Oral Uracil and Tegafur Plus Leucovorin Compared With Intravenous Fluorouracil and Leucovorin in Stage II and III Carcinoma of the Colon: Results From National Surgical Adjuvant Breast and Bowel Project Protocol C-06

Purpose The primary aim of this study was to compare the relative efficacy of oral uracil and tegafur (UFT) plus leucovorin (LV) with the efficacy of weekly intravenous fluorouracil (FU) plus LV in prolonging disease-free survival (DFS) and overall survival (OS) after primary surgery for colon carcinoma. Patients and Methods Between February 1997 and March 1999, 1,608 patients with stage II and III carcinoma of the colon were randomly assigned to receive either oral UFT+LV or intravenous FU+LV. Results Of the total patients, 47% had stage II colon cancer, and 53% had stage III colon cancer. Median follow-up time was 62.3 months. The estimated hazard ratio (HR) for OS of patients who received UFT+LV versus that of patients who received FU+LV was 1.014 (95% CI, 0.825 to 1.246). The estimated HR for DFS was 1.004 (95% CI, 0.847 to 1.190). Cox proportional hazards model analyses with regard to age (< 60 v ≥ 60 years), stage, or number of involved nodes (none v one to three v ≥ four nodes) revealed no interaction with OS or DFS. Toxicity was similar in the two groups. In the UFT+LV arm, 38.2% of patients experienced any grade 3 or 4 toxic event compared with 37.8% of patients in the FU+LV arm. Primary quality-of-life end points did not differ between the two regimens, although convenience of care analysis favored UFT+LV. Conclusion UFT+LV achieved similar DFS and OS when compared with an intravenous, weekly, bolus FU+LV regimen. The two regimens were equitoxic and generally well tolerated.

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Microsatellite instability (MSI) in stage II and III colon cancer treated with 5FU-LV or 5FU-LV and irinotecan (PETACC 3-EORTC 40993-SAKK 60/00 trial)

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.4001 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 4001-4001 ◽

Cited By ~ 16

Author(s):

S. Tejpar ◽

F. Bosman ◽

M. Delorenzi ◽

R. Fiocca ◽

P. Yan ◽

...

Keyword(s):

Colon Cancer ◽

Microsatellite Instability ◽

Multiple Testing ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Biological Effects ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Stage Ii ◽

Stage Iii

4001 Background: Patients with high MSI (MSI H) tumors are increasingly being recognized as a prognostic and predictive subgroup in colon cancer (COC). We investigated the incidence of MSI-H in stage II (n=395) and stage III (n=859) COC, its association with histopathological variables and its prognostic and predictive impact. Methods: The study accrued 3278 patients with Stage II and Stage III COC to receive post-operative 5-FU -LV with or without irinotecan (IRI). Paraffin tissue blocks of 1327/1405 available patients were successfully analyzed for MSI status using the NCI extended panel of 10 markers. MSI-H was defined as instability in ≥3 markers. Relapse Free Survival (RFS) and Overall Survival (OS, median follow up 68 months) were assessed. Results: MSI H was present in 22% (85) of Stage II and 12% (103)of Stage III colon cancer . MSI H status was significantly associated with age <60, higher T stage, higher grade, lower N stage and right sided tumor location. The table presents univariate RFS and OS hazard rates (with 95% confidence intervals) for prognostic and predictive impact per stage and arm, estimated by a survival regression analysis using Cox proportional hazards model and of selected P values by Wald tests. Conclusions: Microsatellite instability is a strong prognostic factor for RFS and OS when considering Stage II and Stage III COC. Subgroup analysis suggests a stronger effect in Stage II than in Stage III, but is limited by sample size and multiple testing. Taken together with differences in incidence between the stages, this may suggest stage specific biological effects of MSI. In contrast to previous reports (a) in Stage II the prognostic effect of MSI remained significant even in pts treated with 5FU (w/o IRI),(b) There is no evidence for an effect of the addition of IRI. [Table: see text] [Table: see text]

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Relationship between taxane-induced neuropathy and clinical outcomes after adjuvant chemotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.27_suppl.270 ◽

2011 ◽

Vol 29 (27_suppl) ◽

pp. 270-270 ◽

Cited By ~ 2

Author(s):

B. P. Schneider ◽

M. Wang ◽

V. Stearns ◽

S. Martino ◽

V. E. Jones ◽

...

Keyword(s):

Breast Cancer ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Disease Free Survival ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Time Dependent ◽

Individual Treatment ◽

Axillary Lymph ◽

Landmark Analysis

270 Background: Neuropathy is a common and potentially enduring and disabling complication of adjuvant taxane therapy. Recent studies have identified candidate host single nucleotide polymorphisms (SNPs) associated with taxane-induced neuropathy (Schneider et al. ASCO 2011, abstr. 1000). We therefore sought to determine whether neuropathy was associated with breast cancer recurrence. Methods: This study included 4,950 eligible women with axillary lymph node positive or high-risk node-negative breast cancer who received up to 4 cycles of AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2) every 3 weeks, followed by either: (1) paclitaxel 175 mg/m2 every 3 weeks x 4 (P3), (2) paclitaxel 80 mg/m2 weekly x 12 (P1), (3) docetaxel 100 mg/m2 every 3 weeks x 4 (D3), or (4) docetaxel 35 mg/m2 weekly x 12 (D1). Chemotherapy doses were based on actual body weight. Cox proportional hazards model were used to determine the relationship between neuropathy and disease free survival (DFS) and overall survival (OS) treating neuropathy status as a time dependent covariate and using a landmark analysis. Results: Of 4,702 patients who received at least 1 taxane dose, grade 2-4 neuropathy developed in 20%, 27%, 16%, and 16% in the P3, P1, D3, and D1 arms, respectively. In a model including age, tumor size, nodal status, treatment arm, neuropathy, and the neuropathy- treatment interaction, there was no relationship between neuropathy and DFS and OS in the entire population, for any of the individual treatment arms, or for any breast cancer subtypes, whether analyzed as a time-dependent covariate or using a landmark analysis. Baseline covariates associated with an increase rate of neuropathy included black race (25% vs. 19% grade 2-4, p=0.02) and obesity (21% vs. 19%, p=0.04), but not age. Conclusions: There was no association between taxane-induced neuropathy and DFS or OS in patients treated with contemporary AC-taxane therapy, including weekly paclitaxel. These findings show that taxane-induced neuropathy is not associated with outcome, thus suggesting that validation of SNPs predictive of neuropathy may be useful in identifying patients at higher risk for neuropathy but not taxane benefit and thereby improve therapeutic individualization.

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External Validation of a Nomogram to Predict Survival and Benefit of Concurrent Chemoradiation for Stage II Nasopharyngeal Carcinoma

Cancers ◽

10.3390/cancers13174286 ◽

2021 ◽

Vol 13 (17) ◽

pp. 4286

Author(s):

Pui-Lam Yip ◽

Shing-Fung Lee ◽

Cheuk-Wai Horace Choi ◽

Po-Chung Sunny Chan ◽

Ka-Wai Alice Cheung ◽

...

Keyword(s):

Proportional Hazards ◽

Proportional Hazards Model ◽

External Validation ◽

Multivariable Analysis ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Stage Ii ◽

Concurrent Chemoradiation ◽

Clinical Parameters ◽

Concordance Index

A nomogram was recently published by Sun et al. to predict overall survival (OS) and the additional benefit of concurrent chemoradiation (CCRT) vs. radiotherapy (RT) alone, in stage II NPC treated with conventional RT. We aimed to assess the predictors of OS and to externally validate the nomogram in the IMRT era. We analyzed stage II NPC patients treated with definitive RT alone or CCRT between 2001 and 2011 under the territory-wide Hong Kong NPC Study Group 1301 study. Clinical parameters were studied using the Cox proportional hazards model to estimate OS. The nomogram by Sun et al. was applied with 1000 times bootstrap resampling to calculate the concordance index, and we compared the nomogram predicted and observed 5-year OS. There were 482 patients included. The 5-year OS was 89.0%. In the multivariable analysis, an age > 45 years was the only significant predictor of OS (HR, 1.98; 95%CI, 1.15–3.44). Other clinical parameters were insignificant, including the use of CCRT (HR, 0.99; 95%CI, 0.62–1.58). The nomogram yielded a concordance index of 0.55 (95% CI, 0.49–0.62) which lacked clinically meaningful discriminative power. The nomogram proposed by Sun et al. should be interpreted with caution when applied to stage II NPC patients in the IMRT era. The benefit of CCRT remained controversial.

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Clusterin expression (CLU) as a prognostic marker in colorectal carcinoma (CCR).

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.563 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 563-563

Author(s):

Julia Alcaide ◽

Antonio Rueda ◽

Isabel Rodrigo ◽

Teresa Tellez ◽

Rafael Funez ◽

...

Keyword(s):

Multivariate Analysis ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Univariate Analysis ◽

Disease Free Survival ◽

Normal Mucosa ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Staining Procedure ◽

Positive Staining

563 Background: Increased CLU is involved in malignant progression and anticlusterin treatment with antisense oligonucleotides enhances apoptosis induced by several citotoxics. However, clinical significance of CLU expression in human CRCs has been scarcely studied. We investigated whether changes in CLU could be related to carcinogenesis and survival (sv) of CRC patients (pts). Methods: Formalin-fixed and paraffin-embedded specimens were examined from 31 adenomas and 103 CRCs resected at Costa del Sol Hospital. The study was approved by Research Ethics Committee. Immunohistochemistry using monoclonal anti-α chain clusterin antibody (Upstate-Millipore, Watford, England) was performed, following standard staining procedure. CLU was scored as negative (CLU–) (no staining) or positive (CLU +) (>10% of tumor cells with strong staining). Cytoplasmic CLU in tumors was evaluated for cancer cells only, and in normal mucosa for epithelial cells only. Sv curves were calculated and plotted according to Kaplan-Meier method. Predictors that were significant at p<0.10 in univariate analysis, were entered into a Cox proportional hazards model for multivariate analysis, remaining significant at p<0.05. Results: Median follow-up was 54 months. Median age was 70 years (45-91). TNM stage distribution was: I (13%), II (48%), III (25%) and IV (14%). Epithelial normal cells were always CLU-, but 16% (5/31) of adenomas was CLU+ and this percentage increased in CRCs (30%, 31/103). Positive staining always presented an apical cytoplasmic pattern. Recurrence was more frequent in CLU+ (61%,19/ 31) than in CLU- tumors (37%, 27/72) and CLU was significantly associated with lower disease-free survival (DFS) (p<0.05). In multivariate analysis, CLU and stage remained significant independent prognostic factors for DFS (Table). Conclusions: CLU has a role in colon carcinogenesis and prognostic value. CLU is associated with decreased DFS among pts with CRCs. These findings have important implications for identifying CRC pts with more aggressive tumors who may benefit from targeted therapy against clusterin. [Table: see text]

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Tumor sidedness, adjuvant chemotherapy (AC), and other factors affecting survival in patients with stage II colon cancer (CC-II).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.768 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 768-768

Author(s):

Shiva Kumar Reddy Mukkamalla ◽

Donny V. Huynh ◽

Ponnandai Sadasivan Somasundar ◽

Ritesh Rathore

Keyword(s):

Colon Cancer ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Tumor Grade ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Metastatic Colon Cancer ◽

Chi Square ◽

Factors Affecting ◽

Academic Level

768 Background: The role of AC in CC-II is not well defined due to lack of conclusive randomized trial data. This updated analysis using National Cancer Database (NCDB) addresses the overall survival (OS) benefit from AC in CC-II using more refined and case appropriate population cohort. Methods: NCDB was queried for patients diagnosed with CC-II from 2004-2008 with survival information through 2013. Only those patients with pathologically confirmed CC diagnosis were included. Patients undergoing any surgical procedure less than a partial colectomy were excluded. Pearson Chi-square test, Kaplan Meier survival curves and Cox proportional hazards model were used for statistical analysis. Results: A cohort of 36,630 patients was identified for analysis. Elderly patients received less frequent AC (p < 0.0001) and AC was associated with an improved 5-year OS with no difference noted in outcomes from single or multi-agent regimens. AC was an independent predictor of OS regardless of age, gender, race, comorbidity index, insurance status, income level, year of diagnosis, tumor sidedness, tumor grade, adequacy of lymph node evaluation, pathologic tumor (pT) status, colectomy type, margin involvement or academic level of treating institution. In multivariate analysis, right-sided cancers had better survival outcomes compared to left-sided cancers (HR 0.91; p < 0.0001). Conclusions: This study validates previous findings of improved OS from AC in CC-II while addressing some of the shortcomings of prior retrospective studies. Only patients with CC-II without any other primary cancer diagnoses were included. To our knowledge this is the most uptodate analysis of AC in CC-II which includes cases diagnosed up to 2008. Our study found similar improvement in 5-year OS irrespective of chemotherapy regimen. Interestingly, improved OS was seen in right sided tumors compared to left sided tumors, in contrary to that seen with metastatic colon cancer (Venook et al). [Table: see text]

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A randomized trial of two dose levels of cyclophosphamide, methotrexate, and fluorouracil chemotherapy for patients with metastatic breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1988.6.9.1377 ◽

1988 ◽

Vol 6 (9) ◽

pp. 1377-1387 ◽

Cited By ~ 240

Author(s):

I F Tannock ◽

N F Boyd ◽

G DeBoer ◽

C Erlichman ◽

S Fine ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Metastatic Breast ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Rank Test ◽

Primary Surgery ◽

Dose Levels

This study was designed to assess the role of dosage of chemotherapy for treatment of metastatic breast cancer. One hundred thirty-three patients without prior chemotherapy for metastatic disease were randomly allocated to receive two different dose levels of cyclophosphamide (C), methotrexate (M), and fluorouracil (F), administered intravenously (IV) every 3 weeks. Patients were stratified by sites of disease (visceral, bone, or soft-tissue dominant) and by interval from primary surgery to first recurrence. Doses on the higher-dose arm were 600 mg/m2 (C,F) and 40 mg/m2 (M) with escalation if possible; doses on the lower-dose arm were 300 mg/m2 (C,F) and 20 mg/m2 (M) without escalation. Patients who failed to respond to lower-dose CMF were crossed over to the higher-dose arm. Patients randomized to the higher-dose arm had longer survival measured from initiation of chemotherapy (median survival, 15.6 months v 12.8 months, P = .026 by log-rank test), but the effect of dose was of borderline significance (P approximately 0.12) when adjusted for a chance imbalance between the two arms in the time from first relapse to randomization, using the Cox proportional hazards model. Response rates (International Union Against Cancer [UICC] criteria) for patients with measurable disease were higher-dose arm: 16/53 (30%) and lower-dose arm: 6/53 (11%), (P = .03). Only one of 37 patients responded on crossover from the lower- to the higher-dose arm. Patients experienced more vomiting, myelosuppression, conjunctivitis, and alopecia when receiving higher doses of chemotherapy. A series of 34 linear analogue self-assessment scales were used to make detailed quality of life assessments on a subset of 49 patients. These scales confirmed greater toxicity in the immediate posttreatment period, but also a trend to improvement in general health and some disease-related indices, in patients receiving higher-dose chemotherapy. This trial suggests that better palliation is achieved by using full-dose chemotherapy.

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Primary fallopian tube carcinoma: a single-institution retrospective study of 57 cases

10.21203/rs.2.14782/v1 ◽

2019 ◽

Author(s):

Zhihua Ma ◽

Li Gao ◽

Han Li ◽

Yan Xue

Keyword(s):

Proportional Hazards ◽

Proportional Hazards Model ◽

Disease Free Survival ◽

Residual Tumor ◽

Tumor Stage ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Free Survival ◽

Hazards Model ◽

Disease Free

Abstract Background In order to identify the characteristics and factors affecting the treatment and prognosis of primary fallopian tube cancer(PFTC),we analyzed the clinical profile of PFTC in the past 10 years in our hospital, which is center in Western China. Methods A retrospective analysis was performed on 57 patients diagnosed as PFTC at the Department of Obstetrics and Gynecology, the First Affiliated Hospital of Xi’an Jiaotong University from past ten years. The clinical index and a Cox proportional hazards model was used for univariate and multivariate survival analyses. Results The mean age of PFTC at diagnosis was 57.35±9.01 years. Palpable pelvic and/or abdominal mass (68.4%) was the main clinical symptom. Preoperatively, 80.7% patients were misdiagnosed with ovarian cancer, and 43.8% of patients were at stage III. 26 patients were relapsed at the median of 18.5 (3-83) months. The 5-year overall survival (OS) rate was 15.4%, and the 5-year disease-free survival (DFS) was 11.5%. Additionally, univariate analysis showed that tumor stage and size of residual tumor were both related to 5-year OS and DFS. While level of serum carbohydrate antigen 125(CA125) pre-treatment was only related to DFS. The Cox proportional hazards model demonstrated that residual tumor size was the only independent factor related to both 5-year OS and DFS. Conclusions PFTC is a more common malignancy at post-menopause stage in women. The symptoms are not typical in most case and often diagnose at late clinical stage. Tumor stage, level of CA125, and residual lesion size affected the disease-free survival or/ and overall survival. Trial registration Not applicable.

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Different Anatomical Subsites of Colon Cancer and Mortality: A Population-Based Study

Gastroenterology Research and Practice ◽

10.1155/2018/7153685 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 3

Author(s):

Xing-kang He ◽

Wenrui Wu ◽

Yu-e Ding ◽

Yue Li ◽

Lei-min Sun ◽

...

Keyword(s):

Colon Cancer ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Underlying Mechanism ◽

Population Based ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Survival Outcomes ◽

Cancer Specific Survival ◽

Kaplan Meier

Background. In terms of incidence and pathogenesis, right-sided colon cancer (RCC) and left-sided colon cancer (LCC) exhibit several differences. However, whether existing differences could reflect the different survival outcomes remains unclear. Therefore, we aimed to ascertain the role of location in the prognosis. Methods. We identified colon cancer cases from the Surveillance, Epidemiology, and End Results database between 1973 and 2012. Differences among subsites of colon cancer regarding clinical features and metastatic patterns were compared. The Kaplan-Meier curves were conducted to compare overall and disease-specific survival in relation to cancer location. The effect of tumour location on overall and cancer-specific survival was analysed by Cox proportional hazards model. Results. A total of 377,849 patients from SEER database were included in the current study, with 180,889 (47.9%) RCC and 196,960 (52.1%) LCC. LCC was more likely to metastasize to the liver and lung. Kaplan-Meier curves demonstrated that LCC patients had better overall and cancer-specific survival outcomes. Among Cox multivariate analyses, LCC was associated with a slightly reduced risk of overall survival (HR, 0.92; 95% CI, 0.92-0.93) and cancer-specific survival (HR, 0.92; 95% CI, 0.91-0.93), even after adjusted for other variables. However, the relationship between location and prognosis was varied by subgroups defined by age, year at diagnosis, stage, and therapies. Conclusions. We demonstrated that LCC was associated with better prognosis, especially for patients with distant metastasis. Future trails should seek to identify the underlying mechanism.

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Assessment of pelvic lymph node micrometastatic disease in stages IB and IIA of carcinoma of the uterine cervix

International Journal of Gynecological Cancer ◽

10.1136/ijgc-00009577-200605000-00037 ◽

2006 ◽

Vol 16 (3) ◽

pp. 1188-1194 ◽

Cited By ~ 6

Author(s):

Jhtg Fregnani ◽

M. R.D.O Latorre ◽

P. R. Novik ◽

A. Lopes ◽

F. A. Soares

Keyword(s):

Uterine Cervix ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Disease Free Survival ◽

Disease Status ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Micrometastatic Disease ◽

Risk Of Recurrence ◽

Hazards Model

The objective of this study was to assess the frequency of micrometastatic disease (MID) in pelvic lymph nodes (PLNs) in carcinoma of the uterine cervix (CUC) and to determine the risk of recurrence. The PLNs from 289 patients with CUC (IB and IIA) were studied. Each PLN was assessed via immunohistochemistry using a single histologic section (AE1/AE3). Metastatic deposits were measured and the disease status was classified into three groups: 1) absence of metastatic disease (MOD); 2) MID, one or more metastatic PLN with only isolated tumor cells and/or micrometastases (up to 2 mm); and 3) macrometastatic disease (MAD), presence of one or more metastatic PLN with macrometastases (more than 2 mm). Eleven patients (3.8%) were classified as having MID and 37 (12.8%) as having MAD. The 5-year disease-free survival (DFS) rates for MOD, MAD, and MID were 88.7%, 80.4%, and 50.0%, respectively (P < 0.001). The Cox proportional hazards model showed that MID was an independent variable for recurrence when adjusted for MAD, depth of tumor invasion, severity of inflammatory reaction, and use of adjuvant radiotherapy. We conclude that the frequency of MID in PLN was low. However, patients with MID presented a high risk of recurrence and reduced DFS.

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Association of gender-related tumor recurrence with a polymorphic variant of LMTK3 in stage II and III colon cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.454 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 454-454

Author(s):

Wu Zhang ◽

Armin Gerger ◽

Melissa Janae Labonte ◽

Dongyun Yang ◽

Pierre Oliver Bohanes ◽

...

Keyword(s):

Colon Cancer ◽

Tumor Recurrence ◽

Proportional Hazards Model ◽

Univariate Analysis ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Stage Ii ◽

In Vivo Studies

454 Background: Recent evidence suggests that Lemur Tyrosine Kinase 3 (LMTK3) activates estrogen receptor alpha (ERα) transcriptional activity in breast cancer. The mutant variants of two single nucleotide polymorphisms (SNPs) in LMTK3 (rs8108419 and rs9989661) were independently associated with reduced time to tumor recurrence (TTR), suggesting these SNPs were functionally significant. In colon cancer (CC), ERβ expression has been shown to be predominant with low levels of ERα also expressed. ERα stimulates cell proliferation, while ERβ negatively regulates the estrogen-dependent activity of ERα. Based on these previous findings, we hypothesized that LMTK3 rs808419 and rs9989661 may predict TTR in stage II and III CC. Methods: Either blood or FFPE tissue specimens were obtained from 234 patients (107 females and 127 males; median age 59 yrs (range 22–78 yrs)) with stage II (105 pts) or III (129 pts) CC at the University of Southern California. The median follow-up was 4.4 years. LMTK3 rs8108419 and rs9989661 were determined by PCR-RFLP. The primary endpoint of the study was TTR. This study was conducted adhering to the reporting recommendations for tumor marker prognostic studies (REMARK). Results: The minor allele of LMTK3 rs9989661 (C; frequency=30.5%) showed significantly longer median TTR (5.9 vs 12.2+ yrs; HR: 0.41, 95%CI: 0.15-1.18, log-rank p=0.086; univariate analysis) in female CC patients. After Cox proportional hazards model adjustment for stage and type of adjuvant chemotherapy, this result remained significant (HR: 0.25, 95%CI: 0.077-0.778, Wald test p=0.017). No significant association was found between TTR and LMTK3 rs9989661 in men and rs8108419 in both genders. Conclusions: This is the first report demonstrating LMTK3 rs9989661 associations with gender-related TTR in CC. We hypothesize that there is an ERα-dependent loop mechanism with higher estrogen levels in females exerting the effect on ERβ. Larger prospective trials are warranted to confirm these findings, and in vitro and in vivo studies are needed to identify the underlying biological mechanism.

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