bluuebunny/crossref_metadata_2025 huggingface dataset:
Protein expression and clinical features of ovarian cancer in the elderly
Authors: Liu J. , Hirsch M. S. , Lee H. , Matulonis U. A.
Published: March 2020

5574

Background: Ovarian carcinoma is the leading cause of death due to gynecologic malignancies, and age at the time of diagnosis has been suggested to predict for a poorer prognosis. However, few studies have determined if specific biomarkers can predict a difference in prognosis between younger and older patients. We have constructed a tissue microarray (TMA) with correlative clinical data comprised of cases of advanced papillary serous (PS) ovarian cancer to evaluate the features of ovarian cancer in the elderly. Methods: Two cohorts (patient’s age =65 and =55 at diagnosis) were identified by retrospective review of PS ovarian carcinoma pathology cases seen between 1999 and 2005. Patients with stage III or IV were included; those with BRCA mutations were excluded. A high density TMA (with 4 cores per primary tumor) was constructed, and sections were immunostained with ER, PR, and ErbB2. Clinical data were obtained by chart and database review; age, stage, and protein expression were then correlated with overall survival. Correlation of protein expression and age was also examined. Results: 154 cases were examined, with 74 cases in the =55 group and 80 cases in =65 group. There was no difference in survival between the 2 cohorts (p=0.42), but overall survival differed significantly between those patients diagnosed at =70 and >70 years of age (p=0.004). Tumors from the =65 cohort were more likely to express ER (66.7% ≥65, 44.1% ≤55; p=0.009) and less likely to express PR (34.7% ≥65, 57.1% ≤55; p=0.009). Only 3 cases in the older cohort, and none in the younger cohort, expressed ErbB2; these findings were not significant. Protein expression did not correlate with overall survival. However, multivariate analysis revealed that stage IIIc or IV disease (HR 2.38, p=0.04) and age>70 (HR 1.93, p=0.008) were independent risk factors for poorer outcome. Conclusions: This study suggests that patients with advanced PS ovarian carcinoma diagnosed at age >70 have poorer overall survival. PS ovarian cancer in older patients is more likely to express ER and less likely to express PR, but this does not correlate statistically with clinical outcome. Other characteristics of ovarian cancer in the elderly may account for their poorer prognosis, and this TMA will be a valuable tool to assess additional biomarkers.

No significant financial relationships to disclose.
A phase II study of the feasibility of sequential carboplatin (C) followed by paclitaxel (P) and gemcitabine (G) as first-line chemotherapy for stage Ic-IV ovarian (OC), fallopian tube (FTC), and primary peritoneal carcinoma (PPC)
Authors: Agarwal R. , Paul J. , Carty K. , Perren T. , Reed N. , Gourley C. , Parkin D. , Gore M. , Kaye S.
Published: March 2020

5578

Background: We previously explored the feasibility of adding G to C + P in a phase II study, in which 4 cycles of C followed by 4 cycles of concurrent weekly P and G were given (BJC (2004) 91:627–32). Although highly active (med PFS 19.5m), the feasibility of this 1st-line regimen was limited by dyspnea during the weekly P+G phase. The current trial assessed whether the dyspnoea could be ameliorated by altering the schedule. Methods: Untreated FIGO stage Ic-IV OC, FTC and PPC patients (pts) were eligible. Chemotherapy (CTX) consisted of 4 cycles of C (AUC 7) q21 days, followed by 4 cycles of concurrent P (175 mg/m2) d1 and G (1,000 mg/m2) d1 and d8 q21 days. The primary endpoint of the study was the percentage of pts completing the planned 8 cycles of CTX. The planned sample size was 54 pts, based on a one stage single arm study design with 95% power to reject the null hypothesis (completion rate less than 60%), assuming a true completion rate of 80% using one-sided alpha=0.05. Results: All 54 pts were recruited between June 05 and June 06. Details for 44 pts are currently available for the C phase. 38% of these pts had one or more dose reduction (DR), and 68% had dose delays (DD). The commonest reason for DR and DD was neutropenia. Details for 33 pts are currently available for the P+G phase. 27% of these pts had a DR of P and 51% had a DR of G. 71% of pts omitted G on D8, and 64% had a DD. The commonest reasons for DR and DD were neutropenia and thrombocytopenia. Overall, the KM estimate of the percentage completing 8 cycles is 75% (95% CI 61%-89%) based on the current data. Dyspnoea (Grade 2 only) was observed in 4.5% and 3% pts during the C and P+G phases respectively. No significant treatment related CXR changes were observed. The overall response rate was 68% (95% CI 45–86%; 36% CR, 32%PR, 14% SD, 5%PD, 14% NE; n=22). The median follow-up is 7.5 months and the PFS at 8 months is 92% (95% CI 77–97%). Conclusion: This schedule appears to ameliorate the previously observed dyspnoea, while retaining comparable efficacy. The feasibility of this regimen is limited by myelosuppression which could potentially be overcome by: a) reducing the dose of gemcitabine to 750 mg/m2, or b) using prophylactic Peg-GCSF.

[Table: see text]
The relationship between tumor size and stage in early versus advanced ovarian cancer: A retrospective chart review
Authors: Horvath L. E. , Werner T. , Jones K.
Published: March 2020

5580

Background: Ovarian cancer has a different prognosis between early (I and II) and advanced stage (III and IV). The mechanism of disease progression is unknown, but patients with advanced disease may have a higher propensity for seeding of the abdominal cavity early in the disease process than those with early stage. Theoretically if this is so, then patients with advanced stage should have smaller sized tumors than patients with early stage. Methods: This was a retrospective chart review of patients in the tumor registry in 2003 to 2006. Patients had epithelial ovarian cancer, other cell types were excluded. Only cases with documentation of surgical and pathologic staging and measured dimensions on pathologic specimen were included. Patient stage and all available dimensions measured on diseased ovaries were recorded. The dimensions for each patient were averaged into a single dimension for that patient, and then these measurements were totaled and averaged. Results: There were 110 patients analyzed: 85 with advanced disease, 25 with early stage. The average measurement was 4.8 cm in advanced disease, and was 10.7 cm in early stage disease. This difference was statistically significant (p < 0.001). Conclusions: Overall, patients with early stage ovarian cancer have diseased ovaries that are more than twice as large as those found in advanced disease. This finding supports the fact that early versus advanced ovarian cancer are 2 separate disease processes. Early stage grows locally and does not disseminate, and advanced stage disseminates while the tumor is still relatively small. Theoretically there may be a factor that separates these 2 into different diseases, where advanced disease patients have a substance produced by their tumor that allows for early dissemination, and early stage lacks this substance and only grows locally. Basic science research comparing the tissue microarrays of early versus advanced stage disease may be able to identify this difference. If the difference is found, perhaps therapy can be targeted against this difference.

No significant financial relationships to disclose.
The significance of radiotherapy for adenocarcinoma of uterine cervix
Authors: Shimada M. , Kigawa J. , Terakawa N. , Nishimura R. , Takano T. , Yaegashi N. , Takehara K. , Suzuki M. , Yokoyama Y. , Hiura M.
Published: March 2020

5590

Background: We conducted the present study to determine the significance of radiotherapy for cervical adenocarcinoma. Methods: A total of 1,133 patients with cervical cancer, who underwent radiotherapy in 7 institutes between 1996 and 2005, were enrolled in this study. There were 966 squamous cell carcinoma (SCC) and 167 adenocarcinoma (AC). The mean age of patients with AC was 53.6 (range: 28–81) and 55.9 (range: 22–92) for SCC. Patients were distributed as follows: 370 in stage 1b, 116 in stage IIa, 344 in stage IIb, 16 in stage IIIa, 240 in stage IIIb, and 47 in stage IVa. All patients were identified with the medical records. Of 1,133 patients, 544 received radiotherapy as primary treatment, and 589 underwent adjuvant radiotherapy. Results: Regarding primary treatment, the 5-year survival rate for AC was 41.8% and that for SCC was 62.5% (p=0.0172). The rate of refractory or recurrence for patients with AC was significantly higher than that for SCC (53.3% vs. 33.3%, p=0.0068). Patients with AC more commonly showed recurrence inside irradiated field compared with SCC (83.3% vs. 58.2%, p=0.0240). The outcome for patients with AC was significantly worse compared with SCC in adjuvant treatment (5-year survival rate: 27.5% vs. 45.4%, p=0.0434). Recurrence for AC were significantly higher observed than that for SCC (40.0% vs. 24.7%, p=0.0008). The incidence of recurrence inside irradiated field and lymph node involvement did not differ between AC and SCC (30.1% vs. 43.8%, 46.7% vs. 44.0%). Conclusions: Cervical adenocarcinoma had poorer prognosis because of its low radiosensitivity compared with SCC. New strategy for cervical adenocarcinoma should be necessary.

No significant financial relationships to disclose.
Phase II trial of mifepristone (RU-486) in advanced or recurrent endometrioid adenocarcinoma or low-grade endometrial stromal sarcoma (LGESS)
Authors: Burke T. W. , Navo M. A. , Smith J. A. , Jung M. S. , Broaddus R. , Iyer R. B. , Lu K. H. , Sun C. C. , Atkinson E. N. , Ramondetta L. M.
Published: March 2020

5595

Background: Endometrial cancer is the most common cancer of the female genital tract. It affected 41,200 women in the year 2006 and caused 7,350 deaths. Therapy options for recurrent/advanced endometrial cancer are limited. Treatment with radiation and chemotherapy has shown only limited success. Methods: In a phase II IRB approved trial, Mifepristone was given to patients with progesterone receptor positive advanced or recurrent endometrioid adenocarcinoma or low-grade endometrial stromal sarcoma at a dose of 200mg/day orally. Patients were evaluated every 4 weeks to assess treatment-related toxicities and response. Imaging was obtained initially at 8 weeks then every 12 weeks for evaluation of response. Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 was used to assess toxicity. Results: Twelve of 13 enrolled patients were evaluable for response in the first phase of accrual. Stable disease was noted in 3/12 (16, 20, and 44+ weeks). Two were endometrioid endometrial cancer and one with LGESS. No complete responses were seen, one patient remains in treatment. The most frequently reported grade 1–2 tumor related toxicities were anorexia, mood alterations, and fatigue (55%). Twenty-seven percent had asymptomatic elevations of ACTH. The most common Grade 3 toxicities were fatigue and dyspnea (27% and 18%). Only one patient experienced a Grade 4 dyspnea. No serious treatment-related adverse events occurred. Conclusions: Single agent mifepristone in patients with recurrent endometrioid adenocarcinoma or low-grade endometrial stromal sarcoma showed no complete responses. Stable disease was reported 25%, one patient remains stable at 44 weeks. Recent reports suggests that mifepristone may also work via non hormonal targets while single agent mifepristone has minimal activity in this setting. Further evaluation in combination therapy in endometrial cancer should be considered.

No significant financial relationships to disclose.
Endometrial cancer survivorship in obese patients: A lifestyle intervention program
Authors: Von Gruenigen V. E. , Waggoner S. , Gibbons H. , Kavanagh M. , Courneya K. , Lerner E.
Published: March 2020

5596

Background: The majority of early stage endometrial cancer (EC) survivors are obese, have cardiovascular disease and are at significant risk of death from causes other than cancer. The purpose of this study was to examine outcomes at 6 and 12 months in obese EC survivors enrolled in a randomized trial of a nutrition and exercise counseling program. Methods: Patients (pts) with early stage (I or II) EC with a body mass index ≥ 25 diagnosed from 1999–2005 were invited to participate. The intervention (I) group received 6 months of nutritional and exercise counseling while the control (C) group received an informational brochure only. Primary outcome variable was weight loss. Quality of life (QoL) was measured by the Functional Assessment of Cancer Therapy-General (FACT-G) and Medical Outcomes Short-form (SF-36) survey. Exercise [leisure score index (LSI)] and eating patterns (quantitative food records) were assessed at baseline, 3, 6 and 12 mos. Repeated measures ANOVA and independent samples t-test were used for analysis. A sample size of 50 pts with a type1=0.05 and type 2=0.20 error rate was used to test the hypothesis that pts in the I group would lose weight as compared to the C group. Results: 45 pts were enrolled and 23 were randomized to I and 22 to the C group, stratified by BMI. Baseline QoL was decreased in morbidly obese pts (BMI ≥ 40) as compared to pts with a BMI < 40 (FACT-G: 78.0 vs. 83.7; p=0.140; physical SF-36: 40.6 vs. 49.1 p=0.008). Women in the I group lost weight and increased exercise over the 12 mos as compared to controls ( Table ). Repeated measures ANOVA demonstrated a borderline significant interaction effect for weight (F=2.7, p=.074) and a significant interaction effect for exercise (F=5.0; p=.005) over time. The I group had lower intake of calories and total fat during the intervention. Conclusions: Obese EC survivors can undergo and maintain positive lifestyle changes. Future studies will examine long-term changes in co-morbidities and mortality.

[Table: see text]

No significant financial relationships to disclose.
Neuropsychological sequelae of tamoxifen and exemestane after AC-chemotherapy in postmenopausal women with early breast cancer
Authors: Schilder C. M. , Eggens P. C. , Boogerd W. , van Dam F. S. , Schagen S. B.
Published: March 2020

566

Background: Cognitive deficits and cognitive complaints in daily life have been associated with adjuvant chemotherapy in breast cancer survivors. The role of endocrine treatments with respect to these cognitive problems is unclear. Because estrogen deficiency may have adverse effects on certain cognitive functions, it is plausible that endocrine treatments affect cognitive functioning in addition to chemotherapy. The current aim was to investigate whether cognitive functioning of breast cancer patients treated with AC-chemotherapy and endocrine therapy differs from healthy controls and to examine possible distinctive effects between tamoxifen and exemestane. Methods: Postmenopausal breast cancer patients from the TEAM-trial, randomized to receive tamoxifen (n=30) or exemestane (n=51), underwent neuropsychological testing and were interviewed regarding cognitive complaints in daily life 1.5–4 years post AC- chemotherapy. At the time of testing, all patients still received their assigned endocrine treatment. Depression was measured with the Hopkins Symptom Checklist (HSCL), fatigue with the Multidimensional Fatigue Inventory (MFI). Healthy controls (n=48) underwent the same assessment. Results: After controlling for age and IQ, both tamoxifen and exemestane users scored significantly lower on ‘information processing speed’ than healthy controls (Reaction times; p = .023 and p = .008). Tamoxifen users scored significantly lower on ‘mental flexibility’ (Stroop Card 3; p = .007) and ‘category fluency’ (p = .<0001) than healthy controls. A significant higher proportion of both tamoxifen and exemestane users reported memory problems in daily life compared to healthy controls (27.6 and 25.5% versus 6.3%, p = .02). Reported cognitive complaints did not correlate with test scores but with fatigue and depression. Conclusions: These results suggest that endocrine treatments combined with AC-chemotherapy have an effect on certain cognitive functions and provide indications for distinctive cognitive effects of different types of endocrine therapy.

No significant financial relationships to disclose.
The impact of epoetin-alpha on anemia, red blood cell (RBC) transfusions, and survival in breast cancer patients (pts) treated with dose-dense sequential chemotherapy: Mature results of an AGO phase III study (ETC trial)
Authors: Moebus V. , Lueck H. , Thomssen C. , Harbeck N. , Nitz U. , Kreienberg R. , Jackisch C. , Schneeweiss A. , Huober J. , du Bois A. , Untch M.
Published: March 2020

569

Background: Dose-dense chemotherapy has been shown to have a significant advantage in disease-free survival (DFS) and overall survival (OS) in high risk breast cancer pts, but leads to a higher number of RBC transfusions (CALGB C9741, AGO-ETC). Controversial results have been reported regarding the influence of Epoetin-alpha on DFS and OS in cancer pts. Methods: From 12/98 until 4/03, 1,284 pts were recruited into a multi-center phase-III trial. Breast cancer pts with at least 4 involved lymph nodes and below 65 years of age were randomized between a standard regimen (4 × EC followed by 4 × Paclitaxel) and a dose-dense arm consisting of three courses each of epirubicin (150 mg/m2), paclitaxel (225 mg/m2) and cyclophosphamide (2,500 mg/m2) at 2 weeks interval (ETC). A second randomization ± Epoetin-alpha was performed in the ETC arm only (150 IU/kg/sc three times weekly). Results: In 10/06, 1255 (98%) pts were evaluable. 658 pts were randomized in the dose-dense ETC arm, of whom 333 received Epoetin-alpha. Median follow- up is 62 months. Anemia was seen significantly more often in the ETC-arm alone compared to treatment with Epoetin-alpha (p<0.0001). Altogether, 11% of all patients were treated with RBC transfusions. Standard EC->T treatment resulted in 1% RBC transfusions, but 28% in the ETC arm alone vs. 13% in the ETC + Epoetin-alpha-arm (p<0.0001) received RBC transfusions. Despite this significantly higher transfusion rate the median Hb-value dropped from 12,8g/dl at cycle 1 to 10,7g/dl at cycle 9 in the ETC arm alone. In contrast the same value remained stable with Epoetin-alpha (12,4g/dl at cycle 1 and 9 each). At a median follow-up of 62 months, there is no difference between the ETC-arm alone and the ETC + Epoetin-alpha-arm concerning 5-year DFS and OS ((71% vs. 72% (p=0.86) and 83% vs. 81% (p=0.89)). Conclusions: The dose-dense adjuvant ETC-regimen significantly improves DFS and OS but is combined with relevant hematological toxicity. Epoetin-alpha significantly reduces the number of RBC transfusions and prevents anemia. However, the prevention of anemia has no influence on DFS and OS in the adjuvant treatment with dose-dense ETC.

[Table: see text]
Nijmegen breakage syndrome 1 (NBS1) gene polymorphism and chemotherapy-induced neutropenic fever in breast cancer patients
Authors: Sun A. , Yu T. , Wang L. , Lu J. , Gonzales G. , Pusztai L. , Singletary S. , Ross M. I. , Wei Q. , Buchholz T. A.
Published: March 2020

574

Background: Neutropenic fever (NF) is a serious complication of the chemotherapies given to breast cancer patients and often limits their use. Hence, identifying which patients are at increased risk to develop NF is very important. The NBS1 gene product is important for the repair of double-strand DNA breaks and is activated by chemotherapy. The objective of this study was to determine if genetic variations of NBS1 polymorphisms predict the risk of chemotherapy-induced NF in breast cancer patients. Methods: Blood from 306 newly diagnosed breast cancer patients treated with chemotherapy were prospectively collected on a study approved by the institutional review board. The relationship of chemotherapy administration (e.g. dose, timing) and growth factor use were correlated with the absolute neutrophil count (ANC) and NF development. For each patient, we assessed three polymorphisms (924T>C, 8360G>C, and 30537G>C) of NBS1 gene using polymerase chain reaction-restriction fragment length polymorphism method. Two-sided Chi-square test was used for univariate analysis and a multivariable logistical regression analysis was used to calculate odds ratios. Results: In total, 167 (55%) patients experienced ANC less than 1,000 cells/microliter (CIN1000) and 30 (10%) patients developed NF. For 8360G>C polymorphism, 9.7% of patients had a 8360CC variant genotype and these patients had increased risk of NF than the other genotypes (NF in CC 20.7% vs. in others 8.1%; Odds Ratio [OR] = 3.0; 95% confidence interval [CI] = 1.1 - 8.0, p = 0.034). In multivariable logistic regression model, 8360CC genotype (OR = 5.0, 95% CI = 1.6 - 16.1, p = 0.007) and growth factor support (OR = 19.6, 95% CI = 4.4 - 87.6, p < 0.001) were significantly associated with NF development. No genotypes of 924T>C and 30537G>C polymorphisms increased the risk of NF and there was no statistical association between the three NBS1 gene polymorphisms and CIN1000. Conclusions: Breast cancer patients with 8360CC variant polymorphism in NBS1 gene have increased risk in developing NF with systemic chemotherapy. Analysis of polymorphisms of NBS1 and other DNA repair genes could potentially help identify who will develop chemotherapy-induced bone marrow toxicities.

No significant financial relationships to disclose.
Toxicity of concurrent radiotherapy with CMF chemotherapy in the E-CMF adjuvant breast carcinoma regimen
Authors: Church D. N. , Flubacher M. , Cameron A. , Bahl A. , Braybrooke J.
Published: March 2020

582

Background: In the adjuvant management of breast cancer although delivery of radiotherapy (RT) concurrently with anthracyclines is contraindicated, toxicities are acceptable when the chemotherapy regimen used is CMF. The NEAT trial (NEJM 2006; 355:1851- 1862), presented at ASCO in 2003 demonstrated a significant survival advantage for sequential 4x epirubicin and 4x CMF chemotherapy (E- CMF) compared with 6x CMF and was adopted in the UK as a standard regimen. In order to limit treatment duration, RT may be given concurrently with chemotherapy during the CMF phase of treatment. We have reviewed the toxicity associated with this approach. Methods: Retrospective review of all patients treated with concurrent breast RT and CMF chemotherapy as part of the E-CMF regimen in our institution. Toxicities were graded according to the Radiation Therapy Oncology Group (RTOG) toxicity criteria. Confidence intervals were calculated by the binomial method using Stata version 9. Results: 77 patients received concurrent therapy between March 2004 and May 2006. Baseline characteristics; median age: 48, ER positive: 63.5%, HER2 positive: 11.7%, node positive disease: 85.7%. Type of surgery; lumpectomy: 61.0%, mastectomy: 39.0%, nodal dissection: 100%. Chemotherapy delivery; completed without delay: 35.1%, completed therapy with dose reduction/delay: 48.1%, discontinued therapy prematurely due to toxicity 16.8%. Sites of RT; breast: 62.3%, chest wall: 35.1%, axillary nodes: 45.5%, supraclavicular fossa: 36.4%. Schedule of RT; 50Gy/25#: 18.2%, 46/45Gy/20#: 67.6%, 45Gy/15#: 14.3%. Median interval between final dose of epirubicin and start of RT: 55 days. Toxicity; cutaneous grade 3–4 acute radiotherapy toxicity: 31.2% (95%CI 21.1–42.7%); cutaneous infective cellulitis: 14.3% (95%CI 7.4–21.1%); grade 3–4 neutropenia: 54.4% (95%CI 42.8–65.9%); febrile neutropenia requiring hospitalisation: 22.1% (95% CI 13.4–33.0%). The median duration of stay in hospitalised patients was 8 days (range 3–23 days). Conclusions: Toxicities were significantly greater than documented previously for concurrent therapy. RT should not be given concurrently with CMF chemotherapy as part of the E-CMF regimen.

No significant financial relationships to disclose.
Three-year disease-free survival (DFS) as surrogate end-point for predicting five-year overall survival (OS) benefit in adjuvant taxane-based chemotherapy for breast cancer (BC): Analysis of 10 randomized clinical trials (RCTs)
Authors: Giannarelli D. , Bria E. , Cuppone F. , Ciccarese M. , Nisticò C. , Carlini P. , Milella M. , Lorusso V. , Terzoli E. , Cognetti F.
Published: March 2020

584

Background: The issue regarding the eventual correlation between DFS at earlier follow-up (i.e. 3-yrs) with 5-yrs OS has not actually been explored in trials addressing the role of taxanes in BC. All RCTs in which patients were randomized to receive a standard or a taxane-based regimen for early BC were analyzed to evaluate this topic. Methods: All phase III trials with at least 60 month follow-up were considered eligible. The correlation has been explored according to a linear regression model considering both each single outcome pair (DFS/OS) for all arms (extracted by curves), their differences, and each outcome Hazard Ratio (HR) or calculated Relative Risk (RRs), following 2 steps: 1) correlation between 5-yrs DFS and OS (to confirm the evidence); 2) correlation between 3-yrs DFS and 5-yrs OS (predictive role). The correlation was estimated according to Pearson (r) and R2 coefficients (parametric) and Spearman (Rho) coefficient (non- parametric). A model to calculate the target sample size to determine 5-yrs OS benefit of 3%, 5% and 7%, respectively, was calculated as well. Results: Ten RCTs (17,067 patients) with available data for outcomes were gathered. For 5-yrs DFS/OS, a linear correlation was found between rates (r=0.74, R2=0.55; p<0.0001; Rho=0.83; p<0.0001), and HRs (r=0.90, R2=0.81; p<0.0001; Rho=0.91; p<0.0001). Three-yrs DFS correlates with 5-yrs OS, with both rates (r=0.81, R2=0.66; p<0.0001; Rho=0.92; p<0.0001), and RRs (r=0.84, R2=0.71; p=0.002; Rho=0.85; p=0.002). Three-yrs DFS and 5-yrs OS absolute differences strongly correlate (r=0.86, R2=0.74; p=0.001; Rho=0.84; p=0.002). The sample size model (on the basis of the r-coefficient=0.81), calculates 2,733, 863, and 389 pts to improve 3-yrs DFS of 4%, 7% and 10%, which means to improve 5-yrs OS of 3.2%, 5.7% and 8.1%, respectively. Conclusions: By these data, 3-yrs DFS is a reliable surrogate end-point for OS when testing new drugs in early BC, and is able to predict a late survival benefit. Thanks to the smaller patient sample size, RCTs with this design will provide early results in a shorter time period, allowing a faster data transfer to clinical practice.

No significant financial relationships to disclose.
CYP2D6*4 polymorphism as blood predictive biomarker of breast cancer relapse in patients receiving adjuvant tamoxifen
Authors: Gonzalez-Santiago S. , Zárate R. , Haba-Rodríguez J. , Gómez A. , Bandrés E. , Moreno S. , Borrega P. , García-Foncillas J. , Aranda E.
Published: March 2020

590

Background: Polymorphisms in cytochrome P450 2D6 gene affect the plasma concentration of tamoxifen active metabolites (endoxifen). Some drugs are known to be CYP2D6 inhibitors. We aim to determine the relationship between CYP2D6*4 polymorphisms, concomitant CYP2D6 inhibitors use and clinical outcomes of breast cancer patients receiving adjuvant tamoxifen (TAM). Patients and Methods: CYP2D6*4 (1934 G>A+1) genotype was determinated from DNA of blood samples using PCR-RFLP technique and Taqman Allelic Discrimination Assay in a series of 84 breast cancer patients receiving adjuvant TAM. CYP2D6 inhibitors were recorded. Chi-square test and logistic regression models were used to determinate association between genotype, use of concomitant CYP2D6 inhibitors and disease relapse rate. Results: In our 84 patients series mean age was 51.5y. (33–71). 14.8% were stage I, 58.0% stage II and 27.2% stage III. 61.4% were nodes positive and 98.7% tumors had positive hormonal receptors. We observed disease recurrence in 36.9% of cases. The mean following-up was 5.5 y. Genotype frequency was: wt/wt (57.1%), wt/*4 (40.5%) and *4/*4 (2.4%). 50% (18 of 36) of patients with the wt/*4 + *4/*4 genotypes had disease relapse compared with 27% (13 of 48) with wt/wt genotype (P= 0.041). Only 6 patients received concomitants CYP2D6 inhibitors, mainly antidepressants, all of them with the wt/*4 genotype. 50% presented disease relapse. Clinical pathological variables were evaluated and significant relation was found between stage and disease relapse by univariate analysis (P= 0.001). We investigated whether CYP2D6*4 genotype and stage to diagnosis could influence in disease relapse. For these analyses we use as reference group the genotype wt/wt. We observed that combined genotype wt/*4 + *4/*4 was more strongly associated with disease recurrence than wt/wt genotype (adjusted hazard ratio [HR], 2.82, 95% confidence interval [CI] 1.0- 7.9) P= 0.049. Conclusions: Breast cancer patients with the CYP2D6 *4/*4 or wt/*4 genotype could have lower benefit of TAM adjuvant treatment and tend to have a higher risk of disease relapse. Pre-treatment CYP2D6 genotype determination from blood sample could predicts TAM clinical outcomes and help to oncologist in treatment decision.

No significant financial relationships to disclose.
Neoadjuvant chemotherapy with a dose-dense sequential combination of epirubicin and cyclophosphamide followed by paclitaxel and gemcitabine ± trastuzumab in stage II and III breast cancer. Correlation between pathologic complete response (pCR) and biologic markers
Authors: Sanchez A. , Dueñas-García R. , Jaén-Morago A. , Chacón I. , García-Tapiador A. , Martínez-Ortega E. , de la Torre-Cabrera C. , Dueñas B. , Ribelles N. , Sánchez-Rovira P.
Published: March 2020

595

Background: To evaluate the efficacy, measured as pCR, and safety of a noncross-resistant sequential and dose- dense schedule as neoadjuvant treatment for early breast cancer patients (pts). To correlate pCR with gene expression. Methods: Histologically confirmed stage II-III breast cancer pts, including inflammatory tumors, were treated first with epirubicin and cyclophosphamide (90/600 mg/m2) for 3 cycles and then with paclitaxel and gemcitabine (150/2,500 mg/m2) for 6 cycles. All drugs were administered on day 1, every 2 weeks with growth factor support. Weekly trastuzumab (2 mg/kg with a loading dose 4 mg/kg) was given concomitantly with paclitaxel and gemcitabine in Her2 positive pts. A biopsy was performed before treatment for the gene expression study. Pts underwent surgery, radiotherapy and adjuvant hormonal therapy according to institutional practice. Results: 73 pts with a median age of 45.3 (range 28.6–73.6) were enrolled; 42 (57.5%) T2, 12 (16.5%) T3 and 19 (26%) T4 (13 inflammatory). Median tumor size was 4 cm (1–10). 30 pts (41.1%) were hormonal receptor negative, 32 (43.8%) ki-67 positive, 10 (13.7%) p53 positive, 31 (42.5%) GIII and 20 (27.3%) Her2 positive. All pts responded; 27 (36.9%) achieved a pCR (absence of invasive tumor in the breast); 32.1% in Her2 negative pts and 50% in Her2 positive pts. 47 pts (64,4%) underwent conservative surgery. G3/4 hematologic toxicities were leukopenia in 6 pts (9%), neutropenia in 8 pts (12%) and anemia in 1 (2%). Most frequent G3/4 nonhematologic toxicities were nausea (13%) and vomiting (15%). Asymptomatic decrease in cardiac ejection fraction was observed in 1 pt treated with trastuzumab with subsequent normalization. Conclusions: These results show a highly effective regimen in terms of pCR with a good toxicity profile. The addition of trastuzumab increased the pCR rate in Her2 positive pts. Updated results, including correlation between pCR and biological markers and disease-free survival will be presented at the meeting.

No significant financial relationships to disclose.
The effect of margin status on local recurrence following breast conservation and radiation therapy for DCIS
Authors: Kell M. R. , Dunne C. , Canning C. , Morrow M.
Published: March 2020

597

Background: There is no consensus on what constitutes an adequate surgical margin in patients receiving breast conserving surgery (BCS) and postoperative irradiation (RT) for ductal carcinoma in situ (DCIS). Inadequate margins may result in high local recurrence, and excessively large resections may lead to poor cosmetic outcome without oncological benefit. Methods: A comprehensive search for published trials which examined outcomes after adjuvant RT following BCS for DCIS was performed using medline and cross referencing available data. Reviews of each study were conducted, and data were extracted. Fixed and random effects methods were used to combine data. Primary outcomes were in breast tumour recurrence (IBTR) related to surgical margins. Results: Analysis of 3,606 patients from randomized trials confirms that patients with negative margins are significantly less likely to recur than those with positive margins after RT (RR 0.53, 95% CI= 0.42 to 0.66, p<0.01). Combined data from randomized and non randomized trials, of 5,500 patients, demonstrates that where the margin status is close or unknown there is significant risk of IBTR compared to a negative margin (RR=1.68, 95% CI= 1.22–2.33, p<0.01). When specific margin thresholds are examined a 2 mm margin is superior to less than 2 mm (OR=0.67, 95% CI 0.51 -0.89, p<0.01), however we saw no significant difference in the rate of IBTR between a 2 mm margin and >5 mm (OR=1.49, 95% CI 0.54 to 4.9, p>0.05). Conclusions: Surgical margins negative for DCIS should be obtained following BCS for DCIS. A margin threshold of 2mm appears be as good as a larger margin when BCS for DCIS is combined with RT.

No significant financial relationships to disclose.
Prognostic significance of human papillomavirus (HPV) tumor status for patients with head and neck squamous cell carcinoma (HNSCC) in a prospective, multi-center phase II clinical trial
Authors: Fakhry C. , Westra W. , Li S. , Cmelak A. , Ridge J. , Pinto H. , Forastiere A. , Gillison M.
Published: March 2020

6000

Background: Retrospective, single-institution studies suggest that patients with HPV- positive (HPV+) HNSCC may have a better prognosis than patients with HPV-negative (HPV-) tumors. Methods: The effect of tumor HPV status on treatment response and survival outcomes was prospectively evaluated in a multi-center, phase II clinical trial conducted by the Eastern Cooperative Oncology Group. Patients with newly diagnosed, resectable, stage III or IV HNSCC of the oropharynx or larynx were uniformly treated with two cycles of induction chemotherapy (IC; paclitaxel 175 mg/m2 and carboplatin AUC 6) followed by chemoradiation (CRT; weekly paclitaxel 30 mg/m2 administered concurrently with standard fractionation external beam radiation therapy, total dose of 70 Gy in 35 fractions over 7 weeks). Tumor HPV status was determined by in situ hybridization on formalin-fixed, paraffin-embedded tumors. The independent effect of tumor HPV status on survival was evaluated by Cox-proportional hazards models. Results: Genomic DNA of oncogenic HPV type 16, 33, or 35 was specifically located within tumor cell nuclei of 40% (95%CI 29.7- 50.1) of evaluable cases. Factors associated with HPV+ tumor in univariate analysis included Caucasian race (p=0.02), improved ECOG performance status (p=0.01), an oropharyngeal primary (p<0.001), early tumor stage (p=0.02), and basaloid histology (P<0.001). Response rates assessed after IC (81.6% vs. 55.2%, p=0.01) and CRT (84.2% vs. 56.9%, p=0.07) were higher in patients with HPV+ than HPV- tumors. After a median follow-up time of 39.1 months, patients with HPV+ tumors had a risk of progression that was 72% lower (HR=0.28, 95% CI: 0.07–1.0) and a risk of death that was 79% lower (HR=0.21, 95% CI: 0.06–0.74) than patients with HPV- tumors, after adjustment. Conclusion: The improved prognosis of HPV+ HNSCC has been confirmed in a prospective clinical trial and may be explained in part by enhanced sensitivity to chemotherapy and radiation.

No significant financial relationships to disclose.
Incidence of human papillomavirus (HPV)-related head and neck cancers in the U.S. from 1998–2003: Pre-HPV vaccine licensure
Authors: Saraiya M. , Kawaoka K.
Published: March 2020

6003

Background: While smoking and alcohol are implicated in the majority of head and neck cancers, human papillomavirus (HPV) has been responsible for 15–35% of head and neck cancers worldwide. In head and neck sites such as the oropharynx, tonsil, and tongue, HPV is associated with 50–90% of squamous cell cancers. Recent recommendation of an HPV vaccine, protecting against infection with HPV types 16 and 18 have prompted this current assessment of the burden of squamous cell cancers (SCC) at these sites. Methods: Using data from CDC’s National Program of Cancer Registries and/or NCI’s SEER Program for cases diagnosed from 1998–2003, covering 83% of the U.S. population, we assessed the squamous cell cancers (SCC) of the base of tongue, oropharynx, and tonsil in the U.S. population on the basis of age group, gender, race/ethnicity, stage, US region, and year of diagnosis. Incidence rates were age- adjusted to the 2000 U.S. standard population and are expressed per 100,000 individuals. Results: The average annual incidence rates per 100,000 individuals during 1998–2003 are: base of tongue, 1.16 (95% confidence interval 1.14–1.18); oropharyngeal, 0.90 (95% CI 0.89–0.92); and tonsillar, 1.35 (95% CI 1.34–1.37). Blacks have the highest incidence of base of tongue, oropharyngeal, and tonsillar SCC (1.25, 1.61, and 1.47, respectively) while Asian/Pacific Islanders have the lowest incidence (0.37, 0.25, and 0.49, respectively). The South has the highest incidence of base of tongue, oropharyngeal, and tonsillar SCC (1.24, 1.06, and 1.52 respectively). Tonsillar cancer had the highest incidence rates for Whites, Asian/Pacific Islanders, American Indians/Alaska Natives, and Hispanics (1.37, 0.49, 0.85, and 0.89, respectively), but oropharyngeal cancer was the highest in Blacks (1.47). Both base of tongue and tonsillar SCC show a significant annual increase (2.68%, 2.96%, respectively). Conclusions: Increasing incidence rates among those head and neck cancers that are HPV- associated such as tonsillar and base of tongue suggest that the HPV vaccine may have a significant impact on these cancers.

No significant financial relationships to disclose.
The impact of previous tracheostomy in patients with locally advanced squamous cell carcinoma of the larynx submitted to concurrent chemotherapy and radiation
Authors: Dias F. L. , Herchenhorn D. , Small I. A. , Araújo C. M. , Ferreira C. G. , Kligerman J.
Published: March 2020

6004

Background: The combination of chemotherapy and radiotherapy is a standard treatment for locally advanced larynx cancer. Patients presenting with previous tracheostomy due to aiway obstruction have a worse clinical outcome when submitted to a total laryngectomy or radiotherapy; the impact of previous tracheostomy is not clear in patients submitted to chemotherapy combined with radiation. Methods: A single-institutional study, patients with stage III and IV laryngeal carcinoma were prospectively selected from 2000 to 2003. Treatment consisted of Cisplatin 100 mg/m2 every three weeks for 3 cycles concurrent with radiotherapy to a total dose of 70.2 Gy. Prognostic factors like stage, age, performance status, chemotherapy completion, treatment response and previous tracheostomy were correlated on univariate and multivariate analysis with treatment response, progression-free and overall survival. Results: Forty-nine patients were selected, previous tracheostomy was performed in 12 (24,5%) before chemo/radiation therapy. Patients with tracheostomy had an inferior median overall cancer-specific survival (12 months versus 56 months), HR 2.37 (CI 95% 1.43–3.93) p=0.001, progression free-survival HR 2.8 (CI 95% 1.61–4.89) p<0.001 and lower rates of complete responses (40 versus 75%). The impact of previous tracheostomy was not altered when adjusted by number of chemotherapy cycles, tumor stage, performance status, age or treatment response. On a cox regression analysis for overall cancer-specific survival it was the strongest prognostic factor HR 7.75 (CI 95% 2.75–21.84) p<0.001. Conclusions: Previous tracheostomy is an independent negative prognostic factor for patients submitted to chemotherapy combined with radiation. Tracheostomty should be considered in the design of future studies and to select patients to different treatment strategies.

No significant financial relationships to disclose.
Chemo-selection as a strategy for organ preservation in patients with T4 laryngeal squamous cell carcinoma
Authors: Worden F. P. , Wolf G. , Eisbruch A. , Lee J. , Bradford C. R. , Chepeha D. , Teknos T. , Prince M. , Hogikyan N. , Tsien C. , Urba S. G.
Published: March 2020

6005

Background: We previously reported high rates of overall survival (OS) and laryngeal preservation in two sequential phase II trials with stage III/IV laryngeal squamous cell carcinoma patients (pts), who attained a >50% response after 1 cycle of induction chemotherapy, and who were treated with chemoradiation. Since then, all pts were re-staged to correspond with the most recent American Joint Committee on Cancer staging guidelines. Here we report the outcomes of the T4 pts from both studies. Methods: Pts received 1 cycle of cisplatin 100 mg/m2 & 5-FU 1,000 mg/m2/day × 5 days (P+5FU). Pts with > 50% response received chemoradiation with 70 Gy & P 100 mg/m2, days 1, 22, & 43. Pts with ≤ 50% response underwent laryngectomy. Final planned tumor assessment by direct laryngoscopy with biopsy was performed 8 wks after chemoradiation. Pts who were histologic complete responders, received 2 cycles of P+5FU. Pts with residual disease had planned salvage surgery. Results: Thirty-two T4 eligible (cartilage invasion 31, base of tongue involvement 1) pts were enrolled, 23 M; 9 F; median age 56; stage: IVA 31, IVB 1; site: 19 supraglottic, 13 glottic. After 1 cycle induction chemotherapy, 26 pts (81%) had > 50% response & received chemoradiation; 5 (16%) had surgery; & 1 refused surgery. After chemoradiation, 22 pts had a complete histologic response, & 4 pts required immediate salvage larngectomy for residual disease. Of those responding to chemoradiation, 2 pts eventually required salvage laryngectomy. Currently, 17/32 (53%) are alive (15 without disease), 10 are dead of disease, & 5 are dead from other causes. Toxicity: grade 3/4 granulocytopenia 19%, grade 3/4 mucositis 49%. Median time to follow-up is 45 months. The 3 yr overall survival (OS) is 75% (95% CI=55%, 86%), & the 4 yr OS is 70% (95% CI = 50%, 83%). The 3 yr disease-free survival (DFS) is 77% (CI=58%, 88%), & the 4 yr DFS is 72% (CI=52%, 85%). Conclusions: Our results suggest that chemo-selection is an alternative, organ preservation strategy to total laryngectomy for pts with T4 laryngeal squamous cell carcinoma.

No significant financial relationships to disclose.
ERCC1 immunohistochemical expression and cancer-specific survival in patients with locally advanced squamous-cell carcinoma of the head and neck treated by cisplatin-based induction chemotherapy
Authors: Mountzios G. , Handra-Luca A. , Hernandez J. , Taranchon E. , Lacau-St Guily J. , Soria J. , Fouret P.
Published: March 2020

6011

Background: The excision repair cross-complementation group 1 (ERCC1) enzyme is a key element of the nucleotide excision repair (NER) pathway which removes cisplatin-induced DNA adducts and has been associated with resistance to platinum-based chemotherapy. We assessed the correlation of ERCC1 immunohistochemical expression with objective tumor response and cancer-specific survival in patients with locally advanced head and neck squamous-cell carcinoma (HNSCC) treated with cisplatin-based induction chemotherapy (CBIC). Methods: The initial cohort comprised 107 patients who had received CBIC (modified Al Saraf protocol) from 1992 to 1996 for locally advanced HNSCC. P53 mutations had been previously studied. Pre-therapeutic biopsy samples from 96 patients with a known tumor response were available. Two independent observers blinded to clinical annotations evaluated ERCC1 expression using the H-score protocol. The median H-score value was a priori selected as the cutpoint in order to dichotomize ERCC1 expression for statistical analysis. Results: In 68 cases [71%, 95% CI: 61% - 79%] tumors expressed ERCC1 intensively and diffusely. Using the logistic regression method, the 28 patients [29 %, 95% CI:21%-39%] with tumors expressing ERCC1 at lower levels had a four time greater odds of benefiting from an objective response to chemotherapy [OR 4.3, 95% CI: 1.4 - 13.4; p = 0.01]. ERCC1 and p53 status, but not their association, were independent predictors of tumor response. In a Cox proportional hazard model adjusted on well-established prognosticators including age, T, N, M, tumor differentiation and localization, ERCC1 low expression was associated with a lower risk of cancer death [RR 2.13, 95% CI: 1.03 - 4.43; p=0.04], while p53 status had no prognostic value. Conclusions: Patients with ERCC1 negative tumors are more likely to derive a substantial benefit from CBIC, translated to a lower risk for cancer-related death compared to patients with ERCC1 positive tumors. Large prospective trials should evaluate ERCC1 and other critical biomarkers involved in DNA damage repair process as molecular predictors of responsiveness to chemotherapy in patients with HNSCC.

No significant financial relationships to disclose.
Final results of a phase II study of erlotinib, docetaxel and cisplatin in patients with recurrent/metastatic head and neck cancer
Authors: Kim E. S. , Kies M. S. , Glisson B. S. , Tsao A. , Ginsberg L. E. , Holsinger F. C. , Burke B. J. , Truong M. , Papadimitrakopoulou V. A. , Lippman S. M.
Published: March 2020

6013

Background: Interrupting the epidermal growth factor receptor (EGFR) signaling pathway has shown promise in a variety of cancers and preclinical data has demonstrated possible synergy with platinums and taxanes. Treatment options for recurrent/metastatic HNSCC are limited. A study of cisplatin and docetaxel showed a response rate of 40% and 9.6 month median survival. Erlotinib, an EGFR tyrosine kinase inhibitor, had a 4.3% response rate as single agent in HNSCC. Because of the possible synergy and efficacy, we proposed to study the combination of cisplatin, docetaxel and erlotinib in advanced HNSCC. Methods: Patients (pts) were required to have adequate performance status, measurable disease, no prior EGFR therapy, and may have received prior induction, concomitant or adjuvant chemotherapy, but not for recurrent/metastatic disease. Sites of disease included squamous cell head and neck sites excluding nasopharynx and sinus. Treatment included docetaxel 75 mg/m2 and cisplatin 75 mg/m2 intravenously every 3 weeks and erlotinib 150 mg by mouth daily. All agents were started on day 1. Pts were treated with growth factor support. Results: The trial has completed accrual to 50 pts. 47 pts are available for analysis at this time. Median age is 56 years (range 39–72). ECOG PS is 0, 1, 2 (6, 29, 2 pts). 43 pts are evaluable for efficacy. All responses were confirmed via RECIST. Complete responses have been in observed in 4 pts, partial responses in 25 pts and 12 pts have stable disease for an overall response rate of 67% and disease control rate of 95%. After a follow-up of 19 months, median overall survival was 11 months (8.61, 22.5, 95% CI) and progression free survival was 6.01 months (4.37, 8.25). 6 pts had grade 3/4 febrile neutropenia, 4 pts had grade 3/4 dehydration, 3 pts had grade 3 diarrhea, and 2 pts had grade 3/4 GI bleeding. The most common grade 1–2 toxicities were diarrhea, nausea, and rash. Conclusions: The combination of cisplatin, docetaxel and erlotinib is well tolerated and has very encouraging activity in recurrent/metastatic HNSCC. Tissues are being collected and analyzed for correlative markers including downstream EGFR pathway markers (p-akt, mek, k-ras). Final efficacy and biomarker results will be presented at the annual meeting.

No significant financial relationships to disclose.