, in the trastuzumab arm (DFS: 68%, 95% CI: 61–74) than in the observation arm (DFS: 60%, 95% CI: 54–66; HR = 0.77, 95% CI: 0.57–1.03; p = 0.079). In the per-protocol population, DFS was significantly higher in the trastuzumab arm (DFS: 70%, 95% CI: 63–76) than in the observation arm (DFS: 59%, 95% CI: 53–65; HR = 0.69, 95% CI: 0.51–0.94; p = 0.0156). The OS was not different between these 2 arms. Conclusion This study did not show superiority of the concomitant anthracycline-taxane arm which was more toxic in high-risk node-positive breast cancer patients. Long-term results of the HER2-positive subpopulation are in line with those of the other adjuvant trastuzumab trials but quantitatively less pronounced mostly because of lack of power.

Background: Olaparib is a PARP inhibitor that has shown high response rates and clinical activity in patients with advanced HER2-negative breast cancer (BC) and a germline BRCA1 and BRCA2 mutation. There is also evidence of cellular sensitivity to PARP inhibitors associated to defects in other genes involved in homologous recombination DNA repair (HRR) or mismatch repair pathway (microsatellite instability MSI). Moreover, about 15% of patients with ER+/HER2- metastatic BC have at least 100 mutations in their tumor, leading to genomic instability and potential sensitivity to PARP inhibitors. Several preclinical and clinical studies have suggested the benefit of an association of immune checkpoint blockade, like durvalumab, with PARP inhibitor. Indeed, tumors with BRCA1/2 mutations or other deficiency in HRR have high mutagenic burden and produce a larger number of neoantigens. Most BRCA-associated BC are ER+/HER2-. Although loss of the BRCA gene function is a key driver of oncogenesis in these patients, ER-pathway appears to remain a key target for their therapy. Preclinical data indicate that olaparib may enhance endocrine therapy efficacy and circumvent resistance. Therefore, the combination of durvalumab, olaparib and endocrine therapy could be a therapeutic option for patients with BRCA1/2 mutation or for patients with selected ER+/HER2- advanced BC. Trial design: DOLAF is an open-label, international, multicentric, phase II trial assessing the combination of olaparib, fulvestrant, and durvalumab. Olaparib will be administered orally twice daily at 300 mg. Fulvestrant will be administered as two intramuscular injections of 250 mg (Cycle 1 Days 1 and 15, and Day 1 of each subsequent 28-day cycle). Durvalumab will be started 4 weeks after the first dose of olaparib at 1500 mg intravenous every 4 weeks. Eligibility criteria include: ER+/HER2- metastatic or locally advanced BC with documented germline alteration in BRCA1 or BRCA2 or deleterious germline or somatic alterations implicated in the HRR pathway (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCA, FAND2, FANCL, MRE11A, NBN, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D and RAD54L) or in MSI status or other actionable genes (AKT1, ESR1, FGFR1, FGFR2, FGFR3, and PIK3CA) all based on central tumor next generation DNA sequencing. Patients could have received 1 line of endocrine therapy and/or 1 line of chemotherapy in the metastatic setting.Specific aims: To evaluate the efficacy of the combination in terms of progression-free survival rate at 24 weeks using RECIST v1.1. Secondary endpoints include: safety (according to the NCI-CTCAE v5.0), overall survival, progression-free survival, objective response rate, duration of response in the overall study population and in the germline BRCA mutated population. Statistical methods: Given the lack of safety data from this association, a safety run-in of 6 patients was planned. With an optimum two-stage Simon design,α = 2.5%, β = 5%, p0 (the probability of inefficiency maximum) = 50%, p1 (the probability of minimum efficiency) = 65%, it would be necessary to include 149 evaluable patients. The strategy could be considered sufficiently effective if there are at least 87 successes. According to the established design (including a rate of 5% of patients lost to follow-up or non-evaluable), it will be necessary to include 158 patients. We hypothesized that about 20% of screened patients will have a molecular alteration to allow enrollment. Thus, we need to screen 790 patients. The study is recruiting. The safety run-in is over. By July 1, 2020, 62 patients have been screened and 8 have been treated (NCT04053322). Contact information: DOLAF@unicancer.fr Citation Format: Severine Guiu, Judith Balmana, Lise Roca, Anthony Goncalves, Audrey Mailliez, Frederic Bigot, Thomas Bachelot, Florence Dalenc, Nadine Dohollou, Dominique Genet, Isabelle Desmoulins, Camille Chakiba, Suzette Delaloge, Geraldine Martineau, Veronique Haddad, Philippe Follana. Dolaf- an international multicenter phase 2 trial of durvalumab (medi4736) plus olaparib plus fulvestrant in metastatic or locally advanced er-positive, her2-negative breast cancer patients selected using criteria that predict sensitivity to olaparib (UCBG308) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-13-05.

Purpose: UNICANCER-PACS08 compared adjuvant FEC (5-FU; epirubicin; cyclophosphamide) then docetaxel to FEC then ixabepilone in poor prognosis early breast cancer (BC). We evaluated whether replacing docetaxel with ixabepilone would increase 5-year disease-free survival (DFS). Patients and methods: Triple-negative breast cancer (TNBC) or oestrogen receptor (ER) +/progesterone receptor (PR) -/HER2- BC patients were randomised to receive standard FEC (3 cycles) followed by 3 cycles of either docetaxel (100 mg/m(2)) or ixabepilone (40 mg/m 2). Radiotherapy was mandatory after conservative surgery; ER+ patients received endocrine therapy. Results: Seven hundred sixty-two patients were enrolled between October 2007 and September 2010. Baseline characteristics were balanced between arms. Median follow-up was 66.7 months. Median DFS was not reached; 5-year DFS rate was 76% with docetaxel and 79% with ixabepilone (hazard ratio [HR] = 0.80; 95% confidence interval [CI] = 0.58-1.10; p = 0.175). Median overall survival (OS) was not reached; 5-year OS rate was 86% versus 84% (HR = 0.97; 95% CI = 0.66-1.42; p = 0.897). TNBC patients treated with ixabepilone had a 23% lower risk of relapse compared to docetaxel (HR for DFS = 0.77; 95% CI = 0.53-1.11; p = 0.168). DFS was longer with ixabepilone than docetaxel in patients with grade II-III lymphocytic infiltration (HR = 0.55; 95% CI = 0.29-1.05; p = 0.063). All patients experienced >= 1 adverse events (AEs): 75% reported grade III-IV AEs and two (

10066Background: Cardiac dysfunction may occur in patients (pts) receiving adjuvant trastuzumab-based chemotherapy and long follow-up is required to better understand it. This meta-analysis of 3 ad...

16 Background: Radical prostatectomy (RP) is recommended as a standard treatment for localized prostate cancer. However no recommendations exist for pts with detectable PSA after RP. Methods: Pts with localized prostate cancer, treated by RP (R0 or R1), with a PSA level post-RP ≥ 0.2 ng/mL and ≤ 2 ng/mL at randomization and N0 M0 on imaging were included. Pts were randomized (1:1) to radiotherapy (RT) alone (RT arm) or 6 months degarelix hormone therapy (HT) with RT (RT+HT arm). RT consisted of pelvic irradiation (46 Gy in 23 Fr) with a boost on the prostate bed (66 Gy in 33 Fr). The primary endpoint is the event-free survival (EFS). Secondary endpoints are: 5-yr EFS and metastases-free survival, 5 and 10-yr OS, acute and late toxicity (CTCAE V4.0), and QOL. With 122 patients, the probability of selecting the most effective arm is over 80% for a 20% reduction in the HR = 0.80. Results: From Dec-2012 to Sept-2015, 125 pts were included (RT arm: 64 pts; RT+HT arm: 61). Median follow up is 14.7 months (6.2; 33.5). The baseline characteristics are well-balanced: median age was 66 yrs (50-77), all men having an ECOG ≤ 1 (ECOG 0 in 92%), a median Gleason score of 7 (3-9), a median PSA of 0.3 ng/mL (0.09-1.82) post-RP and 0.6 ng/mL (0.12-3.65) at randomization. All pts received 33 Fr of RT. In the RT+HT arm 98.4% of pts received the 6 months of HT planned. All pts were eligible for safety analysis. No grade 4 toxicity or toxic death was reported. Grade 3 acute toxicity, occurring within 6 months of RT, were reported for 11/125 pts (9%): 3/64 pts (5%) in the RT arm and 8/61 pts (13%) in RT+HT arm (NS). Regarding grade 3 toxicities, the following occurred only in the RT+HT arm: erectile dysfunction (3 pts) and urinary incontinence (2 pts); in contrast, dysuria/pollakiuria (2 pts) occurred only in the RT arm. In the RT+HT arm, grade 2 toxicities included hot flushes (8 pts) and decreased libido (7 pts). Conclusions: In terms of acute toxicities the RT+HT arm is well tolerated with the observed toxicities usually expected with concomitant HT. The primary endpoint analysis is expected for 2018. Clinical trial information: NCT01994239.

International audience; Sporadic or hereditary colorectal cancer (CRC) with microsatellite instability (MSI) is frequently characterized by inflammatory lymphocytic infiltration and tends to be associated with a better outcome than microsatellite stable (MSS) CRC, probably reflecting a more effective immune response. We investigated inflammatory mechanisms in 48 MSI CRCs and 62 MSS CRCs by analyzing: (1) the expression of 48 cytokines using Bio-Plex multiplex cytokine assays, and (2) the in situ immune response by immunohistochemical analysis with antibodies against CD3 (T lymphocytes), CD8 (cytotoxic T lymphocytes), CD45RO (memory T lymphocytes), T-bet (Th1 CD4 cells), and FoxP3 (regulatory T cells). MSI CRC exhibited significantly higher expression of CCL5 (RANTES), CXCL8 (IL-8), CXCL9 (MIG), IL-1β, CXCL10 (IP-10), IL-16, CXCL1 (GROα), and IL-1ra, and lower expression of MIF, compared with MSS CRC. Immunohistochemistry combined with image analysis indicated that the density of CD3+, CD8+, CD45RO+, and T-bet+ T lymphocytes was higher in MSI CRC than in MSS CRC, whereas the number of regulatory T cells (FoxP3+) was not statistically different between the groups. These results indicate that MSI CRC is associated with a specific cytokine expression profile that includes CCL5, CXCL10, and CXCL9, which are involved in the T helper type 1 (Th1) response and in the recruitment of memory CD45RO+ T cells. Our findings highlight the major role of adaptive immunity in MSI CRC and provide a possible explanation for the more favorable prognosis of this CRC subtype.

3549Background: The two-stage surgical resection (TSR) of bilobar colorectal liver metastases (CRLM) is widely used and has shown encouraging survival results. The risk of drop-out after the first-...

666 Background: The two-stage surgical resection (TSR) of bilobar colorectal liver metastases (CRLM) is widely used and has shown encouraging survival results. The risk of drop-out after the first-stage hepatectomy remains high and associated with poor survival rates. Our objective was to evaluate the predictive factors of long-term survival, based on the pathologic response to an intensified systemic chemotherapy administered preoperatively. Methods: Data from 899 patients treated for CRLM in our institution were collected prospectively between January 2003 and August 2013. We evaluated the pathologic response to preoperative chemotherapy, and its impact on the second-stage completion and on survival. Results: Sixty-seven patients were eligible for the TSR first stage. All patients underwent an intensified chemotherapy in combination with a biotherapy (Bevacizumab or Cetuximab) in 38cases. The Tumour Regression Grade (TRG), the Blazer grade, and the modified-TRG were used to classify patients as responders (TRG and mTRG 1-3, Blazer 0-1) or non-responders (TRG and mTRG 4-5, Blazer 2) after the first stage. Responders in the three classifications (TRG: p = 0.033; mTRG: p = 0.03, Blazer:p = 0.005), and initial metastases number (p = 0.001) were independent predictive factors for the second-stage completion. Triple chemotherapy were associated with responders in the three classifications (TRG and mTRG: 73.7% versus 26.3% p < 0.0001 ; Blazer : 84.2% versus 15.8% p = 0.001). Median overall survival (OS) of patients who completed TSR was significantly different (44, 84 versus18,39 months; p < 0.0001). There was no statistical difference in OS and recurrence-free survival between the responders and non-responders. Conclusions: A good pathologic response to intensified preoperative chemotherapy is associated with completion of the second stage of TSR, and thus with a longer survival. Knowing this response before the first-stage resection may allow avoiding useless resections for patients who will not benefit from this strategy.

748 Background: Patients with advanced colorectal liver metastases (CRLM) experience poor prognosis. The impact of two-stage resection (TSR) after downstaging by chemotherapy is still controversial. Methods: Data on 899 patients with CRLM in a single institution during a 9-year period (2004–2013) were prospectively collected. We used intent-to-treat analysis to evaluate the survival of patients who underwent TSR associated with intensified chemotherapy before and between the two surgical stages. Results: 73 patients were eligible for the first stage of TSR. In this population, 54 patients underwent an intensified chemotherapy based on FOLFIRINOX (26 patients) or a standard chemotherapy associated with cetuximab or bevacizumab (28 patients). The first surgical stage was a clearance of the left liver in 56% of cases. An average of two radio-frequency ablations and two wedge resections were necessary. The post-operative morbidity of the first stage was 18%. 78% of patients received chemotherapy between the two stages. The average interval between two stages was 228 days (36-1561). 68% of TSR patients completed the second stage. The second resection was mainly a standard right lobectomy (32%). Morbidity after the second resection was 12%. One patient died post-operatively because of post operative liver failure. Median overall survival of patients who completed TSR was 48 months. In contrast, there was no survival advantage for patients who underwent only the first stage because of progression (median overall survival: 19 months) (p = 0.0003). The median overall survival of the whole population was 43 months and the median recurrence-free survival was 15 months. Conclusions: Intensified chemotherapy in association with TSR allows excellent outcome in patients with advanced CRLM. Chemotherapy delivered between the two surgical stages is responsible for an important waiting time but could contribute to a better control of the evolution of the disease.

11052 Background: The Recurrence Score (RS) predicts outcome in node- and node+, ER+ pts treated with endocrine therapy and predicts chemotherapy benefit. We studied the prognostic impact of RS in ...

Introduction Most of sporadic or hereditary colorectal cancers (CRC) with microsatellite instability (MSI) have a peculiar histopathologic pattern, notably with a frequent inflammatory lymphocytic component. MSI CRC are associated with a better outcome than microsatellite stable (MSS) CCR, probably in relation with a more effective immune response. The aim of our work was to highlight the inflammatory mechanisms occurring in MSI CRC, by analyzing the cytokines and the in situ immune response encountered in this tumor subtype. Methods A panel of 48 cytokines was measured from 48 MSI CRC and 62 MSS CRC using the bioplex cytokine multiplexed assay (Biorad, Hercules, CA, USA). Immunohistochemistry was performed on a tissue microarray constructed from the same tumors, with the following markers: CD3 (T lymphocytes), CD8 (cytotoxic T lymphocytes), CD45RO (memory T lymphocytes), T-bet (Th1 CD4 cells) and FoxP3 (regulatory T-cells). After immunostaining of each marker, T-cell density was assessed by image analysis. Results Analysis of the 48 cytokines allowed us to assess a higher level of IL1β, IL1-Rα, IL16, Gro-a, IL-8, Ip-10, Mig, Mip-1α, Mip-1β, Rantes and IFN-γ in MSI CRC than in MSS CRC (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 317. doi:1538-7445.AM2012-317