bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of NCI Clinical Announcement upon use of chemoradiation for women with cervical cancer
Authors: Trimble E. L. , Gius D. , Harlan L. C.
Published: March 2020

5537

Background: On the basis of 5 NCI-sponsored randomized phase III trials, in 1999 the NCI issued a Clinical Announcement recommending that women with cervical cancer who require radiation also receive concomitant platinum-based chemotherapy. We undertook a population-based cohort study to determine whether the 1999 NCI Clinical Announcement was associated with changes in clinical practice in the United States. Methods: Through the NCI’s SEER program, we identified 973 women with invasive cervical cancer diagnosed in 1997, 773 diagnosed in 2000, and 1370 diagnosed in 2001. Hospital records were re-abstracted and treated physicians were contacted to verify initial therapy provided to each patient. Results: In multivariate analysis, we found a significant increase in the use of chemoradiation between 1997 and 2001/2001 among women with cervical cancer of all stages for which radiation would be appropriate. (see table ). Compared to women with well-differentiated tumors, women with moderately or poorly differentiated tumors were more likely to receive chemoradiation. Women aged 75 years or older were significantly less likely to receive chemoradiation than younger women. We saw no impact of race/ ethnicity or insurance status upon receipt of chemoradiation. Conclusions: Publication of the results from these 5 sutdies, extensive professional educational efforts, and the NCI’s Clinical Announcement were associated with widespread adoption of chemotherapy in the treatment of cervical cancer in the United States.

[Table: see text]

No significant financial relationships to disclose.
Population-based study of the incidence, mortality and prognostic factors of small cell carcinoma of the cervix: Analysis of the Surveillance, Epidemiology and End Results database
Authors: Chen J. , MacDonald O. K. , Gaffney D. K.
Published: March 2020

5546

Background: Small cell carcinoma (SmC) is a rare histology of the cervix uteri that is generally associated with a poor prognosis. This is a population-based study of SmC using the Surveillance, Epidemiology and End Results (SEER). Methods: From 1977 to 2003, 290 women with SmC of the cervix uteri were identified. In addition, 27,527 patients with squamous cell carcinoma (SC) and 5231 with adenocarcinoma (AC) of the cervix were identified for comparison. The annual incidence of each histology was determined and examined for trend. The patient and disease characteristics at diagnosis were examined for each histology, and prognostic factors were evaluated for SmC. Mortality rates of SmC and other histologies were compared via log-rank tests. Results: Mean annual incidence of SmC was 0.03 per 100,000 women compared to 3.5 and 0.62 for SC and AC. A significant change in incidence was identified for SC and AC (p<0.05), but not for SmC (p=0.595). Patients with SmC were more likely to be treated with radiotherapy and to present with more advanced stage, lymph node involvement and distant metastasis than SC and AC (p<0.05). Survival rates for SmC at 2 and 5 years were 46.8% and 35.7%, which were worse compared to SC (HR 0.45; 95% CI: 0.36–0.57) and AC (HR 0.31; 95% CI: 0.25–0.39). The difference in survival is predominantly in patients with early stage, localized disease, and those treated with surgery ( Table ). Multivariate analysis of SmC, race, FIGO stage, age and hysterectomy alone significantly impacted prognosis (p<0.05), while year of diagnosis, lymph node involvement, tumor size, marital status and other treatment modality did not. Conclusions: SmC is an uncommon histologic variant of cervix cancer associated with a worse prognosis compared to SC and AC with a predilection for metastasis at diagnosis. FIGO stage, age and race are prognostic factors for survival.

[Table: see text]

No significant financial relationships to disclose.
Induction of VEGF secretion in ovarian cancer by PDGF BB
Authors: Matei D. , Kelich S. , Cao L. , Menning N. , Emerson R. , Emerson R. , Rao J. , Sledge G.
Published: March 2020

5557

Background: We identified the PDGFR as a potential target in epithelial ovarian carcinoma (EOC). This led us to test whether inhibition of the receptor affects ovarian cancer cell proliferation and survival and regulates other processes critical to tumor growth and metastasis. We postulated that the PDGF-PDGFR axis regulates VEGF secretion in EOC. Methods: VEGF secretion in ovarian tumors, cancer cells, serum and ascites was measured by IHC, Western Blot and ELISA. The HOG Gyn03–62 protocol was a phase II protocol for patients with recurrent platinum resistant EOC. Patients were treated with imatinib and docetaxel. Serum and tumor samples from patients enrolled on this protocol were analyzed for VEGF. Results: VEGF expression was quantified by IHC in ovarian tumors. Of 21 PDGFR expressing ovarian tumors, seven specimens immunostained strongly for VEGF and six tumors demonstrated 2+ VEGF reactive extracellular (secreted) material. PDGF and VEGF secretion was measured in 17 specimens of malignant EOC ascites. The levels of PDGF BB and VEGF were strongly correlated (Pearson coefficient =0.728, p-value=0.001), suggesting that the two pathways interconnect. There was no correlation between PDGF AA and VEGF levels. VEGF levels were measured in 13 paired serum samples from patients enrolled in the clinical protocol HOG: Gyn03–62, before and after treatment. VEGF serum levels were stabilized or decreased in 9 of 13 EOC patients treated with imatinib. In conditioned media from primary cells, VEGF secretion was four fold higher for tumor derived cells than for cells derived from the normal ovarian epithelium. PDGF increased ten-fold VEGF secretion in PDGFR expressing immortalized ovarian cells (C272/hTert/E7 and C889/hTert), while imatinib reduced VEGF production to basal state. The effects of imatinib were mediated via inhibition of Akt and MAPK pathways, by stabilization of HIF1 alpha. In ovarian cancer cells overexpressing consitutively active Akt, imatinib inhibited only partially the secretion of VEGF compared to control cells, suggesting that the PI3K/Akt pathway is significantly implicated in PDGF-stimulated VEGF secretion. Conclusions: These results suggest that by blocking the PDGFR, imatinib inhibits VEGF production. This affects the tumor microenvironment favoring ovarian tumor growth and metastasis.

No significant financial relationships to disclose.
Recurrence in ovarian carcinoma stage I A/B grade 1 and 2 with and without chemotherapy
Authors: Simpkins F. , Abu Shahim F. , Bakkum-Gamez J. N. , Jones M. B. , Rocconi R. P. , Mathews K. S. , Moore K. N. , Fong D. N. , Rose P. G.
Published: March 2020

5565

Background: The goal of this study was to determine the recurrence rates (R) of patients with grade 1 and 2 stage 1A and IB ovarian tumors treated with and without chemotherapy. Methods: We conducted a five-center retrospective study of patients with Stage 1A/B grade 1 and 2 ovarian carcinoma. All women underwent comprehensive staging including a minimum of unilateral salpingo-ophorectomy, unilateral pelvic and para-aortic lymphadenectomy, and omentectomy. Clear cell histologies were classified as grade 3 and excluded. The minimum cancer-free survivor follow-up was 3 years. Results: We identified 82 patients with Stage 1A/B grade 1 and 2 who met criteria for the study. The median age was 58 yrs (range 29 to 83) and the median follow-up was 5.3 yrs (range 3 to 11 yrs). The majority were of endometrioid histology (51), followed by mucinous (19), papillary serous (11), and mixed (1). Recurrences were of endometrioid (4), mucinous (1), or papillary serous (1) histology. For Stage 1A, overall recurrence rate was 9% (6/67). The overall recurrence rates for Stage 1A, grade1 tumors was 6% and among grade 2 tumors 12% (p=0.40). Among Stage 1A patients not treated with chemotherapy, there was a 7% (2/29) and 9.5% (2/21) recurrence rate for grade 1 and grade 2 tumors, respectively. For the grade 1 tumors, both patients are alive with disease at 3 and 5 yrs. For the grade 2 tumors, one is alive without evidence of disease at 7 yrs and the other died from disease at 4 yrs. Time to recurrence (TTR) was 2.3 yrs for grade 1 tumors and 2.6 yrs for grade 2 tumors. For Stage 1A patients treated with a platinum chemotherapy regimen, there were no recurrences (0/5) for grade 1 tumors and a 16% (2/12) recurrence rate for grade 2 tumors. Of the recurrences, one patient died from disease at 1.4 yrs and the other is alive with stable disease at 6 yrs. Time to recurrence was 2.85 yrs for grade 2 tumors. For grade 1 or 2, Stage 1A tumors, recurrence rates and time to recurrence were not effected by chemotherapy administration (R, p=0.55 and p=0.54, respectively; TTR, grade 2, p=0.85). No recurrences were observed in the 15 patients with Stage IB, grade 1 and 2 tumors. Conclusions: In comprehensively staged patients with Stage 1A/B, grade 1 and 2, low recurrence rates suggest adjuvant chemotherapy may not be indicated.

No significant financial relationships to disclose.
Neoadjuvant chemotherapy for low-grade serous carcinoma of the ovary
Authors: Schmeler K. M. , Sun C. C. , Bodurka D. C. , Deavers M. T. , Coleman R. L. , Ramirez P. T. , Gershenson D. M.
Published: March 2020

5571

Background: Neoadjuvant chemotherapy (NACT) has been associated with significant tumor reduction prior to interval debulking surgery, enabling optimal cytoreduction in up to 50% of patients with high-grade ovarian carcinomas deemed initially unresectable. Since low-grade serous carcinoma (LGSC) appears to be relatively less chemosensitive, we sought to evaluate the outcomes of women with ovarian LGSC treated with platinum-based NACT. Methods: Using institutional databases, we identified 18 women with low-grade serous carcinomas of the ovary who were treated with neoadjuvant platinum-based chemotherapy between 1978 and 2003. Patient demographic and clinical variables were abstracted from the medical records. Progression-free survival (PFS) and overall survival (OS) were estimated using the method of Kaplan-Meier. Results: The median age at diagnosis was 44 years (range, 21 to 81 years). NACT was given for extensive or non-resectable disease in 16 patients (89%) and for unknown reasons in 2 patients (11%). Ten patients (42%) underwent exploratory laparotomy with biopsy only prior to beginning chemotherapy. A median of 6 cycles of chemotherapy was given (range, 2 to 16) and included the following regimens: platinum/taxane (n=12 patients); platinum/cyclophosphamide (n=3 patients); and platinum/leuprolide acetate (n=3 patients). Of the 13 patients who had CA-125 levels available, 8 (62%) had a ≥50% reduction between pre- and post-NACT levels. However, response, determined by radiographic survey at completion of NACT, demonstrated one patient (6%) with a complete response, no patients (0%) with a partial response, and 16 patients (89%) with stable disease. One patient (6%) was not evaluable. Fifteen patients (83%) underwent interval cytoreductive surgery, which was optimal in 8 cases (53%), suboptimal in 4 cases (27%) and unknown in 3 cases (20%). Median PFS and OS for all patients were 18.6 and 56.1 months, respectively. Conclusions: A low response rate to platinum-based NACT was observed among women with LGSC of the ovary. These findings suggest that LGSC is not as responsive to conventional chemotherapy as high-grade serous carcinoma. Prospective clinical trials, focusing specifically on LGSC, are needed to make meaningful advances for this group of patients.

No significant financial relationships to disclose.
Prediction of survival in patients with epithelial ovarian cancer based on the timing and rate of normalization of CA125 levels during primary chemotherapy
Authors: Matthews K. S. , Rocconi R. P. , Kemper M. , Hoskins K. E. , Huh W. K. , Wang W. , Straughn J. M.
Published: March 2020

5585

Objective: CA125 is the tumor marker used to evaluate response to chemotherapy in patients with epithelial ovarian cancer (EOC). The aim of this study was to determine if the timing of normalization or percent decrease in CA125 levels during primary chemotherapy could predict survival. Methods: Patients treated at our institution for EOC with primary taxane/platinum-based chemotherapy for 6 cycles between 1996 and 2005 were eligible. Patient demographics, chemotherapy administration, CA125 levels, and survival outcomes were abstracted. Progression-free- survival (PFS), overall survival (OS), and platinum sensitivity (> 6 months from chemotherapy completion) were compared to CA125 levels during primary therapy. Baseline levels, change over time, and timing of CA125 normalization were calculated. Analyses were performed using Kaplan-Meier method and compared using the log-rank test, Chi-square test and Fischer’s exact test. Results: 269 patients with EOC were identified. When stratified by which cycle of chemotherapy achieved normalization, PFS ranged from 25 months at 1st cycle to 4 months at 6th cycle (p< 0.001). OS showed a similar benefit from 74 months at 1st cycle to 22 months at 6th cycle (p<0.001). Platinum sensitivity improved from 23% (normal CA125 after 6th cycle) to 72% (normal CA125 after 1st cycle) (p=0.003). Patients with normalization after the 3rd cycle or sooner compared to patients with normalization after the 4th cycle demonstrated improved PFS (19 vs. 6 months; p<0.001), OS (48 vs. 27 months; p=0.001) and platinum sensitivity (78 vs. 22%; p<0.001). Linear regression models of the slope of the decline of CA125 levels correlated with PFS (p=0.03); however, the models failed to predict an OS advantage. Conclusion: Earlier normalization of CA125 levels during primary chemotherapy for EOC predicts improvement in platinum sensitivity, PFS, and OS. This data provides prognostic information that may influence future decisions regarding chemotherapy.

No significant financial relationships to disclose.
Treatment and prognosis of epithelial ovarian cancer in Iran
Authors: Khodabakhshi R. , Yahyazadeh Jabbari S. , Gohari M. , Sadrolhefazi B. , Mosavizadeh A. , Shahidi J. , Ameri A. , Madani H. , Sharifi B. , Bahor F.
Published: March 2020

5586

Background: Ovarian cancer is the most lethal gynecologic malignancy in the US, with 14,500 women dying of this disease annually. The aims of this study are to describe brief epidemiologic variations, response rate for usual chemotherapy regimen and progression free survival analysis in Iranian patients. Patients and Methods: 98 women with confirmed ovarian cancer who have been undergone surgery followed by chemotherapy at three hospitals in Tehran (Iran) between 1997 and 2003 were enrolled in this retrospective study. FIGO staging system has been applied. We have collected data regarding age, pathologic variations, surgical procedure (complete, partial, biopsy), chemotherapy, response rate, and time to progression of disease. Results: From a total of 98 patients, there were 80 (81.6%) epithelial, 12 (12.2%) germ cell, 5 (5.1%) granulosa cell tumors and one case of lymphoma. Response rate have been evaluated for 60 patients with epithelial cancer. Overall mean age was 46.7 and average age for epithelial tumors and non-epithelial tumors were 49.6 and 34.3 respectively. Complete surgical procedure with staging and optimal residue had been performed for 18 patients. Stage III was the most common stage (46.1%). In 78.3% of patients complete or partial response were seen, while 21.7% of patients showed stable or progressive disease. The most important prognostic factors were stage, and extent of surgical procedure. Median progression-free survival was 24.2 months. Conclusion: Overall average-age of our patients is lower than expected. Besides, a large proportion of the patients are referred in advanced stages. Although, higher response rate has been produced by taxane-based regimen in comparison of traditional chemotherapy; but it was not statistically significant. Retrospective evaluation, low number of the patients, non-uniform usage of chemotherapy regimen could influence our results.

No significant financial relationships to disclose.
A phase II multicenter trial of paclitaxel and carboplatin in women with advanced or recurrent malignant mixed müllerian tumors (MMMT) of the uterus
Authors: Ramondetta L. M. , Lacour R. A. , Euscher E. D. , Iyer R. B. , Atkinson E. N. , Gano J. B. , Milam M. R. , Ramirez P. T. , Levenback C. F. , Burke T. W.
Published: March 2020

5589

Background: Systemic therapy for advanced malignant mixed müllerian tumor of the uterus (MMMT) after surgery has been disappointing. Currently, the most common treatment regimen is ifosfamide and platinum. Moderate success has been documented using paclitaxel in MMMT of the ovary. The purpose of this study is to evaluate carboplatin and paclitaxel in patients with advanced (IIIb-IVb) and recurrent MMMT of the uterus. Methods: A single arm, prospective, non-randomized phase II trial opened in October 2001. The planned sample size is 37 evaluable patients, with time to progression and response rate as the primary endpoints. Patients receive carboplatin (AUC 5) and paclitaxel (175 mg/m2) every 21 days. Patients treated adjuvantly receive a total of 6 cycles or until progression or toxicity. Patients with disease present at study entry are treated until progression or toxicity. Results: To date, 18 patients have been enrolled. Seven patients received adjuvant treatment and 11 patients had documented disease at study entry. In the adjuvant group, the median progression-free interval was 15.8 months and median overall survival from treatment initiation was 20.2 months. Four of these 7 patients (57%) continue to be followed with a median follow-up of 19.2 months. In the patients with documented disease, the median progression- free interval was 7.8 months and the median overall survival from treatment initiation was 12.4 months. In this group, there were 3 complete and 4 partial responses (63.6% response rate). Over 45% of patients with disease at study entry are alive with a median follow-up of 14.0 months. Four patients experienced grade 4 granulocytopenia. Only two (11%) had treatment-limiting toxicity, one with grade 3 neuropathy and one with grade 3 fatigue. Conclusions: Carboplatin and paclitaxel appear to have improved tolerability and response rate (63.6%) compared to previous reports of ifosfamide and cisplatin (33% RR) in treating MMMT of the uterus. This regimen seems extremely promising and we are awaiting the final results of this trial.

No significant financial relationships to disclose.
Phase II study of adjuvant gemcitabine plus docetaxel (GD) for completely resected stage I-IV high grade uterine leiomyosarcoma (HGuLMS)
Authors: Hensley M. L. , Larkin J. , Ishill N. , Abu-Rustum N. , Sabbatini P. , Konner J. , Tew W. , Spriggs D. , Aghajanian C. A.
Published: March 2020

5591

Background: Patients (pts) with completely resected stage I-IV HGuLMS are at high risk for recurrence, with reported 2-year progression-free survival ranging from 19–30% (Dinh, Gyn Onc 2004; Major, Cancer 1993). No adjuvant treatment has been shown to improve survival, although prospective data are limited. GD achieves objective responses in metastatic uLMS. We sought to determine whether 4 cycles GD given after complete resection of stage I-IV HGuLMS would yield a 2-year PFS of at least 40%, in order to determine whether GD was worth pursuing as an adjuvant strategy in a randomized trial. Methods: Eligible pts with completely resected HGuLMS within 8 weeks of surgery, no prior GD, no evidence of disease on post-resection CT, KPS = 80, and adequate organ function were treated with G 900 mg/m2 over 90 minutes days 1 and 8 + D 75 mg/m2 d8, with GCSF or pegfilgrastim, every 3 weeks for 4 cycles. CT was performed at baseline, after cycle 4, and every 3 months. Progression defined as new evidence of disease on CT. Results: 25 pts (median age 49, range 37–73) enrolled; 23 evaluable (1-never treated, 1-ineligible). Grade 3 related toxicities were: neutropenia (2/23) 8.7%, febrile neutropenia (2/23) 8.7%, anemia (2/23) 8.7%, thrombocytopenia (1/23) 4.3%, diarrhea (1/23) 4.3%, hyperglycemia (2/23) 8.7%, pulmonary (2/23) 8.7%; there were no ≥ grade 4 toxicities. With median follow-up of 29 months (range 0.5 to 45 months) for all pts, PFS at 2 y and 3 y is 45%, and median OS is not yet reached. For the 18 pts with stage I or II uLMS 2-y and 3-y PFS is 58%, and median PFS is 38 months (95%C.I. 6 months to not yet reached). Sites of first recurrence were: lung only-3/23 (13%); pelvis only-5/23 (22%); both-5 (22%). Treatment of recurrence was at physician discretion and included resection, resection plus pelvic radiation, and/or chemotherapy. Conclusions: Pts treated with post-resection GD for stage I-IV HGuLMS had 2-y and 3-y PFS that appears superior to historical rates of PFS. Incorporation of GD into a randomized trial of adjuvant chemotherapy vs adjuvant pelvic radiation for resected stage I and II uLMS is planned.

No significant financial relationships to disclose.
Erlotinib (E), cisplatin (C) and radiotherapy (RT) for patients with locally advanced squamous cell cervical cancer—A phase I trial
Authors: Rodrigues A. N. , do Carmo C. C. , Viegas C. , Erlich F. , Lima R. , Martins R. , Hercenhorn D. , Fontão K. , Small I. A. , Ferreira C. M.
Published: March 2020

5592

Background: Pre-clinical data indicates that inhibition of epidermal growth factor receptor (EGFR) potentiates the effect of RT. This phase I trial aimed to determine the maximal tolerated dose (MTD) of erlotinib, an oral EGFR tyrosine kinase inhibitor, when administered concurrently with standard chemoradiation (CRT) for cervical cancer. Methods: In a modified Fibonacci design, three cohorts of three patients received escalating doses of E (50/100/150 mg) one week before and combined with C (40 mg/m2, weekly, 5 cycles) and RT (external beam RT - 4,500 cGy in 25 fractions, followed by 4 fractions/600 cGy/weekly of brachytherapy). Eligibility criteria included histologically proven squamous cell cervical carcinoma, stage IIB to IIIB; no prior therapy; ECOG PS <3 and adequate end-organ functions. Patients were allowed four additional weeks of toxicity observation after CRT + E before proceeding to the next cohort. Frozen tissue for molecular studies was collected before treatment. Results: Between 12/04 and 8/06, 15 patients were enrolled, 3 at dose level (DL) 50 mg, 4 at DL 100mg and 6 at DL 150 mg. Patients presented median age 47 (36–59), stage IIB (46,2%) and IIIB (53,8%). Overall E+CRT was well tolerated; 3 patients did not complete the planned schedule.One patient at DL 100mg withdrew informed consent due to grade 2 rash; at DL150mg one patient presented Raynaud’s Syndrome and had C interrupted and one patient presented grade 4 hepatotoxicity. The latter was interpreted as DLT and 3 additional patients were included in this cohort. No further grade 4 toxicity occured. Grade 3 toxicity occurred in 33% of the cases, being diarrhea in 3 patients, rash in 2 patients and leukopenia in 1 patient.It shoud be highlighted that E+CRT did not lead to limiting in-field toxicity (radiodermitis, rash or diarrhea). Within the 12 patients who received through E+CRT, median duration of treatment and follow-up was 70 (67–80) days and 9.5 (3–23) months, respectively. The phase II of this trial is ongoing. Conclusions: The MTD has been defined as 150 mg. This is the first report of a combination of erlotinib, cisplatin and pelvic RT. The addition of E to standard CRT does not appear to increase in-field or systemic toxicities.

No significant financial relationships to disclose.
Clear cell endometrial cancer patients have an increased risk of venous thrombotic events
Authors: Garrett L. , Lee L. M. , Oliva E. , Horowitz N. , Duska L.
Published: March 2020

5597

Objective: To document the rate of clinically significant venous thromboembolism (VTE) in patients with clear cell carcinoma of the endometrium (CCC-E). Methods: Institutional review board (IRB) permission was obtained for retrospective record review. The pathology database at our institution located cases of CCCs over the time period 1994–2004. Controls with high grade endometrial cancers were matched for stage, age and date of diagnosis. All patients underwent surgical staging with gynecologic oncology staff surgeons and all patients received VTE prophylaxis peri-operatively. Records were reviewed and data were collected regarding patient age, tumor stage, body mass index, surgical procedure, adjuvant therapy, survival, and presence of VTE. All pathology was reviewed at the MGH. Results: Thirty-nine cases of CCC-E were identified. Complete clinical data were available for 29 cases. Age ranged from 38–85 (mean 64.6) years. 35% of patients had stage I tumors, 10% stage II, 27.5% stage III, and 27.5% had stage IV tumors. 58 age and stage matched controls were selected. The majority were grade 3 endometrioid cancers (50%) with the remainder being serous (35%), mixed histology (7%), carcinosarcoma (5%), and undifferentiated carcinoma (3%). The majority of the control patients had a higher BMI than the case patients. Overall there were 18 VTE events, 10 (34.5%) in those with CCC-E and 8 (13.8%) controls p = 0.046. A higher proportion of VTE occurred in those with stage III/IV disease (n=16) as compared to those with early stage (n =2) p =0.01. When considering the timing of VTE, the VTE observed in those with CCC-E occurred at presentation or with disease recurrence (8 vs 1) while nearly all VTE in the control group occurred in the postoperative period. (7 vs 2). This was statistically significant p =0.01 Conclusion: Patients with CCC-E are at increased risk of VTE compared to patients with other high- risk endometrial cancers. This is particularly true for those with advanced stage disease. Presentation with a VTE and postmenopausal bleeding should raise the suspicion for CCC-E. Likewise, in those with known CCC-E development of a VTE may be a harbinger of recurrence. Consideration should be given to extended prophylaxis in patients with CCC-E to prevent VTE.

No significant financial relationships to disclose.
Interaction between body mass index and bone turnover during aromatase inhibition: Evidence from the letrozole (L), exemestane (E), and anastrozole (A) pharmacodynamics (LEAP) trial
Authors: McCloskey E. , Hannon R. , Lakner G. , Clack G. , Miyamoto A. , Eastell R.
Published: March 2020

560

Background:
High body mass index (BMI) protects against postmenopausal osteoporotic fracture, mediated in part by higher endogenous levels of oestradiol. Third-generation aromatase inhibitors (AIs) show superior efficacy and tolerability than tamoxifen in the adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer. We examined the interactions between BMI and bone turnover during treatment with 3 aromatase inhibitors in the LEAP trial, an open, randomized, pharmacodynamic study in postmenopausal women.
Methods:
Healthy volunteers from the UK and Hungary with normal bone density and BMI between 18 and 34 kg/m
2
were randomized to receive A (1 mg/day), L (2.5 mg/day), or E (25 mg/day) orally, once daily for 24 weeks. Effects on bone resorption (log transformed serum C-telopeptide crosslinks, CTX) and bone formation (bone alkaline phosphatase and propeptide of type I procollagen, PINP) were compared. Changes in biochemical markers of bone resorption and formation during treatment were all statistically inter- correlated (p<0.01) with no notable differences between the 3 agents studied, so that the groups were pooled for analysis. Spearman correlation coefficients and the p-values were computed.
Results:
A total of 90 participants were evaluable at baseline and at 24 weeks (29 A, 29 L, 32 E). As expected, baseline BMI correlated with pre-treatment circulating endogenous oestradiol (r=0.28, p=0.007) and both BMI and oestradiol negatively correlated with baseline serum CTX (r=-0.32, p=0.0025 and r=-0.35, p=0.0007 respectively) and PINP (r=-0.30, p=0.004 and r=-0.26, p=0.016 respectively). Baseline BMI and oestradiol were significantly correlated with the increase in serum CTX (r=0.26, p=0.015 and r=0.23, p=0.032 respectively) and BMI also correlated significantly with the increase in serum PINP (r=0.23, p=0.030).
Conclusions:
Steroidal and non-steroidal AIs increase bone turnover with the greatest increase in women with high BMI and higher oestradiol levels at baseline. As increased bone turnover is an independent risk factor for fracture, a high BMI may not confer a reduced fracture risk in the setting of AI use in early breast cancer.

No significant financial relationships to disclose.
A detailed analysis of the risk factors influencing local and distant breast cancer recurrence during adjuvant endocrine therapy
Authors: Houghton J.
Published: March 2020

562

Background: The ‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC; ISRCTN18233230 ) trial compared the efficacy and safety of 5 years’ anastrozole, tamoxifen, or combination as adjuvant therapy for 9366 postmenopausal women with early invasive breast cancer. Here, risk factors influencing local and distant recurrences during the trial, independent of trial treatment, are assessed. Methods: The influence of standard baseline factors such as hormone receptor status, nodal involvement, tumor size, grade and age were evaluated on both local and distant recurrence rates. The use of other treatments (adjuvant chemotherapy, radiotherapy) and surgical status (mastectomy and axillary surgery) were also included. In addition, weight, body mass index, hysterectomy and prior hormone- replacement therapy were added. Cox models were used to analyze events by prognostic factors, and subsequently adjusted by country, before the production of confirmatory models. Results: For both local and distant recurrence, the highest risk correlated with poorer tumor differentiation, larger tumor size, increased nodal involvement and a negative hormone receptor status (see table ). While surgical status also affected the risk of developing a recurrence, previous treatments were less important, but residence in the USA showed a significant advantage. No association was seen with hysterectomy or weight for any recurrence. Conclusions: Although the pattern of risk varied for local and distant recurrence, tumor grade, size, and nodal involvement were the strongest risk factors for both. In comparison, the impact of previous treatments on hazard risk was lower. These data from a large international clinical trial confirm that women with less differentiated or larger tumors, and those with involved nodes, are at an increased risk of recurrence.

[Table: see text]

[Table: see text]
YB-1 expression and effectiveness of different dose-intensification strategies in high-risk breast cancer: Five-year follow-up results of prospective randomized WSG-AM-01 trial
Authors: Gluz O. , Kates R. , Schmitt M. , Mengele K. , Royer H. , Mohrmann S. , Ting E. , Diallo-Danebrock R. , Kiechle-Bahat M. , Nitz U. , Harbeck N.
Published: March 2020

563

Background: Y-box binding protein (YB-1), known as oncogenic transcription factor, is associated with up-regulation of MDR1, alters p53 function, and induces growth of an aggressive phenotype. In high-risk breast cancer, the prospective randomized WSG-AM-01 trial has reported significantly better event-free (EFS) and overall survival (OS) for tandem high-dose (HD) vs. dose-dense (DD) chemotherapy, especially in basal-like und HER2 subgroups. The present study examines the interaction of a drug resistant phenotype induced by YB-1 within the WSG-AM-01 collective at 5-year follow-up. Methods: 236 tumors (116 HD/120 DD) of 403 randomized patients (60%) were available for construction of tissue microarrays and determination of molecular classification by k-clustering of expression of 34 protein markers. Immunostaining of YB-1 by specific peptide antibody was scored semiquatitatively by intensity. Associations of YB-1 staining with other protein expression factors were studied by Pearson correlations. Univariate survival was estimated by Kaplan-Meier analysis and tested by log rank statistics. Multivariate survival modeling was performed by a generalized Cox model, with linear proportional hazards terms in the first block and time-varying interactions in the second block. Results: At a median follow-up of 61.7 months, the WSG-AM-01 confirms a significant EFS and OS benefit for HD in HRBC. In 60% of tumors, there was strong YB-1 expression. YB-1 was significantly associated with several proliferation and drug resistance markers, such as p53, EGFR, S6 and with basal-like/Her2 subtypes.YB-1 expression was highly predictive for response to HD: both EFS (HR=0.29, p=0.001) and OS (HR=0.16, p=0.0001) were significantly improved by HD compared to DD for YB-1 positive tumors; these favorable time-varying hazard ratios signify decreases in early (≤3 years) relapses and deaths, respectively. Conclusions: Among all investigated markers, only YB-1 expression was significantly associated by time- varying interaction analysis with efficacy of HD. The results suggest YB-1 as a potential stratification criterion for future trials as well as a target for treatment of drug resistant HRBC.

No significant financial relationships to disclose.
Second interims analysis of the ARA Plus study: Breast Cancer (BC) adjuvant chemotherapy (CT) with and without darbepoetin- alpha, analysis of serious adverse events
Authors: Ziegler K. , Warm M. , Oberhoff C. , Reimer T. , Mohrmann S. , Schumacher C. , Gluz O. , Nitz U. , Zuna I. , Werner F.
Published: March 2020

564

Background: TAC is one of the most effective regimens. It‘s associated with higher frequency of anemia and chemotherapy-induced neutropenia (CIN). The erythropoiesis stimulating factor (ESF) support of chemotherapy, its complications and survival effect remain unclear. Erythropoetins do prevent chemotherapy-associated anemia (CAA) and subsequent fatigue syndrome but their potential influence on survival is still unclear. One aim of this analysis is to investigate the correlation between CT, growth factor support and toxicity (SAE‘s). Methods: This ARA Plus phase III trial compare chemotherapy ±ARA in breast cancer patients >18 years old, with positive lymph nodes and with M0 disease. Pts get six cycles of of 5-fluoro-uracile 500mg/m2, epirubicine 100mg/m2 and cyclophosphamide 500mg/m2, (FEC, Bonneterre), 3-weekly or six cycles of docetaxcel 75mg/m2, adriamycin 50mg/m2 and cyclophosphamide 500mg/m2, (TAC, BCIRG) and are randomized to ARA 500μg q3w if Hb<13 g/dl or standard support care. Here arte the results. of SAE‘S. Results: A total of 756 pts (373 + ARA/383 -ARA) from 53 sites were enrolled since January 2004, there are 1234 pts. planned up to January 2008. 185 serious adverse events (SAE) are reported. Of these 185 SAE’s 100 (54%) had an ARA-therapy. Most frequent SAE’s were: leucopenia, febrile neutropenia, thrombosis and infections. In 9 (31%) out of the 29 febrile neuropenia SAE’s, ARA was given. 30 thromboses were reported (23+ARA/7-ARA s.) but only 10 at the verty time ARA was given. In 31 severe infections 16 (51,6%; n.s.) were reported in patients receiving ARA Therapy. From 43 patients with intestinal SAE‘s like Diarrhea/Mucositis/Nausea to 30 pts. (69,8 %) ARA eas given. Conclusions: The combination of CT and ARA is safe concerning febrile neutropenia and furthermore appears to be protective factor of this SAE when combined with TAC. There seem to be more SAE‘s concerning thrombosis and intestinal difficulties.These results allow to hypothesize that ARA therapy is associated with higher toxicity concerning thrombosis which could make the use of heparin necessary but on the other side it shows significant reduced neutropenia.

No significant financial relationships to disclose.
Follow-up for breast cancer: Results of a patients survey
Authors: Stemmler H. , Laessig D. , Stieber P. , Bauerfeind I. , Fasching P. , Glattes M. , Goldmann-Posch U. , Hoffmann V. , Untch M. , Heinemann V.
Published: March 2020

568

Background:
International guidelines for the surveillance of post-treatment breast cancer patients recommend a clinical follow-up including routine history, physical examination and regularly scheduled mammograms. This often discussed practice has previously been shown not to be inferior when compared to an intensified follow-up in randomized trials performed in the eighties.
Patients and Methods:
We report the patients’ view on the basis of pooled data of two surveys performed in Germany. The questionnaire was sent out to 2,658 patients with a history of breast cancer.
Results:
A total of 801 patients (30.1%) answered to the questionnaire. The median age was 57 years (range 23–85 years). More than 80% of the patients were disease-free at the time of the survey. Necessity for surveillance was affirmed by a majority (95.6%), and 40.3% of the patients answered that there was a need for more intensive diagnostic effort with regard to laboratory exams and imaging procedures during follow-up. The main expectation from an intensified follow-up include was the increased feeling of security as expressed by 86.6% of the patients. In contrast to the follow-up guidelines, the present survey indicates that most of the regularly scheduled follow-up visits were expanded using extensive laboratory and imaging procedures (ultrasound 81.9%, CT scan 33.8%). In view of the unsatisfactory evidence on follow-up in breast cancer only 25.7% patients indicated that they would participate in a trial randomising between conventional and more intensive follow-up.
Conclusion:
The survey indicates that a majority of physicians do not accept the present follow-up guidelines. To some extent this may be explained by the observation that patients and possibly also their doctors trust that intensified follow-up increases diagnostic security. Clearly, a new surveillance study is warranted which investigates the impact of an intensified surveillance on survival based on the greatly improved possibilities of modern diagnostics and treatment.

No significant financial relationships to disclose.
Cell-cycle complete response after neoadjuvant letrozole predicts superior relapse-free and overall survival: Long-term follow- up of the letrozole P024 study
Authors: Ellis M. J. , Tao Y. , Bhatnagar A. S. , Ross H. Chaudri , Evans D. , Miller W. R. , Eiermann W.
Published: March 2020

570

Background: The P024 study was a double blind randomized endocrine therapy trial that compared 16 weeks of letrozole 2.5 mg daily (LET) with tamoxifen 20 mg daily (TAM). LET proved to be more effective than TAM in terms of tumor response and rates of breast conservation therapy (1). Biomarker studies also indicated that LET was a more effective anti-proliferative agent, with greater declines in Ki67 values (2). However, in the P024 trial patients experienced a very low rate of pathological complete response (pCR). We have therefore proposed that a cell-cycle complete response (CCCR - in which tumor cell Ki67 staining is 1% or less in the surgical specimen) may be an alternative to pCR because CCCR indicates that the endocrine therapy was maximally effective in causing cell-cycle arrest. In initial studies we had already shown that CCCR is more common with LET than TAM (3), and also there was a strong association between the absence of a CCCR and the presence of HER2 gene amplification (4). In this study we examined the relationships between CCCR and relapse-free and overall survival. Methods: Per protocol, patients were followed yearly for breast cancer relapse, all cause mortality and breast cancer specific mortality. Relapse-free and breast cancer specific survival was examined according to CCCR status after patients had been followed for five years on adjuvant TAM. Results: Patients who received neoadjuvant LET and whose tumors exhibited a CCCR had superior relapse-free (log rank P=0.0077) and breast cancer specific survival (P=0.0006). Patients who received TAM with a CCCR had superior RFS (P=0.0224) but not breast cancer specific survival. Conclusions: This study supports the conclusion that CCCR may be a clinically useful measurement for patients who undergo neoadjuvant LET. The value of CCCR after neoadjuvant TAM is less clear. A prospective trial that incorporates information on CCCR into clinical decision making regarding adjuvant chemotherapy may be appropriate. 1. Ann Oncol 12, 1527–32 (2001) 2. Cancer Res 63, 6523–31 (2003). 3. J Steroid Biochem Mol Biol 95, 91–5 (2005). 4. J Clin Oncol 24, 3019–25 (2006).

No significant financial relationships to disclose.
Genomic heritage of sentinel lymph node metastases: Implications for clinical management of breast cancer patients
Authors: Ellsworth D. L. , Ellsworth R. E. , Becker T. E. , Deyarmin B. , Patney H. L. , Hooke J. A. , Shriver C. D.
Published: March 2020

571

Background: Sentinel lymph node (SLN) biopsy status is a key prognostic factor for breast cancer patients. Sentinel nodes are believed to receive early disseminating cells from the primary tumor, but little is known about the origin of metastases colonizing the sentinel nodes. We used allelic imbalance (AI) to examine genomic relationships among metastases in the sentinel and non-sentinel axillary lymph nodes from complete axillary dissections in 15 patients with lymph node positive breast cancer. Methods: Sentinel nodes were localized by standard scintigraphic and gamma probe techniques using 1.0 mCi technetium-99m sulfur colloid. Pathologically positive nodes were identified by H&E histology and immunohistochemistry. Primary breast tumors and metastases in sentinel and axillary nodes were isolated by laser microdissection. AI was assessed at 26 chromosomal regions and used to examine the timing and molecular mechanisms of metastatic spread to the sentinel and axillary nodes. Results: Overall AI frequencies were significantly higher (p<0.05) in primary breast tumors compared to lymph node metastases. A high level of discordance was observed in patterns and frequencies of AI events between metastases in the sentinel and non-sentinel axillary nodes. Phylogenetic analyses showed that 1) multiple genetically-divergent lineages of metastatic cells independently colonize the lymph nodes; 2) some lymph node metastases appeared to acquire metastatic potential early in tumorigenesis, while other metastases evolved later; and 3) importantly, lineages colonizing the sentinel nodes appeared to originate at different times and to progress by different molecular mechanisms. Conclusions: Genomic diversity and timing of metastatic nodal spread may be important factors in determining outcomes of breast cancer patients. Metastases colonizing the sentinel nodes appear to arise at different times during disease progression and may not be descendants of progenitor cells that colonize the lymph nodes early in tumorigenesis. Metastatic growth in the sentinel nodes thus may be a consequence of stimulating factors from the primary tumor that affect proliferation of previously disseminated cells rather than the timing of metastatic spread.

No significant financial relationships to disclose.
Endocrine effects of letrozole + triptoreline compared to tamoxifen + triptoreline as adjuvant treatment of premenopausal patients with early breast cancer
Authors: Rossi E. , Esposito G. , Rella F. Di , Gravina A. , Landi G. , Nuzzo F. , Pacilio C. , Monaco K. , Piccirillo M. , de Matteis A.
Published: March 2020

578

Background: Few data have been reported on endocrine effects of combining LHRH-analogues with aromatase inhibitors (AI) in premenopausal patients. However, promising data in postmenopausal patients make this information interesting in view of extending adjuvant AI to premenopausal patients. We are conducting a phase 3 trial (Hormonal adjuvant treatment bone effects (HOBOE)) comparing tamoxifen (Tam), letrozole (L) and L + zoledronate (Z) for the effect on bone mineral density at 1 year. Postmenopausal and premenopausal patients are eligible, the latter also receiving monthly triptorelin (Tr). Methods: This analysis is limited to 76 premenopausal patients with early endocrine-responsive breast cancer, 28 treated with Tam+Tr and 48 with L+Tr±Z, assuming that Z has no endocrine effects. Serum 17-β-estradiol, FSH, LH, Δ4-androstenedione, testosterone, dehydroepiandrosterone-solphate, progesterone, ACTH and cortisol are measured at baseline and after 6 months of treatment. We compared, for each hormone, 6-month values between treatment groups by applying Exact Wilcoxon-Mann-Whitney test. Results: Baseline values for all the hormones were comparable between treatment groups. At 6 months, statistically significant differences were found for estradiol, FSH, LH and cortisol (see table , with median and range values by treatment group). No differences were found in plasma levels of testosterone, progesterone, ACTH, androstenedione, and dehydroepiandrosterone between the two groups. Conclusions: These data support that letrozole compared to tamoxifen, in combination with triptorelin, induces a more intense estrogen suppression also in premenopausal patients. Such evidence makes reasonable the hypothesis that the higher efficacy of letrozole versus tamoxifen shown in postmenopausal patients could be confirmed also in premenopausal patients.

[Table: see text]

No significant financial relationships to disclose.
Correlation between changes in 2- or 3-year disease-free survival (DFS) and 5-year overall survival (OS) in adjuvant breast cancer trials from 1966–2006
Authors: Ng R. C. , Pond G. R. , Tang P. A. , MacIntosh P. W. , Siu L. L. , Chen E. X.
Published: March 2020

581

Background: Although disease-free survival (DFS) is accepted as a valid endpoint in adjuvant breast cancer trials, improvement in 2- or 3-year DFS has never been formally established as an adequate surrogate for 5- or 10-year overall survival (OS). We set out to establish if changes in 2- or 3-year DFS can be used to accurately predict changes in 5- or 10-year OS. Method: We conducted a systematic Medline search for phase III randomized adjuvant breast cancer trials published between 1966–2006 with >100 patients per arm with data for 2- and 3-year DFS as well as 5- or 10-year OS. Only trials of systemic therapies (e.g. chemotherapy, hormonal therapy) were included. We excluded studies investigating the effects of surgery, radiotherapy and neoadjuvant treatment. A univariate regression model weighted by trial sample size was constructed to determine if changes in 2-year DFS between treatment arms within trials were predictive of changes in 5- year OS. Computations of the correlation coefficient, proportion of variation, predicted estimates and 95% prediction interval were undertaken. Results: 126 studies containing 149 treatment arms met the inclusion criteria. Median sample size per trial was 533 and median follow up time was 81 months. Only 26 trials provided 10-year OS data thus association with 10-year OS was not attempted. Results were similar between analyses using either 2- or 3-year DFS, hence only 2-year DFS statistics are reported. 2-year DFS was a significant predictor of 5-year OS regardless of what other covariates were included (p<0.001). For every 1% increase in difference between treatment arms in 2-year DFS, the estimated difference in 5-year OS increased by 0.52%. The proportion of variation explained (R2) ranged from 0.38 to 0.49, with a wide prediction interval. Indeed, if a future trial accrued 1,000 patients and the 2-year DFS in the experimental arm was better than the control by 10%, the 95% prediction interval would still range from -0.2% to 11%. Conclusion: There is a statistically significant correlation, of moderate strength, between changes in 2-year DFS between treatment arms and changes in 5-year OS but the wide prediction intervals mean that the correlation is not strong enough to be used as a surrogate.

No significant financial relationships to disclose.