ObjectivePrevious studies have found that many gene variations can be detected in both breast cancer and ovarian cancer, which is beneficial for the elaboration of the molecular origin of breast and ovarian cancer. Furthermore, many studies have explored the association of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism with the risk of breast cancer and/or ovarian cancer; however, the results remained inconclusive. Therefore, this study conducted a systematic review and meta-analysis to evaluate the association between MTHFR C677T polymorphism and the risk of breast and ovarian cancer.Materials and methodsA total of 50 studies with 19,260 cases and 26,364 controls including 39 studies for breast cancer and 8 studies for ovarian cancer were identified on searching through PubMed, Embase, Web of Science, China National Knowledge Infrastructure, WanFang, and Database of Chinese Scientific and Technical Periodicals (VIP). Allele model, dominant model, recessive model, homozygous model, and co-dominant model were applied to evaluate the association of MTHFR C677T polymorphism with breast cancer and/or ovarian cancer risk. Moreover, the odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of the association between MTHFR C677T polymorphism and breast and ovarian cancer risk.ResultsA significantly increased breast cancer risk was observed in the overall analysis (for C vs T, OR =1.19, CI: 1.12–1.28, P<0.05; for CC vs TT, OR =1.20, CI: 1.10–1.23, P<0.05; for (CT+CC) vs TT, OR =1.19, CI: 1.11–1.27, P<0.05; for CC vs (CT+TT), OR =1.19, CI: 1.79–1.95, P<0.05), while no significantly increased ovarian cancer risk was detected. In the subgroup analysis based on ethnicity, a significant association of breast cancer and/or ovarian cancer risk with MTHFR C677T polymorphism was observed in Asians. Interestingly, there was no significant association between MTHFR C677T polymorphism and ovarian cancer risk in Caucasians, whereas a significantly increased risk of breast cancer was found in Caucasians.ConclusionThis meta-analysis demonstrates that MTHFR C677T polymorphism may be a risk factor for breast and ovarian cancer, especially in Asians.

4055 Background: First-line chemotherapy in metastatic gastric cancer, either doublet or triplet-regiment, the average OS is less than one year. Anti-VEGF target therapy is proven to be effective both in second and third line settings. As for apatinib, which is the tyrosine kinase inhibitor showed highly affinity for VEGFR2, is permitted by SFDA to be used in the third line treatment of gastric cancer since September 2014. The post-market stage IV clinic trial Ahead-G201 further confirmed it can improve the OS in chemotherapy-refractory gastric cancer. What’s more, apatinib could reverse paclitaxel resistance and improve the R0 resection rate in conversion of unresected gastric cancer in neoadjuvant settings. However, the safety and efficacy of apatinib in combination with docetaxel plus S1 in the first line treatment of metastatic gastric cancer is unknown and worthy of investigation. Methods: With expectation to improve PFS from 5.3m (the START Study) to 7m, this investigator-initiated, single arm, multi-center, registered phase II prospective study was designed to enroll 48 eligible patients diagnosed with metastatic gastric cancer. Each participant was expected to finish six cycles of chemotherapy plus apatinib (docetaxel 75mg/m2, d1, Q3W; S1 according to BSA: <1.25 40mg po bid; 1.25̃1.5 50mg po bid; >1.5 60mg po bid; d1-14, Q3W; apatinib 500mg po qd). The toxicity was determined according to CTCAE 4.0. Efficacy assessed every two cycles (6 weeks) during the study and every 2 months during the follow-up period. The primary endpoint was PFS. The secondary endpoint was OS, ORR, and DCR. The tumor response was determined according to RECIST 1.1 criteria. Results: Baseline characteristics (FAS population): From July 2017 to December 2020, 45 patients from 5 centers across Hubei province were enrolled. Among them, 44 are eligible for analysis. There are 15 females and 30 males, median age 55 years old, median metastasis sites is 2, yet 63.6% of them have involved at least 2 organs. Safety: 90.91% patients reported adverse events (AEs). The incidence of grade 3-4 AEs was 47.73%. Main 3-4 AEs were oral ulceration (13.64%), leucopenia (13.64%), neutropenia (13.64%), hand-foot syndrome (6.82%), hypertension (6.82%), and thrombocytopenia (6.82%). Efficacy: By Jan 31th, 2021, 44 patients were evaluable for response and survival, 26 of them achieved partial response (PR), 9 achieved stable disease (SD), and 8 experienced progression disease (PD). The ORR is 60.47%, the DCR is 81.4%. Median PFS is 7.46m, median OS is 12.42m. So we closed the study in advance. Conclusions: Adding apatinib to standard DS chemotherapy as the first line treatment would be well tolerant in patients with metastatic gastric cancer, the spectrum of toxicity were not exceeding expectation. This modality also exhibits prolonged PFS, which might provide an alternative therapeutic strategy for metastatic gastric cancer. Clinical trial information: NCT03154983.

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3582 Background: Emerging evidence suggested that chemotherapy in combination with anti-angiogenic targeted agents can achieve higher response in multiple solid tumors. Fruquintinib is a highly selective small-molecule VEGFR inhibitor that has been approved for the third-line treatment in metastatic colorectal cancer (mCRC) patients in China. Here, we assessed the efficacy and safety of fruquintinib plus investigator's choice of chemotherapy as second-line therapy in pretreated advanced mCRC patients. Methods: In this prospective, open-label, multicenter, single-arm phase 2 trial (ChiCTR2200059280), patients with mCRC progressed after first-line prior systemic treatment were administered fruquintinib (5~3mg, D1-21, Q4w) and investigator's choice of chemotherapy (fluorouracil ± irinotecan ± oxaliplatin, Q3w) for up to 8 cycles. Patients without disease progression (PD) were followed by fruquintinib maintenance until PD or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), overall survival (OS), and safety. Results: As the data cutoff on February 10, 2023, 37 patients have been enrolled and treated, with 31 evaluable for efficacy. Median age was 63 years (range, 44-76) and 22 (59.5%) were male. The left colon cancer involved in 28 patients (75.7%). All patients were microsatellite-stable phenotype and 11 (29.7%) had mutations in KRAS gene. 16 (43.2%) patients received prior anti-VEGF therapy. 20 (54.1%) and 11 (29.7%) patients had liver and lung metastases respectively. At a median follow-up of 8.4 months, 28 patients are still on treatment. The ORR is 48.4%, with 15 partial response. The DCR is 90.3%. At data cutoff, median PFS has not yet reached. 23 patients (74.2%) remained progression free at 6 months. In terms of safety, the regimen was well tolerated, mainly grade 1/2 adverse events (AEs). Grade 3/4 AEs were neutropenia (21.6%), leukopenia (10.8%), thrombocytopenia (5.4%), proteinuria, diarrhea, hand-foot syndrome and hypertension accounted for 2.7% respectively. 5 pts received reduced doses of fruquintinib. No treatment-related deaths occurred. Conclusions: Fruquintinib combined with chemotherapy followed by fruquintinib maintenance shows promising efficacy and manageable safety profile for mCRC patients in second-line setting. Updated follow up data will be presented in the future. Clinical trial information: ChiCTR2200059280 .

In recent years, immune checkpoint inhibitors have been increasingly used in clinical practice. While considering the efficacy of immunotherapy, it is also necessary to be alert to immune-related adverse effects (irAEs). These include skin, gastrointestinal, liver, endocrine, and pulmonary toxicities. Here, we report a case of irAEs of hypothyroidism with marked hyperlipidemia during sintilimab administration.