bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of the outcome between cervical adenocarcinoma and squamous cell carcinoma patients with adjuvant radiotherapy after radical surgery: SGSG/TGCU Intergroup Surveillance
Authors: Shimada M. , Kigawa J. , Nishimura R. , Hiura M. , Hatae M. , Takehara K. , Sato A. , Kurachi H. , Mizunuma H. , Sugiyama T.
Published: August 2020

5585

Background: We conducted the present surveillance to clarify the significance of adjuvant radiotherapy and the cause of poor outcome of adenocarcinoma (AC). Methods: A total of 825 patients with FIGO stage Ib-IIb cervical cancer, who underwent type III radical hysterectomy in 10 institutes of SGSG/ TGCU Intergroup between April 1997 and March 2003, were enrolled in this study. There were 543 patients with squamous cell carcinoma (SCC) (261 in stage Ib1, 67 in Ib2, 83 in IIa, 132 in IIb) and 282 with AC (186 in stage Ib1, 39 in Ib2, 11 in IIa, 46 in IIb). Mean age of patients was 49.0 yrs (range: 19–84 yrs) in SCC and 46.6 yrs (range: 18–84) in AC. Two hundred and fifty-five patient with SCC and 69 with AC received adjuvant radiotherapy including CCRT. Results: The 5-year overall survival rate (OS) for patients with SCC and AC were 87.4% and 83.4%. The OS for stage I patients did not differ between SCC and AC. Stage II patients with AC showed significantly worse prognosis compared with SCC (54.5% vs. 87.4% in IIa, 63.3% vs. 78.8% in IIb). There was a significant difference in OS for patients receiving adjuvant treatment between SCC and AC (83.0% vs. 73.9%). Although the OS for stage I patients did not differ between SCC and AC, the OS for stage II patients with AC was significantly lower (86.9% vs. 50.0% in IIa, 75.5% vs. 61.1% in stage IIb). In patients with stage I, SCC showed significantly higher lymphnode involvement compared with AC (16.5% vs. 9.7% in Ib1, 46.3% vs. 20.1% in Ib2). The incidence of lymphnode involvement did not differ between SCC and AC in patients with stage II (36.4% vs.34.9% in IIa and 39.1% vs.45.5% in IIb). When patients had lymphnode involvement, the outcome of patients with AC showed significantly worse than those with SCC (46.4% vs. 72.3%). The local failure defined as recurrence in stump and pelvis was more frequent in patients with AC compared with SCC (24.6% vs.10.7%). Conclusions: Although the incidence of lymphnode involvement did not differ between AC and SCC, AC patients with lymphnode involvement showed significantly worse outcome. The present study indicates that lower sensitivity to radiotherapy might be an important cause for the poorer prognosis in AC.

No significant financial relationships to disclose.
A double-blind randomized trial of pyridoxine versus placebo for the prevention of pegylated liposomal doxorubicin hydrochloride-related palmar-plantar erythrodysesthesia
Authors: Von Gruenigen V. E. , Frasure H. , Fusco N. , Eldermire E. , Eaton S. , Waggoner S.
Published: August 2020

5594

Background: To compare the efficacy of pyridoxine versus placebo in the prevention of palmar-plantar erythrodysesthesia (PPE) and on quality of life (QOL) in patients treated with pegylated liposomal doxorubicin hydrochloride for ovarian, breast, or endometrial cancer. Methods: All patients received pegylated liposomal doxorubicin hydrochloride 40 mg/m2 IV q 4 weeks over 1 hour every 28 days for a maximum of 6 cycles. Patients received pyridoxine 100 mg (group A) by mouth or placebo (group B) twice daily. Nurses conducted standard PPE education for all patients. Patients with Grade 2 or 3 PPE that persisted despite dose reductions/delays were unblinded, and were given pyridoxine if taking placebo. Patients completed the Functional Assessment of Cancer Therapy (FACT) assessment tool. Analyses were conducted by group and comparisons were also made between patients who experienced grade 2/3 PPE versus grade 0/1. Chi-square or Fisher's exact test were used. Results: Thirty-four patients were enrolled with 18 randomized to group A and 16 to group B. Mean age was 64 years (SD=9.6; range 45–81 years). Five patients (group A, 3; group B, 2) were unevaluable (due to pegylated liposomal doxorubicin hydrochloride reaction during first chemotherapy cycle). Overall 15/29 (52%) patients had incidence of PPE (all grades), with 10/29 (34%) having grade 2/3 events (no grade 4 events observed). In group A, 8/15 (53%) patients had a PPE event and 7/14 (50%) in group B; p=0.857. For grade 2/3 events, there was no difference as 6/15 (40%) occurred in group A and 4/14 (29%) in group B; p=0.70. There were no differences in global or domain QOL scores between those patients with Grade 2/3 PPE versus Grade 0/1. Less than half [4/10 (40%)] of patients with Grade 2/3 PPE reported being bothered by side effects of pegylated liposomal doxorubicin hydrochloride treatment. Conclusions: As administered in this study, pyridoxine did not prevent PPE in patients treated with pegylated liposomal doxorubicin hydrochloride. Quality of life differences were not observed; however, not all patients with PPE reported being bothered by side effects of pegylated liposomal doxorubicin hydrochloride treatment. Pyridoxine is not indicated for prevention of PPE during chemotherapy.

[Table: see text]

[Table: see text]
Evaluation of the false-negative rate of standardized and quantitative measurement of estrogen receptor (ER) in tissue using AQUA technology
Authors: Gustavson M. D. , Welsh A. , Jones C. , Mayotte J. , Tu J. , Hopkins J. , Rimm D. , Christiansen J.
Published: August 2020

567

Background: The discovery of an astoundingly high false negative rate for estrogen receptor (ER) testing in Canada has raised questions about the accuracy and reproducibility of ER testing. One solution would be the introduction of a standardized and reproducible diagnostic test that is easily adaptable in the clinical setting. Here, we have tested the AQUA method of quantitative immunofluorescence for the standardized and reproducible quantification of ER protein expression in tissue. Methods: Quantitative Western blotting was used in conjunction with AQUA analysis to create standard curves for assessment of absolute ER protein concentration in tissue (n = 118). We used standard scoring methods and AQUA analysis to quantify ER protein expression in a large cohort of breast cancer samples (n =669). Results: Using a series of standard curves, we determined that the range of the ER AQUA assay is between 100 pg/μg and 1500 pg/μg total protein. ER protein concentration in breast cancer samples showed an expected unimodal distribution for quantitative assessment of ER. Reproducibility studies of AQUA analysis demonstrated significant instrument-to-instrument (laboratory-to-laboratory) reproducibility for 3 instruments across the range of AQUA scores (average %CV = 1.34; R2>0.99; ANOVA p = 0.67). The same cases were then read and classified by 3 pathologists using the Allred scoring system. Although their concordance is similar to that seen in the literature (Kappa = 0.81, 0.88, and 0.89), pathologist concordance rate is lower than for that observed with AQUA analysis (Kappa = 0.95, 0.96, and 0.97). Importantly, 9.0% of cases showed a change of diagnosis (positive/negative) across 3 pathologists whereas only 2.8% of cases changed classification using AQUA analysis. Additionally, misclassified cases occurred across the entire range of Allred scores, but were restricted to a narrow region defined by the cut-point for AQUA scoring. Conclusions: We have demonstrated that AQUA technology can provide for the standardized and reproducible quantification of ER with a 3 fold reduction in misclassification. This approach has the potential to decrease the problem of false negative tests for ER.

[Table: see text]
Functional pathways analyses to identify candidate therapeutic targets in triple-negative breast cancer
Authors: Andre F. , Dessen P. , Job B. , Delaloge S. , Pusztai L. , Lazar V.
Published: August 2020

569

Background: In the present study, we have analyzed dysregulated pathways in triple-negative breast cancers. Methods: Two datasets of cDNA arrays were used to identify differentially expressed genes between triple negative breast cancer and either normal/benign breast tissue or other molecular classes. The first dataset (I) was included 165 samples. The second data set (II) included 148 samples. Pathway analyses (gene set) were done based using BRB array tool and a software developed in house (SBIME). Results: Fifteen and 27 patients presented a triple negative breast cancer in the dataset I and II respectively. Ten and eleven pathways were significantly different between triple negative and other molecular classes in dataset I and II respectively (LS permutation p value<0.01). Six pathways were common between the two datasets (p53, cyclin E, E2F1, p27 phosphorylation, Ran, cycle regulation). We then focused the analyses on differential pathways between triple negative and normal/benign tissue. In the dataset I, targetable pathways were identified (hotelling t-test <10–7) including VEGF signalling pathway, proteasome, Hedgehog and Notch pathway. In addition, an enrichment of histone overexpression was observed in triple negative breast cancer (3% of overexpressed genes, ratio expression >2). In the dataset II, histone (p = 2x10–6), chromosome organization (p = 2x10–4) gene sets were enriched in triple negative breast cancer. We then assessed whether such pathway dysregulations could be linked to genomic aberration enriched in triple negative breast cancer. Using high resolution CGH arrays (Agilent, 4*44K) on 53 triple negative breast cancers, we detected that 31% of triple negative tumors presented a gene gain in 6p21 and 6p22, two regions that contain VEGFA gene (6p21) and a cluster of histones (6p22). Conclusions: Triple negative breast cancers present dysregulation of targetable pathways, including VEGF signaling and chromosome organization. Dysregulation of these two pathways could be related to gene gains in 6p21–22 regions observed in 30% of triple negative breast cancer.

No significant financial relationships to disclose.
Predictors of permanent menopause after chemotherapy for early-stage breast cancer in premenopausal women
Authors: Moore H. C. , Kim J. , Rodriguez C. , Budd G. T. , Rybicki L.
Published: August 2020

575

Background: Optimal choice of endocrine therapy for early-stage breast cancer differs with menopausal status. While amenorrhea is common during adjuvant chemotherapy, there is currently no available test to establish when menopause is permanent. The aim of this study was to determine the age cutoff after which resumption of menses is unlikely following chemotherapy and to assess what additional risk factors may predict for persistent menopause at 5 years after initiation of chemotherapy. Methods: One hundred patients treated with chemotherapy for early-stage premenopausal breast cancer and who remained alive and free of recurrence at least 5 years from the start of treatment were enrolled. Participants were evaluated for current menstrual status and for baseline potential risk factors for menopause: age at start of chemotherapy, race, BMI, smoking history, age at menarche, irregular menses prior to chemotherapy, presence of menses during chemotherapy, type of chemotherapy regimen, hormonal therapy, ovarian protection during chemotherapy, and number of doses of alkylating agent (cyclophosphamide). Recursive partitioning analysis (RPA) was used to identify the age cutoff that best predicts permanent menopause; additional risk factors were assessed using logistic regression analysis. Results: Median age at start of chemotherapy was 43 (range 26–49). RPA identified age >42 at the start of chemotherapy as a significant predictor of permanent menopause (p < 0.001). Cessation of menses during chemotherapy was also associated with permanent menopause (p < 0.001). Both variables remained significant in multivariate analysis (p < 0.001), with the combination of these factors being associated with a 95.4% chance of permanent menopause. Conclusions: In this series, fewer than 5% of premenopausal patients who were at least 42 years old and who experienced cessation of menses during chemotherapy experienced any return of menses over at least 5 years. Upfront use of aromatase inhibitors as adjuvant endocrine therapy for premenopausal hormone-receptor positive breast cancer warrants further investigation for those who are at least 42 years of age and who experience amenorrhea with chemotherapy.

No significant financial relationships to disclose.
Efficacy of oral tegafur-uracil (UFT) as adjuvant therapy as compared with classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in early breast cancer: A pooled analysis of two randomized controlled trials (N-SAS-BC01 trial and CUBC trial)
Authors: Ohashi Y. , Watanabe T. , Sano M. , Koyama H. , Inaji H. , Suzuki T.
Published: August 2020

578

Background: It has been reported that adjuvant oral UFT might be more effective in patients with estrogen receptor (ER)-positive breast cancer (Noguchi et al, J Clin Oncol 2005). 2 randomized clinical trials comparing the efficacy of oral UFT (2 years) with that of classical CMF (6 courses) have been conducted in patients with resected early breast cancer. One study was the N-SAS-BC01 trial (Watanabe et al, J Clin Oncol, in press), conducted in patients with node-negative, high-risk breast cancer. The other was the CUBC trial (Inaji et al, ASCO 2004), performed in patients with node-positive breast cancer. We have performed a pooled analysis of these two randomized trials. Methods: A pooled analysis was performed using individual patient data from the two randomized trials. Hazard ratios (HR) were determined with the Cox regression stratified by study and adjusted for the clinical characteristics of age, tumor size, nodal status, histological type, ER and PgR. The hypothesis was that UFT was noninferior to CMF in all patients or ER-positive patients in terms of relapse-free survival (RFS). Non-inferiority of UFT was concluded if the upper limit of two-sided CI for the HR of RFS did not exceed 1.30; the significance level of CI was determined by the Hochberg multiplicity adjustment (alpha=0.05:two sided). Results: A total of 1,057 patients were analyzed (CMF n=528, UFT n=529). Median follow-up time was 6 years. HR was 1.04 (95% CI: 0.78–1.40) for relapse in all patients and 0.79 (97.5% CI: 0.49–1.27) in ER-positive patients. The table shows HR for RFS according to ER status and age. Conclusions: UFT is noninferior to CMF in terms of inhibiting recurrence of ER-positive early breast cancer. In particular, UFT may be more effective in patients with ER-positive tumors who are 50 years or older.

[Table: see text]

[Table: see text]
Epirubicin plus cyclophosphamide followed by docetaxel plus trastuzumab and bevacizumab as neoadjuvant therapy for HER2-positive locally advanced breast cancer (LABC) or as adjuvant therapy for HER2-positive pathologic stage III breast cancer (PS3BC): A phase II trial of the NSABP Foundation Research Group
Authors: Smith J. W. , Buyse M. , Rastogi P. , Geyer C. , Jacobs S. , Patocskai E. , Wolmark N.
Published: August 2020

580

Background: A previous phase II study evaluating the combination of trastuzumab (tras) and bevacizumab (bev) as first-line therapy in HER2 + MBC showed a response rate of 54%. The purpose of this trial is to determine the cardiac safety profile of these agents with docetaxel (T) following epirubicin plus cyclophosphamide (EC) in women with LABC and PS3BC and the activity in those with LABC. Methods: Since June 2007, 75 women with HER-2 + LABC or PS3BC have begun epirubicin 90 mg/m2 IV plus cyclophosphamide 600 mg/m2 IV q3wks x 4 followed by docetaxel 100 mg/m2 IV q3wks x 4. Targeted therapy: Cohort A (neoadjuvant), bev 15 mg/kg IV with Cycle 4 of EC, continued with the first 3 cycles of T. Standard weekly tras with 4 cycles of T. Postop, bev 15 mg/kg IV and tras 6 mg/kg IV q3wks to complete 1 yr of targeted therapy. Cohort B (adjuvant), bev 15 mg/kg q3wks for 4 cycles and weekly tras with T. After chemotherapy, bev and tras q3wks to complete 1 yr of therapy. Primary endpoints were the rate of cardiac events in both cohorts and pCR rate in breast/axillary lymph nodes in Cohort A. Results: Median age was 50 yrs. In Cohort A, 28 (53%) patients (pts) were stage IIIA, 20 (38%) stage IIIB, and 5 (9%) stage IIIC. 13 (25%) had inflammatory BC. A pCR occurred in 19 of the first 36 pts (53%). Toxicity information on the first 73 pts in both cohorts showed that grade 2 LVEF dysfunction has developed in 5 pts and grade 3 LVEF dysfunction in 2, 1 with NYHA Class II and 1 with Class III symptoms. The latter met criteria for a cardiac event. Conclusions: The regimen is active with an acceptable preliminary rate of cardiac toxicity. Updated results will be presented. This trial is conducted with the support of Genentech.

[Table: see text]
Bevacizumab beginning concurrently with a sequential regimen of doxorubicin and cyclophosphamide followed by docetaxel and capecitabine as neoadjuvant therapy followed by postoperative bevacizumab alone for women with HER2-negative locally advanced breast cancer (LABC): A phase II trial of the NSABP Foundation Research Group
Authors: Rastogi P. , Buyse M. , Swain S. , Jacobs S. , Robidoux A. , Liepman M. , Dy P. , Geyer C. , Wolmark N.
Published: August 2020

584

Background: Bevacizumab with chemotherapy improves outcomes in patients with metastatic breast cancer. The purpose of this trial was to determine the activity and safety profile of bevacizumab with chemotherapy in women with LABC. Methods: Between November 2006 and August 2007, 45 women with HER-2 negative LABC initiated preoperative standard AC x 4 followed by docetaxel 75 mg/m2 IV and capecitabine 825 mg/m2 BID days 1–14 (TX) every 21 days for 4 cycles. Bevacizumab 15 mg/kg IV was given concurrently with chemotherapy every 21 days for a total of 6 preoperative doses. Postoperatively, bevacizumab was resumed for a total of 10 doses. Primary endpoint was pathologic complete response rate (pCR) in the breast. The secondary endpoints include clinical response rates and toxicity. Results: The median age was 50 yrs (range 30–78). 30 patients had stage IIIA (67%), 12 stage IIIB (27%), and 3 stage IIIC (7%) disease. Of these, 10 (22%) had inflammatory breast cancer. 27 patients (60%) had ER-positive disease. A pCR in the breast was documented in 4/44 (9%) patients, which included negative axillary nodes. A complete clinical response was noted in 14/45 (31%). One patient did not have surgery due to progression. Toxicities included hand-foot (grade 2/3–33%/22%), mucositis (grade 2/3–49%/27%), and febrile neutropenia (grade 3–24%). Conclusions: This regimen demonstrated only modest activity with substantial toxicity, and does not appear to warrant further evaluation. This clinical trial is being conducted through the support of Genentech and Roche.

[Table: see text]
Selective benefit of high-dose, platinum-containing, alkylating chemotherapy with stem cell rescue for patients with breast cancers with an expansive growth pattern on histology
Authors: Linn S. C. , Vollebergh M. A. , Hauptmann M. , Wessels L. F. , Nederlof P. M. , de Vries E. G. , Rodenhuis S. , Wesseling J.
Published: August 2020

587

Background: Breast cancer (BC) cells lacking the DNA repair mechanism homologous recombination (HR), a feature of BRCA-deficient tumor cells, are hypersensitive to bifunctional alkylating agents. Metastatic BC patients whose tumors were scored as BRCA1-like with a BRCA1 Comparative Genomic Hybridization classifier had an impressive progression-free survival after platinum-containing (PC), high-dose alkylating (HDA) chemotherapy. BRCA1-like tumors showed an expansive growth (EG) pattern, were generally HER-2 negative and estrogen receptor (ER) negative (Vollebergh et al, Cancer Res. 2009, 69;[Suppl. 2]6050). To further investigate whether BRCA1-like tumors were chemosensitive in general, or were sensitive specifically to PC HDA chemotherapy, we studied outcome of stage III BC patients who had participated in a randomized trial of adjuvant 5 x FEC (5-fluorouracil, epirubicin, cyclophosphamide) versus 4 x FEC followed by high-dose CTC (cyclophosphamide, thiotepa, carboplatin) with autologous stem cell rescue (Rodenhuis et al, New Engl J Med. 2003). Methods: 162 Patients with an ER negative or low (<25% of tumor cells positive) and HER-2-negative tumor were selected from abovementioned trial. EG was used as a surrogate for ‘BRCA1-like'. Currently available whole slides of n = 99 patients were scored for EG. An interaction term was fitted to a multivariate proportional hazards model to evaluate whether effect of CTC treatment in terms of recurrence-free survival (RFS) was modified by EG. Results: While RFS after 5 x FEC was similar for the 15 patients with EG as compared to 38 without EG (33%, and 31% 10-year RFS, respectively), 10-year RFS after high dose CTC was better for the 16 patients with EG (81% (multivariate hazard rate [HR] of CTC versus FEC 0.11 [95% CI 0.02–0.53]) as opposed to the 30 without EG (53% [multivariate HR of CTC versus FEC 0.58 (95% CI 0.3–1.12)]); multivariate test for interaction p = 0.056). Conclusions: Using histological information, by determining the presence of an expansive growth pattern, we were able to identify a group of stage III breast cancer patients who selectively benefited from PC HDA chemotherapy.

No significant financial relationships to disclose.
Evaluation of the incidence and of risk factors associated with trastuzumab-associated cardiac toxicity in routine clinical practice
Authors: Lemieux J. , Côté M. , Provencher L. , Simard I. , St-Pierre C. , Demers E.
Published: August 2020

589

Background: Data on trastuzumab-associated cardiac toxicity (TACT) in routine clinical practice are scarce. Alcohol is a potential cardiotoxic but it has not been evaluated as a potential risk factor for TACT. Methods: This is a single institution retrospective study, conducted at the Centre des Maladies du Sein Deschênes-Fabia, Quebec City. Charts review was used to collect information on tumor, cardiovascular risk factors (coronary artery disease (CAD), heart failure, high blood pressure (HBP), obesity, diabetes), alcohol (yes/no), smoking (yes/no), type chemotherapy, anthracyclines doses, trastuzumab doses and left ventricular ejection fraction (LVEF). A questionnaire about smoking and use of alcohol (before chemotherapy, during chemotherapy and during trastuzumab alone) was administered to patients. TACT was defined as a decrease in the LVEF of ≥15% or ≥10% with a resulting LVEF < 50% or any follow-up LVEF of < 45%. Results: Data were collected on 117 patients with non-metastatic breast cancer who started adjuvant trastuzumab between 2002 and 2007. Questionnaires on alcohol use/smoking were administered to 61 patients from these 117 patients. Median age was 53 years old and 95.7% received anthracyclines-based chemotherapy. Median follow-up of LVEF was 16.3 months. TACT developed in 25.6% of patients (10.3 % with a decreased in the LVEF of ≥15%, 7.7% with a decreased in the LVEF of ≥10% with a resulting LVEF < 50% and 7.7% with a LVEF < 45%). None of the following risks factors for TACT were significant (using logistic regression): age (p =0.95), CAD (p = 0.29), HBP (p = 0.46), body mass index (p = 0.64), diabetes (p = 0.29), smoking (p = 0.9), anthracycline doses (p = 0.12), baseline LVEF (p = 0.26). Alcohol use was not associated with TACT (p = 0.76). Further data will be collected in next months about alcohol use. Conclusions: In routine clinical practice, TACT was observed in 25.6% of patients, which is higher than what was reported in trastuzumab phase III clinical trials. Results about alcohol use and TACT will be updated in the spring 2009.

[Table: see text]
Effect of adjuvant chemotherapy on bone resorption marker beta C-telopeptide (B-CTX) in postmenopausal women
Authors: Ali S. M. , Chapman J. W. , Demers L. , Shepherd L. , Han L. , Wilson C. , Pritchard K. , Leitzel K. , Pollak M. , Lipton A.
Published: August 2020

594

Background: In NCIC CTG MA.14, a randomized trial of tamoxifen versus tamoxifen + octreotide LAR, we found a measure of bone resorption, serum B-CTx, to be significantly associated with bone-only first recurrence. Administration of chemotherapy was permitted, and chemotherapy was a stratification factor (never, concurrent, sequential). It was unclear whether pretrial B-CTx serum levels would be affected by prior administration of chemotherapy, and whether timing of chemotherapy was associated with who had bone only, or bone and other site relapse. Methods: Serum B-CTx concentration (Serum CrossLaps Nordic Biosciences, Copenhagen, DN) was determined pretrial therapy in 621 of 667 primary breast cancer patients on MA.14. We tested for differences in continuous B-CTx levels in those who had assessment before (any) chemotherapy (included those who had none) versus those who were assessed after chemotherapy with an ANOVA test. We also used exact Fisher tests to examine whether there was an association between timing of (any) chemotherapy and 1) B-CTx values in upper 2.5% range for healthy pre-menopausal women; 2) bone only recurrence; and 3) concurrent bone and other relapse. Results: Serum B-CTx was assessed before (any) chemotherapy on 382/621 (61.5%) of patients, and after chemotherapy on 239/621 (38.5%). There were no significant differences in serum B-CTx values (p = 0.27). We found 92/621 (14.8%) of patients had high serum B-CTx levels compared with healthy pre-menopausal women; similar proportions of these women received chemotherapy after B-CTx assessment (p = 0.42). Furthermore, there were no differences in timing of (any) chemotherapy and those who had bone only recurrence (p = 0.48) or bone and other type of relapse (p = 0.76). Conclusions: Chemotherapy in the adjuvant setting had no significant effect on bone resorption marker B-CTX serum levels.

No significant financial relationships to disclose.
Neoadjuvant biweekly dose-dense chemotherapy with fluouracil, epirubicin, and cyclophosphamide (FEC 90), followed by docetaxel in patients with HER2-neu negative primary breast cancer
Authors: Rodriguez-Abreu D. , Murias A. , García M. , Vega V. , Garcia C. , Mori M. , Báez-Acosta B. , Diez A. , Almenarez J.
Published: August 2020

596

Background: A primary goal of therapy for large early stage breast cancers is to achieve breast conserving surgery (BCS) through tumor mass reduction with neoadjuvant chemotherapy. In addition, induction of pathological complete response (pCR) is reported to prolong disease-free survival. Encouraged by results from recent studies of dose-dense chemotherapy in the adjuvant setting, we studied preoperative treatment with biweekly 5-fluorouracil, epirubicin, and cyclophosphamide followed sequentially by triweekly docetaxel. Methods: Eighty-one women with stage IIA to IIIB breast cancer were entered into this trial between August 2003 and April 2008. Patients received 5-fluorouracil 600mg/m2, epirubicin 90 mg/m2, and cyclophosphamide 600 mg/m2 (q2w x 4 cycles) followed by docetaxel 100 mg/m2 (q3w x 4 cycles). Granulocyte colony-stimulating factor was administered each cycle to reduce the risk of neutropenic complication. After chemotherapy, patients underwent surgery, and received standard adjuvant radiotherapy and hormone therapy as usual clinical practice. The primary endpoint of this trial was pathological response rate and the secondary endpoints were BCS rate and toxicity. Results: A total of 79 patients were analyzed. The median age was 50y (28–74), the median tumour size was 4 cm. 50 patients (63.2%) were ER positive and/ o PR positive. 48 patients (60.7%) were pre-menopausal. Median follow-up was 36m, 64 patients had stage II (81%) and 15 had stage III (19%). Clinical response was seen in all cases. A pCR with no evidence of tumor in the breast and lymph nodes was confirmed in 21 patients (26.5%). BSC was performed in 61 patients (77.2%). Treatment was well tolerated, 8 patients (10.1%) had grade 3/4 hematological toxicity. Others adverse events including, anorexia, fatigue, nausea, vomiting, mucositis, myalgia, nail changes, peripheral neuropathy, hand-foot skin reactions were mild and manegeable. Conclusions: The neoadjuvant biweekly dose-dense chemotherapy with fluouracil, epirubicin and cyclophosphamide (FEC 90), followed by docetaxel is safe and demostrates a high pathological response rate (pCR) of 26.5% with an increase rate of BCS of 77.2%.

No significant financial relationships to disclose.
Prediction of responsiveness to adjuvant anthracyclines in high-risk breast cancer patients
Authors: Brünner N. , Ejlertsen B. , Jensen M. , Nielsen K. V. , Balslev E. , Rasmussen B. B. , Willemoe G. L. , Hertel P. B. , Knoop A. , Mouridsen H.
Published: August 2020

597

Background: HER-2, TOP2A, and TIMP-1 have shown predictive properties regarding benefit from anthracyclines in patients with breast cancer. In the present study, TIMP-1 IHC was integrated with TOP2A FISH and HER-2 status in two separate profiles. Methods: The DBCG 89-D trial randomized 980 high-risk Danish breast cancer patients to nine series of CMF or CEF. CEF was superior to CMF in terms of DFS and OS (Ejlertsen et al, EJC 2007). HER-2 status and TOP2A copy number changes were determined as described previously (Knoop et al, J Clin Oncol. 2005). TMA s were constructed and analyzed centrally for TIMP-1 expression by IHC (± tumor cell immunoreactivity). TIMP-1 was combined with HER-2 into a joint HT marker (HT-non-responsive (HT-NR): HER-2 normal and TIMP-1 positive or HT-responsive (HT-R): HER-2 positive and/or TIMP-1 negative) and with TOP2A into a joint 2T marker (2T-NR: TOP2A normal and TIMP-1 positive or 2T-R: TOP2A abnormal and/or TIMP-1 negative). Relationships between IDFS, OS and the HT/2Tprofiles were analyzed using multivariate regression analysis. Results: Among patients with a HT-R profile CEF was superior to CMF in terms of both invasive disease-free survival (IDFS) (HR 0.62; 95% CI 0.45–0.86; p = 0.004) and overall survival (OS) (HR 0.63; 95% CI, 0.45–0.87; p = 0.005). In patients with a HT-NR profile, no significant differences between CEF and CMF were demonstrated for IDFS or OS. A significant HT profile (HT-R or HT-NR) versus treatment (CEF or CMF) interaction was detected by the Wald-test for both IDFS (p = 0.036) and OS (p = 0.047). An even more pronounced separation was observed regarding the 2T profile, and in patients with a 2T-R profile treatment with CEF was superior to CMF in terms of IDFS (HR 0.48; 95% CI 0.34–0.69; p < 0.001) and OS (HR 0.54; 95% CI, 0.38–0.77; p < 0.001). No significant difference was observed in patients with a 2T-NR profile. A highly significant 2T profile versus treatment interaction was detected for IDFS (p < 0.001) and OS (p = 0.004). Conclusions: Profiles created by joining TIMP-1 with either HER-2 status or TOP2A gene status seems advantageous compared to the use of a single marker.

[Table: see text]
Association of tobacco (T) use with risk of distant metastases (DM), tumor recurrence, and death in patients (pts) with HPV-positive (+) squamous cell cancer of the oropharynx (SCCOP)
Authors: Worden F. P. , Hooton J. , Lee J. , Eisbruch A. , Wolf G. T. , Prince M. , Moyer J. , Teknos T. , Chepeha D. B. , Bradford C. R. , Carey T.
Published: August 2020

6001

Background: Chemoradiation (CRT) for HPV (+) SCCOP is associated with a more favorable prognosis than HPV-negative (-) SCCOP. However, the interaction of HPV and T in terms of etiology and disease progression remains unclear. HPV (+) SCCOP pts were prospectively studied to determine if T use was a key variable in discriminating which pts would develop DM, locoregional recurrences (LR), or second primaries (SP). Methods: From 1999–2007, 124 pts with stage III/IV SCCOP were enrolled in one of two CRT trials. Tumor specimens were analyzed for HPV presence and type. Use of T, determined via self-reporting and chart review, was recorded as both continuous (number of pack-yrs) and categorical (never, former, and current) variables. Former T users were subdivided into an early cessation group (quit ≥ 20 yrs prior to diagnosis) and a late cessation group (quit < 20 yrs prior to diagnosis). T use and HPV status were analyzed with respect to survival & the development of DM, LR, or SP. Results: Of the 124 pts, 100 (81%) were HPV (+), 22 of which developed disease progression (22%). Twenty-four were HPV (-), 12 of which had disease progression (50%). Seventeen of 124 pts (14%) developed DM [12 HPV (+), 5 HPV (-)]. Nine of 124 (7%) developed LR [5 HPV (+), 4 HPV (-)], and 8 of 124 (7%) developed SP [5 HPV (+), 3 HPV (-)]. Thirty-two HPV (+) pts were never-T users, 88% (28/32) of which remain alive with no evidence of disease; 3 died from other causes and 1 died of lung metastases from SCCOP. Sixty-eight were HPV (+) and had T exposure. Of 46 former T users, 37/46 (80%) are living. Twenty were HPV (+) and in the early cessation group, 35% (7/20) of which had disease progression [3 LR, 3 DM, 1 SP]. Twenty-six HPV (+) pts were former T users in the late cessation group, 11% (3/26) of which had disease progression [2 DM, 1 SP]. Of 22 HPV (+) current T users, 68% (15/22) are alive and 36% (8/22) have developed disease progression. Seventeen of the 24 HPV (-) pts were current T users, 47% (8/17) of which developed disease progression. Conclusions: Never-T users with HPV-positive SCCOP have improved survival & reduced risk of disease progression compared to HPV (+) & HPV (-) former & current T users.

No significant financial relationships to disclose.
A phase III randomized, placebo-controlled trial of docetaxel (D) with or without gefitinib (G) in recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): A trial of the Eastern Cooperative Oncology Group (ECOG)
Authors: Argiris A. , Ghebremichael M. , Gilbert J. , Burtness B. , Forastiere A.
Published: August 2020

6011

Background: G is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor with modest single-agent activity in SCCHN. We hypothesized that the addition of G to D will enhance therapeutic efficacy. Methods: Eligibility criteria included R/M SCCHN; any number of prior regimens (excluding D and EGFR inhibitors); ECOG performance status (PS) 2, if previously untreated, or ECOG PS 0–2, if prior chemotherapy for R/M SCCHN or as part of potentially curative therapy < 6 months (mo) earlier. Patients (pts) were randomly assigned to receive D 35 mg/m2 IV on days 1,8,15, every 28 days plus placebo (arm A) or the same D regimen plus G 250 mg orally, once daily (arm B) until disease progression. Stratification factors were PS, prior chemotherapy and weight loss. At the time of progression, treatment could be unblinded and, for pts in the placebo arm, single-agent G 250 mg/d initiated. We sought to demonstrate an improvement in median overall survival (OS) from 6 to 8.4 mo (28.6% reduction in HR). A total accrual of 314 eligible pts and 286 failures were needed to attain 80% power with 2.5% type I error. Results: 270 pts were enrolled (arm A, n = 136; arm B, n = 134). The study was terminated at interim analysis in November 2008 because it was highly unlikely that the primary endpoint could be met. 60% of pts had ECOG PS of 2; 72% had prior chemotherapy. 24 pts in arm A received G at progression. Data on subsequent treatment with EGFR inhibitors were not collected. Median OS was 6 mo in arm A versus 6.8 mo in arm B (p = 0.74); HR 1.04 (95% CI, 0.79–1.35). Objective response rate in 168 evaluable pts was 6% in arm A vs. 14% in arm B (p = 0.16). Median time to progression was 2 mo and 3.5 mo (p = 0.03) and median progression-free survival 2.2 mo and 3.3 mo (p = 0.18) in arms A and B, respectively. Common grade 3/4 adverse events (AE) in arm A (n = 121) vs. B (n = 115) were neutropenia 1/2 vs. 2/0; fatigue 16/4 vs. 14/0; diarrhea 3/0 vs. 11/1; nausea 4/1 vs. 5/0; vomiting 4/0 vs. 1/1; pneumonia 8/1 vs. 6/1. There were 2 grade 5 AE in arm A and 5 in arm B. Conclusions: The addition of G to D is well tolerated and improves time to progression but not survival in previously treated and poor PS pts with R/M SCCHN.

[Table: see text]
Combined modality therapy with radiation therapy (RT), chemotherapy, bevacizumab, and erlotinib in the treatment of patients (pts) with locally advanced squamous carcinoma of the head and neck
Authors: Meluch A. A. , Spigel D. , Burris H. A. , Lane C. , Peyton J. D. , Shipley D. , Rubin M. , Stipanov M. , Greco F. A. , Hainsworth J. D.
Published: August 2020

6012

Background: Concurrent chemotherapy/RT is the standard of treatment for locally advanced head and neck cancer. Agents targeting EGFR and the angiogenesis pathway have also demonstrated activity. In this phase II trial, we added bevacizumab and erlotinib to an active combined modality regimen in the first-line treatment of pts with locally advanced head and neck cancer. Methods: Eligible pts had previously untreated squamous carcinoma of any head and neck site, with T3/T4 primary lesions and/or N1-N3 nodal involvement. Additional eligibility: ECOG PS 0 or 1; adequate organ function; indwelling central venous catheter; standard bevacizumab exclusions. All pts received induction therapy with 2 courses of paclitaxel (200mg/m2), carboplatin (AUC 6.0), 5-FU (200mg/m2 per day, 24 hour CI days 1–21), and bevacizumab (15 mg/kg); cycles were repeated at 21-day intervals. Pts then received concurrent RT (68.4 Gy, 1.8 Gy/day), paclitaxel (50 mg/m2 weekly x 6), bevacizumab (15 mg/kg weeks 1 and 4), and erlotinib (150 mg daily x 7 weeks). PFS was the primary endpoint. Results: Between December 2006 and July 2008, 60 pts were enrolled; the first 48 pts are included in this preliminary report. The median age was 56 years; T3/T4 = 9/8; N1/N2/N3 = 13/27/4. 45 pts (94%) completed the 6-week induction therapy, and 41 pts (85%) completed all therapy. After induction therapy, 56% of pts had objective response; 77% had objective response after completion of therapy. After a median follow-up of 16 months, the 18-month progression-free and overall survivals are 85% and 87%, respectively. Grade 3/4 toxicity during induction therapy included neutropenia (46%), neutropenic fever (6%), mucositis (14%), diarrhea (14%), and hand/foot syndrome (11%). Severe local toxicity (mucositis/esophagitis) occurred in 31 patients (76%) during combined modality therapy (56% grade 3/20% grade 4). Conclusions: The addition of bevacizumab and erlotinib to concurrent chemotherapy/RT was feasible, with no unexpected toxicity. After short followup, the regimen appears highly active. Updated results will be presented.

[Table: see text]
EORTC 24051: Unexpected side effects of a phase I study of TPF induction chemotherapy (IC) followed by chemoradiation (CRT) with lapatinib (LAP), a dual EGFR/ErbB2 inhibitor, in patients with locally advanced larynx and hypopharynx squamous cell carcinoma (LA-LxHxSCC)
Authors: Specenier P. M. , Lalami Y. , Vermorken J. , Lacombe D. , El-Hariry I. , Bogaerts J. , Awada A.
Published: August 2020

6017

Background: CRT is considered a standard approach for LA-LxHxSCC. TPF IC regimen seems to improve outcome in locally advanced head and neck SCC. The addition of LAP was investigated in combination with a sequential therapeutic approach (IC→ CRT). Methods: Eligible tumors were SCCHN: T3-T4 larynx (Lx), T2-T4 hypopharynx (Hx) N0–3 M0. The objective of this trial is to determine MTD, DLT and recommended dose of LAP when administered with TPF IC (docetaxel (T) 75mg/m2 (60 mg/m2 for the first cycle) d1, CDDP 75mg/m2 d1, 5FU 750mg/m2/d continuous infusion d1-d5 q3weeks) followed by CRT (weekly carboplatin AUC 1.5 and RT 70Gy in 7 weeks; 2Gy/fx). LAP is administered concomitantly with IC (escalating dose 500–1500mg po daily) and during CRT (1,500 mg daily). Results: Seven male patients were included; tumor sites: LX (n = 3) / Hx: (n = 4), median age 59 years (range: 47–79), WHO PS 0–1, no severe or uncontrolled comorbidity. Three pts were included in the first cohort, at dose level 1 (LAP 500 mg daily plus TPF IC). Renal toxicity was observed among these 3 pts (grade 4 [n = 1], grade 2 [n=1] and grade 1 [n=1]), with 1 DLT, leading to treatment interruption in this group. This nephrotoxicity was reversible after stopping lapatinib and hydration of the patients. As LAP plus cisplatinum plus RT was feasible in another study, a second cohort was conducted in 4 pts, receiving LAP at the same dosage, and docetaxel (T) was only introduced from cycle 2 of IC to see what is the role of T in the observed side effect. Two DLTs were observed among this second cohort of subjects: one pt presented a grade 2 renal toxicity, grade 3 diarrhea and dehydration and a second pt presented a grade 3 anorexia and grade 3 stomatitis. Based on the occurrence of 3 DLTs at the first dose level of LAP, patient recruitment was closed. Despite these safety issues, all patients recovered and were treated off-study. They will receive follow-up as foreseen by the protocol. Conclusions: These data suggest that LAP should not be combined with TPF IC regimen for LA-LxHxSCC due to prohibited toxicity.

[Table: see text]
Phase II randomized trial of bortezomib (B) plus irinotecan (I) or B with addition of I at progression in recurrent (R) or metastatic (M) squamous cell carcinoma of the head and neck (SCCHN) (E1304): A trial of the Eastern Cooperative Oncology Group
Authors: Gilbert J. , Lee J. , Argiris A. , Feldman L. , Haigentz M. , Burtness B. , Forastiere A.
Published: August 2020

6020

Background: B, inhibits activation of NF- κβ and inhibits growth of SCCHN cell lines. NF-κβ dysregulation contributes to chemoresistance, including I. Pretreatment with B increases tumor sensitivity to I in vitro. Methods: Eligibility: 0–1 prior chemo regimens, ECOG PS 0–1. Pts randomized to B 1.3 mg/m2 IV d 1, 4, 8, 11 and I 125 mg/m2 IV d 1, 8 every 21 days (Arm 1) or B with addition of I at time of progression (Arm 2). Primary endpoint was response rate (RR) using RECIST and Simon's optimal 2-stage design. Results: 62 pts analyzable (Arm 1, N = 23; Arm 2, N = 39) of 71 enrolled . Pt. characteristics: median age 61 yrs., ECOG PS 1 - 53 %, and 71% had prior chemo. To date, RR (all PRs) 13% Arm 1 and 3% Arm 2 with SD 17% Arm 1 and 23% Arm 2. However, 3 patients remain on active therapy in Arm 2 and PFS and updated RR will be reported. 7 patients (including 3 pts on Arm 2) received 6–10 cycles of therapy. No responses in all 11 analyzable pts in Arm 2 with I added at progression. Median OS 9.1 months - Arm 1 and 7.3 months - Arm 2. Toxicity of B + I (125 mg/m2): grade 3/ 4 neutropenia (31%), vomiting (15%), diarrhea (15%), dehydration (23%). Grade 5 toxicity in 3 pts, 2 possibly related to therapy. Trial amended to decrease I to 90 mg/m2 3 patients (33%) - grade 3 / 4 diarrhea; no grade 3/ 4 neutropenia or grade 5 toxicities. Arm 2: grade 3 / 4 fatigue (15%). Conclusions: B alone is well tolerated. To date, RR low but prolonged stable disease noted in some pts. B in combination with I is a toxic regimen with disappointing activity.

[Table: see text]
Antitumor activity of cediranib in patients with metastatic or recurrent head and neck cancer (HNC) or recurrent non-small cell lung cancer (NSCLC): An open-label exploratory study
Authors: Saura C. , Baselga J. , Herbst R. , del Campo J. , Marotti M. , Tessier J. , Collins B. , Heymach J.
Published: August 2020

6023

Background: Cediranib is an oral, highly potent and selective inhibitor of VEGF signaling, with activity versus VEGFR-1, -2 and -3. FDG-PET has previously been shown to provide early assessment of the effectiveness of anticancer treatment in solid tumors after chemotherapy. The objectives reported here were to assess the effects of cediranib on 1) tumor metabolic activity using FDG-PET (standardized uptake value, SUVmax) and 2) tumor size (RECIST longest diameter). Methods: Eligible pre-treated patients with metastatic or recurrent HNC or NSCLC received cediranib monotherapy 30 mg/day for 3 weeks, or until disease progression or unacceptable toxicity. Patients showing evidence of response (FDG-PET) or clinical benefit at day 22 could continue study treatment and were assessed on days 43 and 71 by RECIST/FDG-PET. Evaluable patients had baseline and at least one post-baseline measurement available. Results: A total of 19 patients were treated; 17 patients had baseline and day 22 FDG-PET and 18 patients had baseline and at least one post-baseline RECIST assessment. Consistent changes in FDG-PET were observed (Table). At days 22, 43 and 71, a total of 5 (29%), 7 (41%) and 6 (35%) patients had ≥25% decrease in SUVmax (FDG metabolic response), respectively. The combined (HNC/NSCLC) best mean % change in tumor size from baseline for all patients was -25.9%. Best responses of PR and SD were seen in 18.8% and 50% of HNC patients, respectively (Table). The most common adverse events were proteinuria (7 [37%]), fatigue, diarrhea and hypertension (each 6 [32%]). Conclusions: This study provided evidence of antitumor activity with cediranib monotherapy as measured by decreases in FDG uptake, reductions in tumor size and RECIST response rate. Cediranib 30 mg/day was generally well tolerated, with a manageable adverse event profile consistent with previous studies. Further studies are warranted in these tumor types.

[Table: see text]

[Table: see text]
Frequency of HPV-associated tonsillar cancer in Sweden
Authors: Attner P. , Näsman A. , Marklund L. , Hammarstedt L. , Lindholm J. , Ramquist T. , Dalianis T. , Munck-Wikland E.
Published: August 2020

6030

Background: Numerous studies has shown an increase of the incidence of tonsillar squamous cell carcinoma (SCC) both in the USA and in Sweden. This increase in incidence is despite a decreasing prevalence in smoking, a well-known risk factor for developing tonsillar cancer. The proportion of human papillomavirus (HPV) positive tonsillar SCC has also been shown to increase. This study aims to examine the incidence of tonsillar SCC and the proportion of HPV positive tonsillar SCC between 2003–2007 in the County of Stockholm, Sweden in correlation to data from 1970–2002. Methods: All patients (n = 120) diagnosed with tonsillar SCC during 2003–2007 in the County of Stockholm were included in this study. Ninety-eight pre-treatment biopsies were available and presence of HPV DNA and HPV-16 E6 and E7 mRNA were tested by PCR and RT-PCR. Incidence data between 2003–2007 for Sweden and in the County of Stockholm was obtained from the Swedish Cancer Registry. Data reported from 1970 to 2002 was also obtained for comparison. Results: HPV DNA was present in 83/98 (85%) of the tonsillar SCC biopsies from 2003–2007. Of the 77 HPV-16 positive tumors, HPV-16 E6 and E7 mRNA were found in 98% of the analyzed cases. The proportion of HPV-positive cancers had significantly increased both from 1970 to 2007 (p < 0.0001) as well from 2000 to 2007 (p < 0.01), with 68% (95% CI, 53–81) 2000–2002; 77% (95% CI, 63–87) 2003–2005; and 93% (95% CI, 82–99) 2006–2007. The incidence rate of HPV-positive tumors almost doubled each decade between 1970–2007, in parallel with a decline of HPV-negative tumors. Conclusions: Today, almost all tonsillar SCC in the County of Stockholm is HPV positive, and the incidence of HPV-positive cancers is still increasing. The data suggest that we are dealing with an epidemic of a virus-induced carcinoma, and that soon practically all tonsillar SCC will be HPV positive; a similar situation observed in cervical cancer.

No significant financial relationships to disclose.