Locally advanced gastric cancer (LAGC) has a worse prognosis. Neoadjuvant therapy has been widely utilized in many cancer types. Apatinib (Apa) and FLOT chemotherapy have already shown good effects in the treatment of gastric cancer. We conducted this phase III trial to evaluate the safety and efficacy of Apa plus FLOT protocol as neoadjuvant therapy for LAGC treatment. Patients(pts) aged>18 years, with a histological or cytological diagnosis of untreated LAGC were eligible and assigned to experimental group (Apa+FLOT) or control group (FLOT). Pts in experimental group received three 14-day cycles of Apa (oral,500mg,qd;discontinued in the last cycle) and four 14-day cycles of FLOT protocol including oxaliplatin (iv, 85 mg/m2, day1), docetaxel (iv, 50mg/m2,day1),5-Fluorouracil(iv,2600mg/m2,day1) and calcium folinate(iv ,200mg/m2, day1), followed by radical surgery after 4 weeks. Pts in the control group only received four 14-day cycles of FLOT protocol, followed by radical surgery after 4 weeks. All pts continued four cycles of FLOT protocol after surgery. The primary endpoint is R0 resection rate. Secondary endpoints are tumor regression grade(TRG), disease-free survival(DFS), overall survival(OS), relapse/recurrence rate, and safety. The target sample was 230 pts; eligibled pts were non-randomized 1:1 to Apa +FLOT or FLOT group. From Feb 2018 to May 2020, 64 pts ( Apa+FLOT vs FLOT : 33 vs 31) were enrolled, 44 pts completed the surgery (20[60.6%] vs 24[77.4%]). Among the surgical patients, 39 pts achieved R0 resection (19[95.0%)] vs 20[83.4%]), 31 pts achieved TRG 1-3(14[70.0%] vs 17[70.8%]).Adverse events (AEs) of any cause were 28(84.8%) vs 29(93.5%). Garde 3/4 AEs were 11(33.3%) vs 10(32.3%).The most common AEs were decreased hemoglobin (26[78.8%] vs 26[83.9%]), leukopenia (16[48.5%] vs 15[48.4%]), granulocytopenia (14[42.4%] vs 19[61.3%]), increase of aspartate aminotransferase (12[36.4%] vs 16[51.6%]). Neoadjuvant therapy of Apa plus FLOT followed by radical surgery for pts with LAGC showed acceptable toxicity and promising efficacy.

Patients around the world often ring a bell on the final day of chemoradiotherapy (CRT) to celebrate treatment completion. This is thought to symbolize hope. Patients appear to derive satisfaction ringing the bell, but its psychological impact is unexamined. Applying a psychological principle named the 'peak-end rule', we hypothesized that ringing the bell would improve patient reported outcomes (PRO) related to overall distress of cancer treatment. We enrolled two cohorts of patients completing definitive CRT in a single-center outpatient radiation oncology clinic. Patients in the control arm completed treatment and filled out the survey mentioned below. A bell was then installed in the clinic, and patients in the intervention arm rang the bell on the final day of CRT and filled out the same survey. We decided against blinded randomization because all patients who receive treatment on that day can see the bell in the hallway at all times and can hear the bell when it is rung. In addition to being unethical, this would confound results of the control group, who would see and hear the bell but be prohibited from ringing it. Hence this is a study limitation. To minimize selection bias, however, we offered enrollment to every eligible patient. Patients evaluated their overall distress from cancer treatment using a survey comprised of an 11-point numerical rating scale in combination with the Verbal Rating Scale. We asked three questions about distress during cancer treatment: "total" distress, "worst" distress, and degree of "unpleasantness". At follow-up a shorter survey was completed that asked the same questions about distress from cancer treatment. All patients were >18 years old, spoke English or Spanish, received neoadjuvant, adjuvant, or definitive RT with curative intent, with or without concurrent chemotherapy. Treatment prior to RT was acceptable. Patients with a CNS primary cancer or palliative treatment intent were excluded. 210 patients were enrolled, 107 in the bell group and 103 in the control group. 163 patients completed follow-up surveys, n=86 (80%) and n=77 (75%) in the bell and control groups, respectively. Demographics and treatment characteristics were well-matched (all nonsignificant). MANOVA with the patient characteristics as covariates was performed on the three aforementioned distress questions. The bell group reported worse overall distress scores than those not ringing the bell (mean [standard deviation] 5.6 [2.8] vs 4.7 [2.7], p=0.045). This difference worsened further at follow up (mean 116 days; 6.4 [2.9] vs 5.1 [3.0], p=0.009). Counter to our hypothesis, ringing the bell on the final day of CRT worsens PRO's of overall distress from cancer treatment, which persisted and worsened in the months after treatment. Emotional arousal created by ringing the bell may magnify the distress from cancer treatment and subsequently worsen the perception of distress from treatment.

Background: HER3 is a tyrosine kinase receptor and involved in cell proliferation and carcinogenesis. Preclinical data suggest that HER3 plays a critical role in the escape mechanism from anti-EGFR directed treatment in metastatic colorectal cancer (mCRC) patients. Additionally, HER3 downstream signaling has shown to stimulate angiogenesis. We therefore hypothesize that variations in genes involved in the HER3 signaling pathway may predict outcome in patients with mCRC treated with first-line FOLFIRI and bevacizumab (bev) or FOLFIRI and cetuximab (cet). Methods: The impact of 4 functional SNPs within the HER3, NRG1, NEDD4 and BTC genes on outcome was evaluated in 585 pts with mCRC treated with either first-line FOLFIRI/bev (n = 293) or FOLFIRI/cet (n = 292) in the randomized phase III FIRE-3 trial. Genomic DNA was extracted from FFPE and the SNPs were analyzed by PCR-based direct sequencing. Results: Baseline characteristics in the FOLFIRI/bev and FOLFIRI/cet cohorts were as follows: female:male ratio=1/3:2/3 in both arms; age >65y (48% and 47%) and median PFS/OS=10.1/23.7 and 9.6/26.5 months. The HER3 rs2271189 SNP showed significant association with PFS. A/A genotype carriers treated with FOLFIRI/bev had a shorter median PFS compared to those harboring any G allele (7.0 vs 10.3 months) in both univariate (HR 1.60, 95% CI 1.09-2.36, p = 0.014) and multivariate analysis (HR 1.64, 95% CI 1.09-2.46, p = 0.018). The same effect on PFS could be seen in patients receiving FOLFIRI/cet. Here again, A/A carriers showed a shorter median PFS than those having any G allele (7.9 vs 10.0 months) in both univariate (HR 1.56, 95% CI 1.13-2.15, p = 0.005) and multivariate analysis (HR 1.40, 95% CI 1.00-1.96, p = 0.05). Conclusions: Our results provide the first evidence that the HER3 polymorphism rs2271189 might serve as a predictive/prognostic marker in pts with mCRC treated with FOLFIRI/bev and FOLFIRI/cet in the first line setting. Targeting HER3 might be a promising approach to further improve treatment options against mCRC and to overcome resistance to both anti-EGFR and anti-angiogenic therapy. Legal entity responsible for the study: Heinz-Josef Lenz. Funding: This work was supported by the National Institute of Health P30CA014089, the Gloria Borges Wunderglo Project, and the Daniel Butler Research Fund. Martin D. Berger received a grant from the Werner and Hedy Berger-Janser foundation for cancer research. Yuji Miyamoto received a grant from the Japan Society for the Promotion of Science (S2606). Ryuma Tokunaga received a grant from the Uehara Memorial Foundation. Disclosure: S. Stintzing: Advisory board member: Amgen, Bayer, Lilly, Merck KgaA, Nordic Pharma, Roche, Sanofi V. Heinemann: Advisory board member: Amgen, Baxalta, Boehringer Ingelheim, Lilly, Merck KgaA, Merrimack, Roche AG, Sanofi, Servier, Sirtex, Taiho. H-J. Lenz: Advisory board member: Merck Serono, Roche. All other authors have declared no conflicts of interest.

As cancer care improves, quality-of-life (QOL) is increasingly paramount but is difficult to quantify. No studies report which side effects (SE) patients undergoing a prolonged course of radiotherapy (RT)-predominant care perceive as the most severe. The prevalence, absolute severity, and natural history of psychosocial SE in cancer patients is well understood, but their severity relative to physical SE is unknown. We conducted a survey to use patient report outcomes to identify and rank SE perceived by 55 patients on the final day of ≥ 4 weeks of RT. Patients who had received ≥ 4 weeks of chemotherapy prior to RT start were excluded. Patients selected from 67 cards listing symptoms all those experienced (40 physical and 27 psychosocial) and the 5 most troublesome. A score of 5, 4, 3, 2, and 1 (15 points total) was assigned to top 5 selected SE, respectively. A total of 49% were female, mean age was 57 years, 58% were Hispanic, and mean RT dose was 57 Gy. Differences in ranking of severity of SE were evident when patient groups were divided by location of RT (Table). Psychosocial SE filled 46% of the 15 points in breast cancer patients compared to only 20% in non-breast cancer patients (p=.01; OR <.01 [<.01, .29]). Incidental cancer discovery (40% of cohort; e.g. mammogram, elevated PSA) versus discovery from symptoms showed 43% vs 23% (p=.01) in this manner but fell out of significance on logistic regression (OR 3.44 [0.59, 20]). Patients receiving concurrent systemic treatment (55% of cohort) perceived physical SE > psychosocial SE in severity (OR 0.12 [0.02, 0.89]). Patients with >6 months’ elapsed time from diagnosis to RT completion (44% of cohort) versus <6 months showed 44% vs 21% in this manner (OR 5.10 [1.08, 24.18]; worst SE anxiety and their sequelae). Perceptions of the SE of cancer RT are dominated by physical QOL concerns and are influenced by the anatomic area receiving RT. However, in certain groups, psychosocial SE are equivalent in severity to physical SE. Roughly half of the most severe SE in breast cancer patients are psychosocial in nature. In other groups, psychosocial SE are more common. Patients living with a cancer diagnosis for >6 months more commonly report anxiety-related psychosocial SE.Tabled 1Abstract TU_42_3738; Table 1Breast/Thorax/Abdomen (n=22)H&N (n=14)Pelvis (n=19)RankSymptomPsychosocial (Psy) or Physical (Ph)ScoreSymptomPsy or PhScoreSymptomPsy or PhScore1Burning or painful skinPh42Trouble or pain with swallowingPh30DiarrheaPh382Feeling tense or anxiousPsy24Sore mouth and/or throatPh23Increased urinationPh263Feeling low (depression)Psy18Loss of appetitePh22Painful urinationPh234Headaches, migrainePh17Difficulty sleepingPh16Weight lossPh165NauseaPh16Change in the way things tastePh15Loss of appetitePh146IrritabilityPsy16Dry mouthPh13Affects my work/home dutiesPsy137Constantly tiredPh15Weight lossPh12Stomach achePh128Affects my work/home dutiesPsy12NauseaPh11Burning or painful skinPh12 Open table in a new tab

The aim was to compare twice-daily radiotherapy by simultaneous integrated boosting (SIB) technique with once-daily radiotherapy for patients of limited-stage small cell lung cancer (LS-SCLC). Consecutive patients with LS-SCLC treated with definitive concurrent chemotherapy with twice-daily radiotherapy schedules by SIB technique or once-daily radiotherapy schedules were reviewed. In the twice-daily radiotherapy (BID) group, gross tumor volume (GTV) was 54Gy in 30 fractions (1.8Gy per fraction twice a day). In the once-daily radiotherapy (QD) group, GTV was 60Gy in 30 fractions (2.0Gy per fraction once a day). Prophylactic cranial radiation (25Gy in 10 fractions) was administered to patients achieving complete response or partial response. The primary endpoints were 1-year overall survival (OS), progression-free survival (PFS) and local regional recurrence free survival (LRRFS). The secondary endpoint was treatment-related toxicity. Between March 2015 and May 2016, 50 patients with LS-SCLC undergoing concurrent chemo-radiotherapy were included (20 patients in the BID group and 30 patients in the QD group). After a median follow-up for the radiotherapy comparison until data collection of 10.5 (4.2-19.7) months, the median PFS in the BID group was not achieved, while the median PFS in the QD group was 8.6 (6.6-10.6) months. The 1-year OS rates in the BID group and QD group were 86.0% vs 78.0% (P=0.724), respectively. The PFS rate at 1-year was estimated at 68.0% in the BID group, compared with 43.0% in the QD group (P=0.336). The LRRFS rates at 1 year were 87.0% in the BID group and 77.0% in the QD group (P=0.370). There was a trend towards improved survival in the BID group. No statistically significant difference was found in the treatment-related toxicities between the two groups. Twice-daily radiotherapy with SIB technique to 54Gy had a superior tendency in survival compared with once-daily radiotherapy to 60Gy for LS-SCLC without adding toxicity. A further randomized study of comparing twice-daily radiotherapy by SIB technique with once-daily radiotherapy for LS-SCLC is required.

Background: Recent data suggest that patients with colorectal cancer who present with desmoplastic (angiogenic) histopathological growth pattern (HGP) colorectal liver metastases (CLM) might derive more benefit from bevacizumab-based chemotherapy than patients who present with replacement (non-angiogenic) HGP CLM. Methods: The immune phenotype ('inflamed', 'excluded', 'desert') was analyzed regarding the association with HGPs in a cohort of 118 patients with resectable CLM [m:f 66:52, median age 62.3 (31.0-80.4) years, median follow-up 32.2 (5.0-92.7) months] treated with 3 months of neoadjuvant and adjuvant bevacizumab-based chemotherapy and liver resection. The HGPs of CLM were assessed on H&E-stained sections according to international guidelines. The immune phenotypes were based on the distribution pattern of cytotoxic T-lymphocytes in CD8-immunostained tissue sections. Results: In 39.8% of the lesions the predominant means of vascularization was vessel co-option, as reflected by the replacement HGP. This non-angiogenic growth was associated with worse recurrence-free and overall survival (RFS, OS) with hazard ratios (HR) of 2.03 and 2.63 (P = 0.002 and P = 0.005, respectively). The HGPs were associated with the immune phenotypes. About 60% of the desmoplastic (angiogenic) HGP CLM were 'inflamed', while this was true for only 17% of the replacement (non-angiogenic) HGP CLM. More than half of the CLM with non-angiogenic growth were characterized by an immune desert as opposed to only 6% of the angiogenic CLM (P < 0.001). The non-inflamed immune phenotypes were associated with worse RFS (HR 1.85; P = 0.03). Conclusions: Immune regulatory and angiogenesis pathways are known to interact. Our data suggest that the inflamed immune phenotype can be induced by systemic treatment in angiogenic CLM. The HGPs therefore are a potential biomarker for treatment that includes targeting the immune contexture. Legal entity responsible for the study: Heinz-Josef Lenz Funding: NIH Disclosure: H-J. Lenz: Consulting or advisory role: Bayer, Novartis, Merck KG, Genentech/Roche, Boehringer-Ingelheim. Research funding: EMD, Bayer, BMS, Genentech/Roche, Merck, Gilead, Medimmune, Array, BostonMedical. All other authors have declared no conflicts of interest.

The MAPK-interacting kinase 1 (MKNK1) is localized downstream of the RAS/RAF/ERK and the MAP3K1/MKK/p38 signaling pathway. Through phosphorylation MKNK1 regulates the function of eukaryotic translation initiation factor 4E, a key player in translational control, whose expression is often upregulated in metastatic colorectal cancer patients (mCRC). Preclinical data suggest that MKNK1 increases angiogenesis by upregulating angiogenic factors. We therefore hypothesize that variations in the MKNK1 gene predict outcome in mCRC patients treated with first-line FOLFIRI and bevacizumab (bev). A total of 567 patients with KRAS wild-type mCRC in the randomized phase III FIRE-3 and TRIBE trials treated with first-line FOLFIRI/bev (discovery and validation cohorts) or FOLFIRI and cetuximab (cet) (control cohort) were included in this study. Five single-nucleotide polymorphisms in the MAPK signaling pathway were analyzed. AA genotype carriers of the MKNK1 rs8602 single-nucleotide polymorphism treated with FOLFIRI/bev in the discovery cohort (FIRE-3) had a shorter progression-free survival (PFS) than those harboring any C (7.9 versus 10.3 months, Hazard ratio (HR) 1.73, P = 0.038). This association could be confirmed in the validation cohort (TRIBE) in multivariable analysis (PFS 9.0 versus 11.0 months, HR 3.04, P = 0.029). Furthermore, AA carriers in the validation cohort had a decreased overall response rate (25% versus 66%, P = 0.049). Conversely, AA genotype carriers in the control group receiving FOLFIRI/cet did not show a shorter PFS. By combining both FOLFIRI/bev cohorts the worse outcome among AA carriers became more significant (PFS 9.0 versus 10.5 months) in univariable (HR 1.74, P = 0.015) and multivariable analysis (HR 1.76, P = 0.022). Accordingly, AA carriers did also exhibit an inferior overall response rate compared with those harboring any C (36% versus 65%, P = 0.005). MKNK1 polymorphism rs8602 might serve as a predictive marker in KRAS wild-type mCRC patients treated with FOLFIRI/bev in the first-line setting. Additionally, MKNK1 might be a promising target for drug development.

Background Tri-phosphorylated trifluridine (FTD) incorporation into DNA is TAS-102's main anti-tumor action. We tested whether genetic polymorphisms in homologous recombination (HR) and cell cycle checkpoint pathway for DNA repair is associated with outcomes in refractory metastatic colorectal cancer (mCRC) patients treated with TAS-102. Patients and methods We analyzed genomic DNA extracted from 233 samples of three cohorts: an evaluation cohort of 52 patients receiving TAS-102, a validation cohort of 129 patients receiving TAS-102 and a control cohort of 52 patients receiving regorafenib. Single nucleotide polymorphisms of genes involved in HR (ATM, BRCA1, BRCA2, XRCC3, FANCD2, H2AX, RAD51) and cell cycle checkpoint (ATR, CHEK1, CHEK2, CDKN1A, TP53, CHE1, PIN1, PCNA) were analyzed by PCR-based direct sequencing. Results In univariate analysis for the evaluation cohort, patients with any G allele in ATM rs609429 had longer overall survival (OS) than those with the C/C variant (8.7 vs. 4.4 months, HR 0.37, 95% CI: 0.14-0.99, P = 0.022). Patients carrying any A allele in XRCC3 rs861539 had significantly longer progression-free survival (PFS) (3.8 vs. 2.3 months, HR 0.44, 95% CI: 0.21-0.92, P = 0.024) and OS (15.6 vs. 6.3 months, HR 0.25, 95% CI: 0.08-0.79, P = 0.012) than those with the G/G variant. In multivariable analysis, ATM rs609429 remained significant for OS (P = 0.020). In the validation cohort, patients having ATM rs609429 with any G allele showed longer OS and PFS; the G/A variant in XRCC3 rs861539 showed longer OS, though without statistical significance. Conclusion Genetic variants in the HR pathway may predict clinical outcome in mCRC patients receiving TAS-102.

A recent genome-wide association study identified seven single-nucleotide polymorphisms (SNPs) in region 16q24, near the Forkhead box-F1 ( FOXF1 ) gene, which confer susceptibility to esophageal adenocarcinoma. We examined whether these SNPs are associated with clinical outcomes in gastric cancer (GC) patients in Japan and the United States. A total of 362 patients were included in this study: 151 Japanese GC patients treated with first-line S1 plus CDDP (training cohort) and 211 GC patients from Los Angeles County (LAC; validation cohort). Genomic DNA was isolated from whole blood or tumor tissue and analyzed by PCR-based direct DNA sequencing. Cox proportional hazard regression analyses were used to assess relationships between FOXF 1 SNPs and progression-free survival (PFS) and overall survival (OS). FOXF1 rs3950627 was significantly associated with survival in both the training and validation cohorts. Japanese patients with the C/C genotype had a longer PFS (median 8.2 vs 5.3 months, hazard ratio (HR) 1.44, P =0.037) and OS (median 16.4 vs 12.2 months, HR 1.44, P =0.043) compared to patients with any A allele. Similarly, LAC patients with the C/C genotype had improved OS (3.9 vs 2.3 years, HR 1.5, P =0.022). Subgroup analyses showed these associations were specific to male patients and primary tumor subsite. Our findings suggest that FOXF1 rs3950627 might be a promising prognostic marker in GC patients.

We analyzed associations between CXCR4/CXCL12 single-nucleotide polymorphisms and outcomes in metastatic colorectal cancer (mCRC) patients who underwent first-line bevacizumab-based chemotherapy. A total of 874 patients were included in this study: 144 treated with bevacizumab and FOLFOX or XELOX (training cohort), 653 treated with bevacizumab and FOLFIRI or FOLFOXIRI (validation cohort A or B) and 77 treated with cetuximab-and oxaliplatin-based regimens (control cohort). One CXCR4 polymorphism (rs2228014) and two CXCL12 polymorphisms (rs1801157 and rs3740085) were analyzed by PCR-based direct sequencing. Patients with a C/C genotype had a prolonged progression-free survival (PFS) compared with those with any T allele (P = 0.030) in the training cohort. Similarly, patients with the C/C genotype had a superior PFS in the validation cohorts, but not in the control cohort. Our findings suggest that a common genetic variant, CXCR4 rs2228014, could predict PFS and may guide therapeutic decisions in mCRC patients receiving first-line bevacizumab-based chemotherapy.

In patients (pts) with non-metastatic GC, MMT added to surgery improves the cure rate. The MMT includes adjuvant chemoradiation (ACR), neoadjuvant chemoradiation (NACR), and perioperative chemotherapy (CT). We used the NCDB data to compare different MMT in pts with non-metastatic GC. A total of 79369 pts with non-metastatic GC diagnosed 2004- 2013 were identified. Pts with known tumor site who underwent surgery and received MMT were selected for this analysis. Treatment included NACR, CT, and ACR. Pts divided into two cohorts cardia GC (cGC) and non-cardia GC (nGC). Among 10796 pts with cGC and 10681 with nGC, demographics, tumor characteristics, and treatment data were abstracted. Overall survial (OS) was selected as the primary study outcome. Cox regression model was used to examine the effect of choice of MMT on OS adjusting for all known prognostic factors. Summary of results included in the table. In 10796 pts with cGC MMT distribution was 24%, 55%, and 21% for ACR, NACR, and CT. These numbers for nGC were 10681, 55%, 7%, and 38%. OS in the treament groups: ACR 42.1 (95%CI: 42.2-44.1), NACR 35.9 (95%CI: 34.2-37.9), CT 34.2 (32.7 -35.8). In cGC, ACR remained superior with median OS of 36.4 (34.5-39.0) vs. NACR 34.0 (32.5-35.6: HR 1.13) and CT 33.3 (31.2-35.6: HR 1.11) p < .0001. These number for nGC were 48.3 (45.6-52.0), 35.1 (31.0-40.9: HR 1.18), and 35.9 (33.5-38.3: HR 1.20) p < .0001. In the cGC, CT resulted in a significant (p < 0.001) reduction in the size of tumor with the median tumor size of 4 cm as compared to 4.5 cm in the ACR, there was no difference in the size of the tumor between CT and ACR group for ncGC.Tabled 1ACRNACRCTN (%) (cGC, nGC)8517 (40) (2618, 5899)6630 (31) (5892, 738)6330 (29) (2286, 4044)Mean Age636264Male (%)668266Race: White/Black/East-Asia/Hispanic/others (%)58/18/7/3/12/1/187/5/1/1/4/1/163/15/5/3/12/1/1Path Stage (0/I, II/III, IV, unknown) (%)0/13/32/48/73/23/34/37/21/17/30/43/8 Open table in a new tab ACR increased the odds of survival by 20% in the nGC and by 10% in cGC pts. Although this is a retrospective analysis the large sample size and long follow up provides confidence in the observation. There is a statistically significat difference in the presentation and outcomes of cGC and nGC. Caution should be exercised in combining these pts in prospective trials.

Stereotactic Radiosurgery (SRS) is considered standard of care for patients with 1-3 brain metastases (BM). Recent observational studies have shown equivalent OS in patients with 5+ BM compared to those with 2-4, suggesting SRS alone may be appropriate in these patients. We aim to review outcomes of patients treated with SRS with 2-4 versus 5+ BM. This analysis included consecutive patients from 1994 to 2015 treated with SRS. Of 1017 patients, we excluded patients with a single BM and patients without adequate survival data, resulting in 391 patients. All risk factors were entered into univariate analysis using Cox proportional hazards model, and significant factors were entered into multivariate analysis (MVA). We additionally analyzed outcomes after excluding patients with prior surgery or whole-brain radiotherapy (WBRT). Median follow-up was 7.1 months. Median KPS was 90, mean age was 59, and most common histologies were melanoma and lung. Median tumor volume was 3.41 cc. Patients with 2-4 BM had a median OS of 8.1 months compared to 6.2 months for those with 5+ BM (P = 0.0136). On MVA, tumor volume, KPS, and histology remained significant for OS, whereas lesion number did not. Similar results were found when excluding patients with prior surgery or WBRT. Rather than lesion number, the strongest prognostic factors for patients undergoing SRS were tumor volume > 10 cc, KPS, and histology. BM number may therefore not be the most important criterion for candidacy for SRS. Patients with 5 or more BM should be considered for SRS.

HIC1 (Hypermethylated in Cancer 1) is a transcription repressor, which cooperates with several partners to suppress the expression of multiple target genes. Among HIC1 targets, SIRT1 (Sirtuin1) plays a critical role in promoting the nucleotide excision repair (NER) pathway, which is the main oxaliplatin-induced damage repair system. HIC1 expression might be influenced by the number of variations in a tandemly-repeated sequence, situated close to the promoter region. We tested the hypothesis that variable number of tandem repeat (TR) in HIC1 will be associated with outcome in metastatic colorectal cancer patients (mCRC pts) receiving 1st-line chemotherapy with oxaliplatin. This study enrolled 3 independent cohorts. Pts treated with FOLFOXIRI + bevacizumab in the phase III TRIBE study served as a training set (TRIBE-B cohort, n = 218). Pts receiving FOLFOXIRI + bevacizumab in the phase II MOMA study served as a validation set (MOMA cohort, n = 176). Pts treated without oxaliplatin (FOLFIRI + bevacizumab) in the TRIBE study served as a control set (TRIBE-A cohort, n = 215). Genomic DNA was isolated from blood samples. Variations in the number of TR were analyzed by PCR and Gel electrophoresis, and tested for the association with PFS and OS. Main patients characteristics' were the following: TRIBE-A; M/F 60/40%, median age 60, TRIBE-B; M/F 60/40%, median age 60, MOMA; M/F 57/43%, median age 61. Median follow-up times were 49.9, 48.0, and 25.3 months, respectively. Pts with number of TR ≤4 or ≥5 were 90/10% (TRIBE-A), 91/9% (TRIBE-B), and 95/5% (MOMA), respectively. In the training cohort, pts with TRs ≥5 showed a significantly shorter PFS compared to those with TRs ≤4 (9.5 vs. 11.6 mo, HR 1.93, P = 0.012), which retained statistical significance in multivariate analysis (HR 2.00, 95%CI: 1.13-3.54, P = 0.018). This preliminary association was confirmed in the validation cohort, and pts with TRs ≥5 showed a worse PFS compared to others (7.9 vs. 9.8 mo, HR 1.85, P = 0.044). This correlation was not observed in the control cohort. Our findings suggest that variable number of TRs in HIC1 could be a predictive marker for oxaliplatin-containing chemotherapy in mCRC pts.

Using approved methods, circulating tumor cells (CTCs) are only isolated from blood in 30%–50% of metastatic colorectal cancer (mCRC) patients. We previously validated a technique to isolate circulating tumor cells (CTCs) in a cohort of mCRC patients by combining immunomagnetic enrichment of EpCAM + /CD45 − cells with qRT-PCR amplification of CK20 and survivin expression. Here, we examined the prognostic utility of CTC epithelial–mesenchymal transition (EMT) and stem cell gene expression. An 8 ml blood sample was collected from 78 consecutive mCRC patients before treatment with investigational and standard chemotherapeutics. The mRNA expression of EMT ( PI3Kα , Akt-2, Twist1 ) and stem cell ( ALDH1 ) markers was measured. Associations between CTC gene expression and progression-free survival (PFS) and overall survival (OS) were determined using Cox regression models. Among patients without CK20 or survivin -expressing CTCs ( n =17), 55% had expression of ALDH1 , PI3Kα and/or Akt-2 . Patients with positive CTC Akt-2 expression had a significantly shorter median PFS (3.0 versus 4.0 months) compared with those without CTC Akt-2 expression in univariable (hazard ratio (HR)=1.61; log-rank P =0.034) and multivariable analyses (HR=1.70; adjusted P =0.041). In univariable analysis, CTC ALDH1 expression was associated with shorter OS (10.0 versus 38.6 months; HR=2.04, P =0.021). Patients with CTCs expressing ALDH1 , PI3Kα and/or Akt-2 had a significantly inferior PFS (3.0 versus 7.7 months; HR=1.88, P =0.015) and OS (10.0 versus 26.8+ months; HR=2.25, P =0.050) in univariable, but not multivariable, analysis. Conclusions: CTC Akt-2 expression may serve as a clinically useful prognostic marker in mCRC patients and warrants further evaluation in prospective trials.

Immunomodulator-targeting therapies are under development in gastric cancer (GC). However, the role of genes modulating antitumor immunity in GC remains poorly understood. We investigated the association of variations in genes involved in immunomodulatory pathways with overall survival (OS) in locoregional GC patients. Extracted genomic DNA was analyzed for 35 functional single-nucleotide polymorphisms in genes, PDCD1, CD274, CTLA4, FOXP3, LAG3, ADORA2A, NT5E and IDO1, in 162 Japanese patients as discovery set and 277 US patients as validation set. The C allele of PDCD1 rs10204525 had univariate and multivariable associations with shorter OS in Japanese cohort (P = 0.015, P = 0.043, respectively). In US cohort the C allele predicted worse OS (P = 0.007). Univariate and multivariable analyses revealed IDO1 rs9657182 associated with OS in the Japanese cohort; moreover, the association was confirmed in the US cohort. Genetic predisposition of the host in the immunomodulators may serve as a prognostic biomarker in patients with locoregional GC.

The Hippo pathway is involved in colorectal cancer (CRC) development and progression. The Hippo regulator Rassf1a is also involved in the Ras signaling cascade. In this work, we tested single nucleotide polymorphisms within Hippo components and their association with outcome in CRC patients treated with cetuximab. Two cohorts treated with cetuximab plus chemotherapy were evaluated (198 RAS wild-type (WT) patients treated with first-line FOLFIRI plus Cetuximab within the FIRE-3 trial and 67 Ras WT patients treated either with first-line mFOLFOX6 or SOX plus Cetuximab). In these two populations, Rassf1a rs2236947 was associated with overall survival (OS), as patients with a CC genotype had significantly longer OS compared with those with CA or AA genotypes. This association was stronger in patients with left-side CRC (hazard ratio (HR): 1.79 (1.01–3.14); P =0.044 and HR: 2.83 (1.14–7.03); P =0.025, for Fire 3 and JACCRO cohorts, respectively). Rassf1a rs2236947 is a promising biomarker for patients treated with cetuximab plus chemotherapy.

Although multiple Phase I/II studies demonstrate safety and low rates of toxicity following SBRT to the intact prostate, there are limited data on hypofractionation after prostatectomy. This Phase I study was performed to evaluate acute toxicity associated with dose escalation to the prostate bed in the post-prostatectomy treatment of prostate cancer. We hypothesize that the toxicity of escalating the dose per fraction, while decreasing the number of fractions, to the prostate fossa in the post-operative setting will be well tolerated; and we expect toxicity to be comparable to normal fractionation schedules. This study was designed to look at acute toxicity, defined as toxicity that occurred within the first 10 weeks of RT, of different dose fractionation schemes. The doses chosen for this study are based on an equivalent biological effective dose to a previously published hypofractionated post-prostatectomy study that showed no increase in acute bowel or bladder toxicity. The dose levels are: Level 1 -3.6 Gy x 15fractions; Level 2- 4.7 Gy x 10 fractions; Level 3 - 7.1 Gy x 5 fractions. Dose escalation is according to a 6+6 schema. For purposes of deciding whether to escalate to a new dose level, expand a dose level or de-escalate from a dose level, we will use toxicities and adverse events that occur during the 1st10 weeks after completion of radiation therapy. Six patients will be enrolled on each new dose level. Dose-limiting toxicity (DLT) is defined as grade 3 or worse fatigue, gastrointestinal (GI) or genitourinary (GU) toxicity by Common Terminology Criteria of Adverse Events (version 4.03). Six patients were enrolled at the first dose level. The median age of the patients was 64 years of age. The Median PSA at time of enrollment was 0.135 ng/mL (range 0.03ng/mL – 0.36ng/mL). The median time from prostatectomy to enrollment was 7 months. None of the six patients received concurrent ADT. Grade 1 urinary frequency was seen in all 6 patients. Four of 6 patients experienced grade 1 urgency, and 3/6 patients experienced grade 1 fatigue. Four of 6 patients started radiation therapy with grade 1-2 incontinence – none of those patients had increased incontinence over their baseline during the 10-week observation period. Similarly, 3/6 patients started radiation therapy with grade 1 or 2 nocturia, none of the patients experienced a change from their pre-radiation baseline. Because no patients suffered grade 3 or higher toxicity, the dose escalation occurred according to the trial design. Patients tolerated 3.6 Gy x 15 fractions to the prostate fossa with minimal acute toxicity. Dose-escalation will proceed to 4.7Gy x 10 fractions to the prostate fossa.

Background: Tumor dormancy has been described as a state of hibernation. Dormancy can be switched to proliferation by different pathways, which may play a critical role in tumor recurrence. In this study, we investigated genetic variations within genes involved in tumor dormancy and their association with recurrence and outcome in patients with colorectal liver metastases (CLM) who underwent neoadjuvant bevacizumab-based chemotherapy.Patients and methods: Genomic DNA was extracted from resected CLM (FFPE) from 149 patients. Single-nucleotide polymorphisms (SNPs) in 14 genes associated with dormancy were analyzed by direct Sanger DNA sequencing and evaluated for response, recurrence-free survival (RFS), overall survival (OS) and recurrence patterns.Results: NME1 rs34214448 C> A was significantly associated with RFS in univariable analysis (P = 0.039) and with intrahepatic recurrence (P = 0.014). NOTCH3 rs1044009 T> C and CD44 rs8193 C> T showed a significant difference in 3-year OS rates (P = 0.004 and P = 0.042, respectively). With respect to radiological response, CD44 rs8193 C> T variant genotypes were associated with a significantly higher response rate (P = 0.033). Recursive partitioning analyses revealed that Dll4 rs12441495 C> G, NME1 rs34214448 C> A and NOTCH3 rs1044009 T> C were the dominant SNPs predicting histological response, RFS and OS, respectively.Conclusion: Our data suggest that gene variations within genes involved in tumor dormancy pathways are associated with response and outcome in patients with resected CLM. These data may lead to new and more effective treatment strategies targeting tumor dormancy.