Breast cancer is the most common cancer in women, accounting for nearly 30% of all female cancers. Breast cancer is the second leading cause of cancer mortality in women in the US. During the last two decades, the benefits of early detection, early intervention, and postoperative treatment have resulted in decreased breast cancer mortality in the US general population. However, the distribution of breast cancer mortality varies among geographic regions of the US. The reasons for this variation remain largely unknown. We choose to look for a possible association between the numbers of physicians in each city within the State of Florida and breast cancer survival among women aged 40+ residing in that particular city. Using Cox Proportionate Hazard Modeling, we found a direct association between the number of physicians practicing in a particular city and breast cancer survival in that particular city (P=0.0153), while controlling for other known risk factors affecting survival. To our knowledge, this is the first study to report an association between physician supply and cancer survival within defined geographic areas. This association shows as physician density consistently dropped in a defined geographic area so did time of survival among women with breast cancer.
TPS3622 Background: Standard neoadjuvant long course chemoradiotherapy (LCCRT) for locally advanced rectal cancer (LARC) results in a complete pathological response rate of 10-30%: but 20-40% of patients (pts) are non-responders, 10-15% have local recurrence. Tumoural immune infiltrates are predictive of response. Preclinical studies show that radiotherapy (RT) via interferon signaling is immuno-stimulatory, enhancing local/distant tumour cell death. RT also stimulates PDL1 production and the immunosuppressive activity of myeloid derived suppressor cells. Hence PDL1 inhibition may be required to enhance the immuno-stimulatory effects of RT. Hypothesis: In pts with resectable LARC, the anti-PDL1 antibody Avelumab post LCCRT may enhance the pathological/imaging response rates whilst potentially reducing local/distant relapse rates. Methods: (1) Trial Design: Phase II single arm trial, across 6 Australian sites (2) Endpoints: (a) Primary; Pathological response rate post-LCCRT, as documented by central pathologist, (b) Secondary; MRI/FDG PET imaging responses at 8 weeks post LCCRT (pre-surgery). Toxicity. (c) Exploratory; Tumoural immune cell subsets/checkpoint expression (by multiplex immunohistochemistry and in-vitro functional assays) and ctDNA analysis at baseline and during treatment. Distant relapse-free survival and the documentation of sites of relapse. (3) Sample size: An increase in the proportion of pathological complete responses by > 25% (from 10% to 35%) will be considered clinically important. Power = 90%, α = 0.05, 41 pts are required– an additional 4 pts to allow for drop-out. Total sample size = 45pts. Treatment: All pts to receive standard LCCRT (50.4Gy RT plus 5FU [225mg/m2/day/CI] or Capecitabine [825mg/m2 BID on RT days] over 5.5 weeks). Post LCCRT (prior to surgery), pts receive 4 cycles Avelumab (10mg/kg, q2 weeks). Surgical resection 10-12 weeks post LCCRT. Fresh tumour biopsy and ctDNA sampling pre LCCRT, pre Cycle 1 Avelumab and at surgery. Response by FDG PET and pelvic MRI pre surgery. Pts to be followed up for 2 years. Major Inclusion Criteria: Pts with LARC, MRI stage T3b-4/N1-2/M0, planned for LCCRT followed by curative resection, tumoural lower border within 12cm from the anal verge, measurable disease (RECIST1.1), ECOG 0-1, adequate organ function and no contraindications to Avelumab therapy. Current Enrolment: 11 of the planned 45 patients enrolled. Clinical trial information: NCT03299660.
Background: PD-1 checkpoint inhibitors are active in microsatellite unstable (MSI) mCRC, which have an inflamed TME but are inactive in MSS-mCRC. The resistance of MSS mCRC is potentially related to the TME which excludes immune cells. The Modulate study tested 2 strategies designed to alter the TME in MSS mCRC, thereby enabling synergy with PD1 inhibitors.Methods: Eligibility included MSS mCRC, measurable disease, failure of standard prior therapies including oxaliplatin, fluoropyrimidine, irinotecan, bevacizumab and an EGFR inhibitor (if ras/raf wild type), adequate organ function, PS0-1 and informed consent. Eligible patients were randomised to arm A (nivolumab 240mg q2w plus the vascular disrupting agent BNC105 16mg/m 2 d1,8 q3w) or arm B (nivolumab 240mg q2w plus the STAT3 inhibitor napabucasin 240mg bd po). All pts had baseline tumour biopsies repeated at 6w and 12w to assess changes in the TME. The primary endpoint was response rate (RR) (iRECIST). Secondary endpoints included toxicity, progression free survival (PFS) and overall survival (OS). A Simon 2 stage design was used, with each arm evaluated independently, with a null response rate (RR) of 2%, desired RR of 15%, a 5%, ß 95%.Results: From September 2018 to March 2020, 45 pts were enrolled to each arm. Baseline demographics arm A/B were male; 59%,54%; median age 62y,63y; PS0 48%,46%; liver metastases 73%,85%. Median treatment duration was arm A/B 12.3 w (2.1-105w) and 7.5 w (0.1 to 24w). Treatment was well tolerated with the most frequent grade 3/4 AEs being anaemia 9% (arm A) and diarrhoea 13% and abdominal pain (11%) (arm B). Immune related AEs were infrequent.Conclusions: Although neither treatment achieved the anticipated RR, it was well tolerated and anti-tumour activity was demonstrated in both arms with encouraging OS for arm A. Ongoing translational evaluation will examine the impact of the interventions on the TME.
A randomised phase II trial of single fraction or multi-fraction SABR (stereotactic ablative body radiotherapy) with atezolizumab in patients with advanced triple negative breast cancer (AZTEC trial) Abstract: BACKGROUND: In patients with advanced triple negative breast cancer (TNBC), immunotherapy has shown acceptable safety and efficacy in a PD-L1 (programmed death-ligand 1) positive population. Pre-clinical evidence has demonstrated that SABR can prime a more effective systemic anti-tumor response in combination with checkpoint inhibition. It is currently unknown if single or multi-fraction SABR scheduling synergises best with atezolizumab therapy. METHODS: This was a multi-centre, open label, phase 2 randomised trial of patients with advanced TNBC, unselected for (PD-L1) status, who had recurred at least 6 months post completion of (neo) adjuvant chemotherapy and received less than 2 lines of treatment in the metastatic setting. Participants were randomised to 20Gy SABR in 1 fraction or 24Gy SABR in 3 fractions to 1-4 sites of disease, with at least one metastasis left unirradiated. Within 5 days following the final fraction of radiotherapy atezolizumab was commenced at a dose of 1200 mg every 21 days and continued for up to 24 months, or until progression or intolerable toxicity. The primary endpoint is progression- free survival (PFS). Secondary endpoints include efficacy according to PD-L1 IHC status (positive: SP142 ≥1%) and TIL (tumour infiltrating lymphocyte) quantity, response assessment, overall survival and safety. Results presented are from interim analysis performed 18 weeks after the last patient commenced treatment. RESULTS: Fifty evaluable patients were recruited and randomised between 20th November 2018 and 12thApril 2021 with a median age of 57 [35 - 79] yrs. Thirty (60%) and 20 (40%) patients had received none or one previous line of chemotherapy in the metastatic setting, respectively. 14/40 (35%) patients were PD-L1 positive at baseline and 26/42 (62%) had TIL≥5%. Median follow-up was 17 months. The median PFS for the 20 Gy arm was 2.5 (90% CI: 1.7-4.5) months, 3.1 (90% CI: 1.8-3.9) months for the 24 Gy arm. For both arms combined, the PFS was 3.1 (90% CI: 1.8-3.9) months, with no difference between the arms, HR 1.2 (95% CI: 0.6-2.1), p=0.64. PFS by PD-L1 IHC status and TIL<5% vs ≥5% was similar. There were 11 (22%) patients with clinical benefit (no PD within 24 weeks of C1D1), these were not significantly different by arm (p=0.74), nor by PD-L1 status (p=0.44) or TIL quantity (p=0.92) (Table 1). Overall survival is immature: estimated 12 months was 78% (95% CI:54-90) for the 20 Gy arm and 57% (95% CI: 33-75) for the 24 Gy arm.. In patients who were PD-L1 positive the ORR was 1/12 (8%) and DC was 3/14 (21%) compared with ORR of 1/14 (7%) and DC of 3/26 (12%) in patients who were PD-L1 negative. CONCLUSIONS: The efficacy between single and multi-fraction SABR in combination with Atezolizumab was similar and toxicity was acceptable. Efficacy was seen in PD-L1 positive and negative patients. Longer follow-up is required to assess the effect on OS.. (Research support and funding provided by the imCORE Network on behalf of F. Hoffmann-La Roche; AZTEC ClinicalTrials.gov Identifier: NCT03464942) Table 1.Response AssessmentResponse, n (%)All patients (n = 50)Patients with measurable disease (n = 32)Best objective response (non-SABR lesion)CR3 (6)2 (6)PR2 (4)2(6)NCR/NPD8 (16)0SD13 (26)13 (41)PD24 (48)15 (47)ORR (CR + PR)5 (10); 95% CI: 3-224 (12%); 95% CI: 4-29DCR (CR + PR + SD + non-CR/non-PD ≥24 weeks)a11 (22%); 95% CI: 12-377 (23%); 95% CI: 10-41aOne patient withdrew at 8 weeks and was not assessable for DCR. Citation Format: Steven David, Peter Savas, Shankar Siva, Michelle White, Michael W Neeson, Shane White, Gavin Marx, Robyn Cheuk, Michelle Grogan, Maria Farrell, Jessica Foudoulis, Annette Dempsey, Paul J Neeson, Mathias Bressel, Sherene Loi. A randomised phase II trial of single fraction or multi-fraction SABR (stereotactic ablative body radiotherapy) with atezolizumab in patients with advanced triple negative breast cancer (AZTEC trial) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD10-02.
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