bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of anastrozole on bone mineral density: 5-year results from the ’Arimidex’, Tamoxifen, Alone or in Combination (ATAC) trial
Authors: Coleman R. E.
Published: March 2020

511

Background: Since reporting the 1- and 2-year results from the ATAC trial bone sub-protocol, 68-month analysis results from the main ATAC trial have shown that, for postmenopausal women with invasive primary breast cancer, adjuvant treatment with anastrozole results in superior efficacy and tolerability compared with tamoxifen. Here we report 5-year bone mineral density (BMD) results from the monotherapy arms (anastrozole, n=81; tamoxifen, n=86) of the bone sub-protocol. Methods: Lumbar spine and total hip BMD were assessed by dual-energy X-ray absorptiometry at baseline and after 1, 2, and 5 years. Results: The median percentage changes in BMD at 1, 2, and 5 years, respectively, are shown in the table . Percentage changes in BMD from baseline to 5 years showed a statistically significant difference in favor of tamoxifen for both lumbar spine (treatment effect [percentage decrease of BMD on anastrozole relative to tamoxifen] −8.1; 95% confidence intervals [CI] −10.1, −6.1; p<0.0001) and total hip (treatment effect −7.4; 95% CI −9.6, −5.3; p<0.0001). For patients with data at baseline, 2, and 5 years, the rate of loss of lumbar spine BMD in the anastrozole group was significantly less from 2 to 5 years than from baseline to 2 years (mean difference in annual rate of change 0.0113, 95% CI 0.006, 0.017; p=0.0002), but there was no evidence of slowing down in the loss of total hip BMD. Five patients with osteopenia at baseline developed osteoporosis on treatment with anastrozole (4) or tamoxifen (1). No patients with normal BMD at baseline became osteoporotic at 5 years. Conclusions: Significant bone loss occurred throughout the 5 years in the anastrozole group, although there appeared to be a slowing down of the rate of bone loss in years 2–5. Although no patients with normal BMD at baseline had become osteoporotic at 5 years, regular monitoring of BMD and bone protection strategies are likely to be required in patients receiving anastrozole in the presence of pre-existing osteopenia.

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Prognostic and predictive value of topoisomerase II alpha in a randomized trial comparing CMF to CEF in premenopausal women with node positive breast cancer (NCIC CTG MA.5)
Authors: O’Malley F. P. , Chia S. , Tu D. , Shepherd L. E. , Levine M. N. , Huntsman D. G. , Bramwell V. H. , Andrulis I. L. , Pritchard K. I.
Published: March 2020

533

Background: It has been suggested that Topoisomerase II alpha (TOP2A) status rather than Her-2/neu status may predict response to anthracycline chemotherapy in breast cancer. Methods: In MA.5, 710 premenopausal women with node positive breast cancer were randomized to receive adjuvant CEF (epirubicin 60 mg/m2 & 5-FU 500 mg/m2 both IV, days 1 & 8, and cyclophosphamide 75 mg/m2 p.o. days 1 through 14); vs CMF (methotrexate 40 mg/m2 & 5-FU 600 mg/m2 both IV days 1 & 8 and cyclophosphamide 100 mg/m2 p.o. days 1 through 14), all for six 28-day cycles. Tissue microarrays (TMAs) were constructed from paraffin embedded specimens from 447 (63%) of these patients. TOP2A was measured by fluorescence-in-situ hybridization (FISH), classifying tumors into 3 groups by TOP2A/CEP 17 ratios: amplified (Amp) if ratio ≥2; deleted (Del) if ratio < 0.8; normal (N) if ratio 0.8 to 2. Cox models assessed interaction between treatment and TOP2A, adjusting for age, nodal status, ER, HER-2/neu status, grade, surgery and tumor size. Results: Thirty-one patients (6.9%) had tumours with Del TOP2A; 53 (11.9%) with Amp TOP2A; and 353 (81.2%) with N TOP2A. 5-year disease-free survival (DFS) was 48%, 51%, and 61% for patients with Del, Amp and N TOP2A respectively (p=0.22 adjusted global test). 5-year overall survival (OS) was 55%, 61% & 75% for patients with Del, Amp, and N TOP2A (p=0.67 adjusted global test). HRs for DFS and OS by treatment and TOP2A are presented in the table . Conclusions: TOP2A status was a significant predictive factor for benefit from CEF treatment for OS. Although there was a trend for TOP2A status predicting improved DFS with CEF, the test for interaction was not significant. In adjusted analysis TOP2A did not reach significance as a prognostic factor for DFS or OS. (This study was supported by the Canadian Breast Cancer Research Alliance (CBCRA), the National Cancer Institute of Canada (NCIC) and the Canadian Cancer Society.)

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Improved prediction of disease-free survival in tamoxifen-treated patients using an expression signature of estrogen-regulated genes as compared to progesterone receptor
Authors: Creighton C. , Rae J. , Chinnaiyan A. , Lippman M.
Published: March 2020

535

Background: Progesterone receptor (PR) is a direct downstream target of activated estrogen receptor (ER) and its expression is a marker of estrogen signaling within breast tumors. Studies suggest the absence of PR predicts the likelihood of distant recurrence in patients treated with hormonal therapies such as tamoxifen, but better clinical measures are needed. Methods: Through analysis of public mRNA expression profiling datasets, we identified 36 genes with the following expression patterns similar to PR: (1) induced by 17β-estradiol (E2) in estrogen receptor (ER)-positive breast cancer cell lines in vitro, (2) under-expressed in ER-negative compared to ER-positive breast tumors, and (3) correlated with PR expression in ER-positive tumors. The average expression of these 36 genes was used as a “risk index” for assessing disease-specific survival in two independent tumor profile datasets of 60 and 67 patients treated with tamoxifen (these data not having been used to initially select the 36 genes), with a high risk group in each dataset defined as those with the bottom 25% of risk index values. Results: The Kaplan-Meier estimates of the rates of distant recurrence at 10 years in the low-risk and high-risk groups were 24% and 64% in the one dataset and 32% and 72% in the other dataset. In both validation datasets, the rate in the low-risk group was significantly lower than that in the high-risk group (P=0.008 and P=0.006 by log-rank, respectively), whereas patient groups defined by histologically-assigned PR status did not show significant risk differences (P=0.70 and P=0.94, respectively). In a univariate Cox model, the risk index combined across both validation datasets provided significant predictive power (P=0.03). Conclusions: Through RT-PCR assay of a larger independent cohort of breast tumor samples, we are currently validating the prognostic value of individual genes within the 36-gene signature.

No significant financial relationships to disclose.
NCIC CTG MA.17: Intent to treat analysis (ITT) of randomized patients after a median follow-up of 54 months
Authors: Ingle J. , Tu D. , Shepherd L. , Palmer M. , Pater J. , Goss P.
Published: March 2020

549

Background: MA.17 evaluated letrozole (LET) or placebo (PLAC) after 5 years of tamoxifen (Tam) and showed [median follow-up 30 months (mos)] significant improvement in disease-free survival (DFS) for LET [hazard ratio (HR) 0.57, p = 0.00008]. The trial was unblinded and PLAC patients (pts) were offered LET. An ITT analysis of all outcomes, before and after unblinding, based on the original randomization was performed. Methods: A stratified log-rank test was used to compare DFS, distant (D)DFS, overall survival (OS) and incidence of contra-lateral breast cancer (CBC). The Cox regression model used baseline stratification variables and two prespecified factors, menopausal status at the start of Tam and time on Tam. Subgroup analyses for DFS and OS were performed for the two prespecified subsets. All p-values were two-sided Results: 5187 pts were randomized at baseline and, at unblinding, 1655 of 2268 PLAC pts accepted LET. At median follow-up of 54 mos (range,16–86) 363 recurrences or CBC’s (144 LET and 219 PLAC) occurred; 118 LET and 176 PLAC pts had recurrent disease and 26 LET and 43 PLAC pts had CBC. 4 year DFS was 94.3% (LET) and 91.4% (PLAC) (HR 0.64; 95% CI, 0.52 - 0.79; p = 0.00002). Corresponding 4 year DDFS was 96.2% and 94.9% (HR 0.76; 0.58–0.99; p = 0.041). 4 year OS was 95.0% (LET) and 95.1% (PLAC) (HR 1.00; 0.78–1.28; p = 0.99). LET was equally effective in node +ve and -ve pts (i.e., similar HRs) in DFS. OS was not significantly different for LET and PLAC in any subgroup. The annual rate of CBC was 0.29% LET (0.18–0.40) and 0.47% PLAC (0.34–0.61); HR 0.61 (0.38–0.98) p = 0.037. 255 pts had died as of the data cut-off (128 LET and 127 PLAC). Conclusions: In this ITT analysis, pts originally randomized to LET within 3 months of stopping Tam did better than PLAC pts in DFS, DDFS and CBC, despite 73% of PLAC pts crossing to LET after unblinding. This highlights the strong beneficial effect of extended adjuvant therapy with LET.

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Pre-treatment and treatment related risk factors for severe late toxicity after chemo-RT for head and neck cancer: An RTOG analysis
Authors: Machtay M. , Moughan J. , Trotti A. , Garden A. S. , Weber R. S. , Cooper J. S. , Swann R. S. , Ang K. K.
Published: March 2020

5500

Background: Concurrent chemoradiotherapy (CCRT) for squamous cell carcinoma of the head and neck (SCCHN) improves tumor control, but its toxicity is formidable. This study evaluates factors that might predict for severe late toxicity following CCRT. Methods: Patients treated with CCRT were analyzed from three RTOG trials of locally advanced SCCHN: 91–11 arm #2 (XRT + high dose cisplatin for larynx cancer); 97–03 (phase II study of various doublets of chemotherapy with XRT); and 99–14 (phase II study of accelerated XRT + high dose cisplatin). Severe late toxicity was defined in this secondary analysis as late (>180 days from the start of XRT) Grade 3–4 pharyngeal/laryngeal toxicity (RTOG/EORTC late toxicity scoring system); requirement for a feeding tube ≥2 years after registration; or potential treatment-related death (e.g. pneumonia) within 3 years. Case-control analysis was performed to determine factors predictive of severe late toxicity, with a multivariate logistic regression model that included pre-treatment and treatment potential factors. Results: The total sample size of patients treated with CCRT from these three studies was 479; 226 were evaluable (119 patients had severe pre-treatment laryngopharynx dysfunction and 134 had persistent/recurrent cancer). There were 98 cases (patients with severe late toxicity) and 128 controls. In the multivariate model, significant predictors of severe late toxicity were older age (odds ratio 1.05 per year, p = 0.002); advanced T-stage (odds ratio 2.21; p = 0.014); larynx/hypopharynx tumor site (odds ratio 3.20; p = 0.011); and neck dissection (ND) after XRT (odds ratio 2.22; p = 0.029). Radiotherapy dose intensity and chemotherapy dose intensity were not predictive. Among 47 patients who underwent post-XRT ND, the crude rate of severe late toxicity was 55%, compared with 40% for the subgroup of 179 patients who did not undergo post-XRT ND (p = 0.05). Conclusions: Severe late toxicity following CCRT is common. Older age, advanced T-stage, and larynx/hypopharynx primary site were independent risk factors. Neck dissection after CCRT may be associated with an increased risk of these complications. This work was supported in part by the Commonwealth of Pennsylvania (Tobacco Settlement Grant).

No significant financial relationships to disclose.
Letrozole suppresses plasma oestradiol (E2) levels more completely than anastrozole in postmenopausal women with breast cancer
Authors: Dixon J. M. , Renshaw L. , Young O. , Murray J. , Macaskill E. J. , McHugh M. , Folkerd E. , Cameron D. , Dowsett M.
Published: March 2020

552

Background: Letrozole (L) is a more potent aromatase inhibitor in vitro than anastrozole (A). One study in 12 patients showed that in patients L provides more complete inhibition of whole body aromatase and suppression of estrone sulphate levels than A but L did not significantly suppress E2 levels more than A possibly because of the small size of the study and the difficulty of measuring E2 in postmenopausal women (Geisler et al, JCO, 20, 751, 2002). The current aim was to conduct a much larger study to determine whether 2.5mg L suppresses E2 significantly more than 1mg A and if so in what proportion of patients this is the case. Methods: 54 postmenopausal women with invasive estrogen receptor positive breast cancer were randomised as part of their adjuvant hormone therapy to receive either: 12 weeks of L followed by 12 weeks of A (L→A) or 12 weeks of A followed by 12 weeks of L (A→L). Blood for hormones were taken at the same time of the day before and after 12 weeks of each drug. E2 was measured by a highly sensitive radioimmunoassay (Dowsett et al, Cancer Res 1987;47:1957–61) with a formal detection limit of 3pmol/l. In this study we also quantified values by extrapolation below this limit. Results: 27 patients had L→A and 27 A→L. Baseline E2 levels varied from 3 to 91 pmol/l with a median of 26 pmol/l. Only 1of 54 (2%) patients had an E2 value ≥ 3pmol/l after L compared with 20 of 54 (37%) after A(p <0.000005). After extrapolation, mean E2 level after A was 2.91 (SEM 0.18) pmol/l with a median of 2.70 pmol/l and after L was 1.76 (SEM 0.10) pmol/l with a median of 1.70 pmol/l (p<0.0001). Mean residual estradiol was 9.2% of baseline with A and 5.6% with L. Conclusions: This study has demonstrated unequivocally that the more complete inhibition of aromatase achieved by 2.5mg of letrozole than 1mg of anastrozole results in a greater degree of suppression of E2, the most bioactive oestrogen.

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Cetuximab in combination with cisplatin or carboplatin and 5-fluorouracil (5-FU) in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R&M SCCHN) (EXTREME)
Authors: Vermorken J. B. , Mesia R. , Vega-Villegas M. E. , Remenar E. , Hitt R. , Kawecki A. , Rottey S. , Zabolotnyy D. , Erfan J. , Amellal N.
Published: March 2020

5537

Background: The epidermal growth factor receptor (EGFR) is expressed in nearly all SCCHN and carries a strong prognostic significance, providing the rationale for using EGFR-targeted agents, such as cetuximab, in this indication. This study assesses the efficacy and safety of cetuximab in combination with chemotherapy commonly used in the treatment of R&M SCCHN. Methods: Patients (pts) were enrolled into this phase III trial from December 2004 to December 2005 and randomized either to Group A: cetuximab (first dose 400 mg/m2 then 250 mg/m2 weekly) plus a maximum of 6 three-weekly cycles of cisplatin (100 mg/m2 IV on day 1) or carboplatin (AUC 5, day 1) and 5-FU (1000 mg/m2/day continuous infusion for the first 4 days of each cycle) or to Group B: cisplatin or carboplatin with 5-FU as before. Cetuximab was administered until progression or unacceptable toxicity. Primary endpoint is overall survival time; secondary endpoints are progression-free-survival, response rate, disease control rate, safety, and Quality of Life. It was planned to randomize a total number of 420 pts in order to detect a difference in improvement in overall survival of 2.5 months. Results: At the end of the recruitment,440 pts have been randomized, to date 320 pts are under treatment, 21 have withdrawn from the study and 99 have completed the study. The Data Safety Monitoring Board (DSMB) has performed an independent preplanned safety analysis from the first 140 pts, 138 pts of whom were treated. Patients were followed for a minimum of 6 weeks: M/F122/16, median age57 years [range, 38–79],median Karnofsky performance status (KPS) 80 [range, 70–100]. In this safety analysis, there were 14 deaths, none of which were treatment related. The most frequent drug related grade 3–4 toxicity was mainly represented by neutropenia, thrombocytopenia and anemia. Conclusions: The DSMB evaluated baseline and safety data, found no reason to stop the trial and recommended continuation of the study.

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Protection of chemo-radiation therapy induced oral mucositis (OM) in pre-clinical and clinical studies
Authors: Rehemtulla A. , Grove W. , Sunkara P. , Naidu M. , Ross B. D.
Published: March 2020

5567

Background: D-methionine, was shown to selectively protect normal but not tumor cells from loss of mitochondrial integrity and viability in response to ionizing radiation. OM is a debilitating complication of radiotherapy (RT) and chemotherapy (CT). MRx-1024, a orally bio-available formulation of this agent was evaluated as a treatment for the protection of OM. Methods: A mouse model of radiation-induced lip erythema was used to evaluate the efficacy of MRx-1024. Pharmacokinetic profile of MRX-1024 in healthy human volunteers as well as evaluation of oral MRX-1024 was accomplished in patients (pts) with head and neck cancer receiving RT or RT+CT. Pts received 1.8–2.0 Gy of RT daily for 5 days each week, to a total of 60 Gy. Selected pts also received cisplatin, 50mg/m2 weekly. MRX-1024 suspension was given 1 hour before and again after each RT fraction. Pts were evaluated weekly using 4 accepted scales for assessing OM. Results: A significant protection of radiation-induced lip erythema was achieved in pre-clinical studies without compromising tumor control. Plasma concentrations of MRx-1024 achieved in normal volunteers after oral administration were similar to those required for efficacy in pre-clinical studies. No major adverse events were attributed to MRx-1024. The incidence of OM from 21 evaluable pts was compared with historical controls from the same institution. MRX-1024 was found to be a safe, easily administered and well-tolerated agent that completely ameliorated the incidence of Grade 4 (21% in historical controls) and reduced the incidence of Grade 3 by 80% over historical controls. In addition, preliminary analysis indicated that MRX-1024 did not compromise antitumor activity. Conclusions: These pre-clinical and clinical studies provide exciting proof of principle evidence for the use of MRx-1024 in the treatment of OM. Follow-up clinical studies are underway to further validate these results.

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Risk of cancer treatment-related osteoporosis and fractures among women with breast cancer receiving aromatase inhibitors
Authors: Mincey B. , Duh M. , Thomas S. , Moyneur E. , Marynchencko M. , Boyce S. , Perez E.
Published: March 2020

557

Background: Aromatase inhibitors (AIs) are a novel hormonal therapy for breast cancer. However, AIs can cause bone loss by blocking estrogen production. This study aims to assess the association between AIs and treatment-related bone loss in a large managed care population of women with breast cancer. Methods: Using medical and pharmacy claims data from over 5 million beneficiaries between 01/01/1998 and 01/31/2005, we identified 12,368 patients with ≥ 2 breast cancer claims in a 6-month period, who also had no bone metastasis and no prior osteoporosis or fracture claims. Patients who received anti-estrogen therapy were also excluded to remove the protective confounding effects. 1,354 patients receiving an AI (anastrozole, exemestane, letrozole) were compared to 11,014 controls who did not receive an AI with respect to their risk of bone loss. The observation start date for the AI and control groups was defined as the service date of the first AI claim and breast cancer claim, respectively. The bone loss endpoints analyzed were osteoporosis (including osteopenia) and clinical fractures. Results: The univariate analysis found that the prevalence of osteoporosis was 8.7% in the AI group vs. 7.1% in the control group, resulting in a statistically significant relative risk of 1.3 (95% CI=1.1–1.6, p=0.01). The prevalence of bone fracture was also statistically significantly elevated in the AI group compared to the controls (13.5% vs. 10.3%) with a relative risk of 1.4 (95% CI=1.2–1.6, p=0.001). Multivariate Cox proportional hazards regressions showed that after adjusting for age and comorbidities, the risk of bone loss remained statistically significantly higher in the AI group than the non-AI group, with 27% (95% CI=4%-55%, p=0.02) and 21% (95% CI=3%-43%, p=0.02) increase in the risk of osteoporosis and fractures, respectively. Conclusions: This retrospective longitudinal analysis of a large cohort of breast cancer patients corroborates previous findings from smaller clinical trials and demonstrates that AI therapies carry an increased risk of bone loss. Monitoring and treatment management strategies to alleviate bone loss risk are warranted in women receiving AI for breast cancer.

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Multimodality therapeutic approach in anaplastic thyroid cancer (ATC): Study of 56 patients
Authors: Koussis H. , Scola A. , Tonello S. , Busnardo B. , Donach M. , Pelizzo M. , Toniato A. , Mazzarotto E. , Mazzarotto E. , Karahontzitis P. , Monfardini S.
Published: March 2020

5571

Background: To investigate the role of multimodality treatment in patients with ATC. Methods: From 1992 to 2005, 56 patients with a histologically or cytologically proven ATC were referred to the Thyroid Centre of Padua University General Hospital. There were 36 females and 20 males, median age 69 years (range 27–90). About one-third of patients had a history of prior nodular goitre. Aggressive local disease was present in 30 patients, distant metastases, mainly to the lung, were present in 32 at diagnosis or quickly developed during the observation period in all but one patient. Patients from our series can be subdivided into 3 groups: Group A: consisted of 19 patients in good general condition which were treated by radiotherapy (RT), total thyroidectomy (TT) and chemotherapy (CHT). All were treated with Cisplatin once a week and by RT 36 Gy in 18 fractions over 3 weeks, followed by TT and by further CHT with Adriamycin and Bleomycin. Additionally, five patients received weekly Docetaxel. Group B: consisted of 19 patients with distant metastasis at diagnosis, who received CHT (Platinum based combination). Group C: consisted of 18 elderly patients in poor general condition; 6 received local RT, while 12 did not receive any treatment. Results: Five complete responses were seen in patients from group A. Four patients had long-term survival (14, 15, 24 and 41 months) with a disease free survival interval of 6, 8, 11 and 32 months. From Group B one patient with a complete remission following antiblastic therapy was later treated by TT and metastasectomia and is still alive without disease after 74 months. Median survival rates for Groups A, B and C were 12, 5.7 and 4 months respectively. Conclusions: In some patients multimodality treatment is associated with increased survival. The best results were obtained in younger patients with less advanced disease. Early diagnosis is mandatory. Only a few patients responded to CHT confirming that anaplastic thyroid carcinoma is often resistant to anticancer drugs. Our experience with combination modalities suggests that aggressive and appropriate combinations of RT, TT and CHT may provide some benefit in patients with ATC. Preoperative RT and CHT may enhance surgical resectability of the primary tumor.

No significant financial relationships to disclose.
Value of positron emission tomography (PET) scan in treatment decision making for nodal metastases in head and neck squamous cell cancer
Authors: Mehrotra B. , Roy R. , Radhakrishnan N. , Gabalski E. , Myssiorek D. , Rush S. , Ebling D. , Pollack J. , Dubner S. , Heller K.
Published: March 2020

5577

Background: Management of neck disease in patients with Head and Neck Squamous cell cancer (HNC) who are initially treated with combined radiation and chemotherapy (CRT) remains controversial. Standard treatment options include neck dissection (ND) or close observation. More recently PET scans have been used to stage and monitor response to therapy in patients with HNC. We performed a retrospective analysis of patients diagnosed with HNC stages N2b or higher, treated with combined CRT, and who were monitored for disease response by PET scans. Our observations on the utility of PET scans in monitoring response to therapy and in determining the role of elective NDs in this setting are reported. Methods: A retrospective review of medical records of all patients diagnosed at our institution with HNC Stages TxN2b, N2c or N3 between the years 2002 and 2005 was undertaken. IRB approval was obtained for this study.To be eligible for this analysis, patients must have had baseline and follow up PET scans at the end of CRT and prior to ND. Data regarding age, gender, primary tumor site, stage, baseline and follow up PET scan results, operative pathology of ND when performed, and local control were recorded. Results: Fifteen patients were identified. Median age was 55 years (range 37–76). Male: Female ratio was 13:2. Primary site of tumor was Pharynx (Base of tongue: n = 3, tonsil: n = 11); Lip and oral cavity: n = 1. Stages: IVa : n = 12; IVb: n = 3. N stage: N2b: n = 12; N2c: n = 1; N3: n = 2. Post CRT, all patients were followed with serial clinical examinations, PET ± CT scans. 13 of 15 patients had negative PET activity in the neck at the completion of CRT and remain disease free in the neck at a median follow up of one year. Post treatment PET scans were positive at the primary site in 2 of 15 patients; and positive in the neck in 2 of 15 patients. These 4 patients underwent ND after completing CRT. Operative pathology was positive for nodal disease in 2 of 4 patients who had persistent mild or significant activity on PET scan either at the primary site or in the neck. Conclusions: Post CRT PET negativity in the neck and at the site of primary tumor is associated with continued disease free status in the neck and these patients may be managed conservatively without requiring a neck dissection.

No significant financial relationships to disclose.
Toxicity of older and younger patients (pts) treated (Rx) with intensive adjuvant chemotherapy (Cx) for node-positive (N+) breast cancer (BC): The CALGB experience
Authors: Muss H. , Berry D. , Cirrincione C. , Budman D. , Henderson I. , Citron M. , Norton L. , Winer E. , Hudis C.
Published: March 2020

559

Background: Recent data show older pts derive the same relapse-free and survival benefits as younger pts when treated with newer more intense adjuvant ADJ Cx regimens (Jama 293:1073, 2005). We now compare toxicity of older and younger pts treated in 3 CALGB ADJ trials that used recently developed, intensive Cx regimens including anthracyclines and paclitaxel (T). Methods: Toxicity data were available for 6174 of 6642 pts (93%) enrolled in 3 CALGB/CTSU randomized clinical trials for N+ BC [8541: comparison of CAF in 3 dose schedules; 9344: AC ± T; 9741: ATC dose-dense vs q3 weeks]. Grade (G) 3–5 (NCI criteria) toxicities were compared by age at enrollment (<50, 51–64, 65+). Results: 7% (458) pts were 65+, 3% were 70+, 38% were 51–64 and 55% were <50 years. Incidence of major toxicities and Cx-attributed causes of death are tabulated below. Discontinuation of Cx for toxicity was reported in 6% of 65+, 4% of 51–64 and 3% of <50 pts. 22 of 6642 pts (0.33%) died of causes attributed to Cx; 7/486 (1.4%) of 65+, 8/2480 (0.32%) of 51–64 and 7/3676 (0.19%) <50. In multivariate analysis older pts were significantly more likely to have WBC < 1000/cmm, any G4 hematologic toxicity, or to have discontinued Cx. There were no significant differences in G3–5 non-hematologic toxicity and no deaths due to neutropenia and sepsis.The incidence of AML/MDS due to Cx significantly increased with increasing age. Conclusions: Older pts who met the strict eligibility criteria for these trials had a higher incidence of Cx-related AML/MDS but not non-hematologic toxicity. It is uncertain if cardiac deaths attributed to Cx are definitely due to treatment. Except for AML/MDS, 5-year non-BC mortality, including Cx-attributed death, is similar in elders to age-adjusted rates in the normal population. Elders treated with intense but more effective ADJ regimens should be cautioned concerning the increased risks of AML/MDS. Physicians should help elders weigh the risks and benefits of ADJ treatment.

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Endocrine and clinical responses to steroid sulfatase inhibition: Results from the first phase I trial in women with breast cancer
Authors: Stanway S. , Purohit A. , Woo L. W. , Wilson R. H. , Stanczyk F. Z. , Dobbs N. , Delavault P. , Potter B. V. , Reed M. J. , Coombes R. C.
Published: March 2020

580

Background: Steroid sulfatase (STS) inhibitors, such as STX64, were developed to block the sulfatase pathway of estrogen formation in postmenopausal (PM) women with ER+ breast cancer. They act by blocking the formation of estrone from estrone sulfate but also inhibit the synthesis of androstenediol (Adiol), a steroid with potent estrogenic properties, which is derived from dehydroepiandrosterone sulfate (DHEAS). Methods: Fourteen PM women with ER+ metastatic breast cancer were recruited for this Phase I trial. All patients had received at least two previous lines of endocrine therapy and all but one had received prior chemotherapy. STX64 was administered orally as an initial test dose (5mg, n=9; 20mg, n=5) followed one week later by 3 two weekly cycles with dosing for 5 days followed by 9 days off treatment for 12–145 days. Blood samples were collected for the assessment of STS activity in peripheral blood lymphocytes and steroid concentrations. For some patients core biopsies of tumor samples were obtained before and during therapy. Results: Almost complete inhibition of peripheral STS (median 98%) and tumor (median 99%) activity was achieved on dosing with STX64. This was associated with significant decreases in the concentrations of estradiol, androstenediol (up to 90%) and unexpectedly, androstenedione (up to 86%). Monitoring the ratios of DHEAS:DHEA (a marker of STS inhibition) in patients receiving extended dosing revealed an inverse relationship between this ratio and serum Adiol concentrations. Three patients with prior adjuvant tamoxifen and aromatase inhibitor therapy showed stable disease for >6 months with a favorable safety profile. Full results will be presented at the meeting. Conclusions: STX64 is a potent, well tolerated STS inhibitor. The unexpected finding that androstenedione levels decreased indicates that peripheral formation, rather than secretion from the adrenal cortex, in the major source of this steroid which is the main substrate for the aromatase. The disease stabilization seen for 4 patients, all of whom had previously progressed on aromatase inhibitor therapy, suggests that STS inhibitors should have considerable therapeutic potential for the treatment of breast cancer.

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Updated cardiac safety results of dose-dense (DD) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) with trastuzumab (H) in HER2/neu overexpressed/amplified breast cancer (BCA)
Authors: Smith C. DangK. , Fornier M. , Sugarman S. , Troso-Sandoval T. , Lake D. , D’Andrea G. , Seidman A. , Sklarin N. , Norton L. , Hudis C.
Published: March 2020

582

Background:
DD q 2 weekly (w) AC → T is superior to conventionally scheduled (cs) AC → T and safe w/long follow-up (Hudis et al, SABCS 2005). With q 3 wk AC, adjuvant (adj) H is safe and effective (Romond et al and Perez et al, NEJM 2005). We therefore tested DD q 2 w AC → T + H × 1 year (y) as adj treatment (Rx) of patients (pts) with HER2/neu (+) BCA to determine cardiac safety. Based on the reported cardiac event (CE) rate of ≤ 4% in the randomized trials using cs chemotherapy (CRx) + H, we evaluated DD q 2 w AC → T + H with a 1° endpoint of cardiac safety defined as discontinuation (DC) of H due to 1) cardiac death or 2) congestive heart failure (CHF). The 2° endpoint is time to recurrence and overall survival.
Methods:
Pts with HER2/Neu IHC 3+ or FISH-amplified BCA were enrolled, regardless of tumor size or nodal status. Rx consisted of AC at 60/600 mg/m
2
× 4 → T at 175 mg/m
2
× 4 q 2 w w/pegfilgrastim 6 mg on d 2 + H × 1 y. Multi-gated radionuclide angiography scan (MUGA) is obtained at baseline and at months (mo) 2 (after AC × 4), 6 (after T × 4), 9, and 18. Pts w/baseline LVEF of ≥ 55% and w/o cardiac illnesses are eligible. Pts w/significant (sig) asymptomatic (asx) LVEF ↓ after DD AC based on mo 2 MUGA did not receive H, and pts w/sig asx LVEF ↓ during H had it DC’d. If the CE rate is > 4%, Rx is deemed not feasible.
Results:
From January 4, 2005 to November 1, 2005, 70 pts were enrolled. Median (med) age is 49 years (range, 27–72). Forty one of 70 pts (60%) had node (+) BC and 27/70 pts (40%) had (-) nodes. Med baseline LVEF is 68% (range, 55%-81%). As of January 9, 2005, all pts had mo 2 MUGA after DD AC and there is no sig LVEF ↓ and the med LVEF is 67% (range, 58%-79%). To date 39 pts had mo 6 MUGA w/med LVEF of 66% (range, 56%-75%) and one pt had a sig asx LVEF ↓ from baseline of 74% to 56%; H was DC’d. Twenty-three pts had mo 9 MUGA w/a med LVEF of 64% (range, 57%-69%). One patient had clinical CHF at mo 4 w/EF of 45% and improved sig w/cardiac medications. One had pneumonitis during radiation (RT). One had atrial fibrillation w/pericarditis after completion of RT.
Discussion:
DD AC → T + H appears to have an acceptable cardiac toxicity profile w/1/70 pts having a CE. Updated cardiac safety data will be presented.

Author Disclosure

Employment or Leadership
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Honoraria
Research Funding
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Genentech, Amgen

Genentech, Amgen
Genentech, Amgen
Influence of pregnancy on breast cancer tumor characteristics and mortality in Iowa women
Authors: Scott-Conner C. E. , Romitti P. A. , Lynch C. F. , Wilkinson N. , Lal G. , Zhou L. , Smith B. J.
Published: March 2020

584

Background: Hormonal factors such as pregnancy influence development and course of breast cancer. We identified women who became pregnant during the preclinical phase or shortly after diagnosis of breast cancer, compared them with similar women who had not been pregnant in that time period, and studied tumor characteristics and mortality. Methods: Birth and fetal death certificates were linked with Iowa Cancer Registry information for 10,624 women ≤50 years of age diagnosed with breast cancer as a first invasive primary between January 1, 1975 and December 31, 2002. Women who were pregnant two years before (n=160) or after diagnosis of breast cancer (n=53)and those who had not been pregnant (NP) (n=5008) were identified using probabilistic computer matching with manual review confirmation. Clinical, pathological and 10-year survival data were compared between these groups. Preliminary analysis revealed similarities between women who were pregnant before and after diagnosis. These were combined for analysis (P). Results: The study subjects distributed themselves across two SEER stages of disease: 1) localized, and 2) locally advanced or regional nodal disease (LABC). SEER stage (50% LABC vs. 39% LABC) and grade (75% high grade vs. 56% high grade) were higher in P than in NP cases. Ten-year survival for localized disease was 0.766 (95% CI 0.649–0.848) for P and 0.874 (95% CI 0.858–0.888) for NP (log rank test p= 0.0178). Ten-year survival for LABC was 0.520 (95% CI 0.373–0.649) for P and 0.629 (95% CI 0.601–0.655) for NP (log rank test p= 0.0234). Multivariate analysis ( table below) showed an adverse effect of pregnancy status on survival, independent of stage, grade, age or progesterone receptor (PR) status. Conclusions: Women who are pregnant within two years of diagnosis of breast cancer have higher grade, more locally-advanced tumors and experience a higher mortality than similar women who are never pregnant. Pregnancy persists as a significant adverse survival variable after adjustment for age, grade, stage, and PR status.

[Table: see text]

No significant financial relationships to disclose.
Should attribution be considered when interpreting adverse event data: A North Central Cancer Treatment Group (NCCTG) evaluation of a phase III placebo controlled trial
Authors: Hillman S. L. , Mandrekar S. J. , Bot B. M. , Perez E. A. , Kugler J. W. , Adjei A. A. , Buckner J. C. , Sargent D. J.
Published: March 2020

6006

Background: In March 1998, the Common Toxicity Criteria version 2.0 was implemented and introduced the collection and reporting of attribution of adverse events to study treatment. Collection and reporting of attribution adds time and cost to the clinical trial process, and its use while reporting adverse events (AE) in the literature has varied. We investigate whether attribution adds value to the interpretation of AE data. Methods: Patients on the placebo arm of trial 97–24–51 (CAI vs. Placebo) were chosen since the true relationship of the event to the study treatment is known (“unrelated”). Attribution was collected per CTCv2.0 and categorized as “not related” (not related or unlikely) and “related” (possible, probable, or definite). All reported AEs and the maximum severity for a given AE were evaluated. Patterns were evaluated using generalized estimating equations adjusting for multiple events per patient. Changes in attribution over time for the same event were computed. Results: 84 patients on the placebo arm experienced a total of 1013 AEs. 47% of AEs were reported as “related” with 36% reported as possibly related. Known CAI AEs were more likely to be reported as “related” (p = 0.005). Pulmonary AEs were more likely to be reported as “not related” (p = 0.0006). No patterns were observed by gender, age, PS, severity or treatment cycle of AE. When the same event was reported on the same patient in multiple cycles, the attribution category changed at least once 36% of the time with 25% changing from “related” to “unrelated” or vice versa. Conclusion: Almost 50% of events on a placebo arm of a phase III trial were reported as being attributed to study treatment and 25% of the time the same event was not consistently attributed. These data suggest that attribution is difficult to determine, unreliable, and thus its value in large phase III trials is questionable.

[Table: see text]

No significant financial relationships to disclose.
Altered fractionated radiotherapy is cost-effective in the treatment of locally advanced head and neck cancer: An economic analysis of Radiation Therapy Oncology Group (RTOG) 90–03
Authors: Konski A. A. , Bhargavan M. , Owen J. , Paulus R. , Cooper J. , Fu K. , Ang K. , Watkins-Bruner D.
Published: March 2020

6007

Background: RTOG 9003 compared altered fractionated radiotherapy (AIFX) to standard radiotherapy (SFX). Overall and disease-free survival was improved in the AIFX schedules but with increased toxicity. The specific aim of this study was to compare the cost-effectiveness of AIFX to SFX. Methods: Costs data included Medicare Part A and Part B costs from all providers—inpatient, outpatient, skilled nursing facility, home health, hospice, and physicians and other Part B providers were obtained from the Centers for Medicare & Medicaid Services (CMS) for patients treated on RTOG 9003 from 1992–1996. Claims were restricted to those with a diagnosis of head and neck cancer. We calculated 56-month expected discounted costs for each arm of the trial in 1996 dollars, with Kaplan-Meier sampling average estimates of survival probabilities for each month and mean monthly costs. Costs were discounted back to the time of entry onto the trial, using an annual discount rate of 3% and indexed to 1996 dollars using the Consumer Price Index. The analysis was performed from a payer’s perspective. Incremental cost-effective ratios were calculated comparing AIFX schedules to SFX. Results: Of the 1,130 patients entered, 1,073 patients were analyzable for outcomes and Medicare cost data and clinical outcomes were available for 130 patients. The expected mean 56-month cost and incremental cost-effectiveness ratios (ICER) compared to SFX are presented in the table . Sensitivity analysis and 95% confidence ellipses will be presented. Conclusions: Although more toxic altered fractionated radiotherapy schedules were found to be cost-effective using a willingness to pay of $50,000/life year in patients >65 years old. These results need to be confirmed in a cohort of younger patients.

[Table: see text]

No significant financial relationships to disclose.
Has demand outpaced supply for clinical trial participants?
Authors: Tam J. T. , Hauser R. , Gura D. , Paraghamian A. , Thomas H. , Lichtman S.
Published: March 2020

6016

Background: Current estimates are less than 5% of adult cancer patients participate in clinical trials. Initiatives to address barriers to accrual (such as age, physician bias, etc) are ongoing. However, with more drugs in the pipeline and more clinical trials being conducted, demand for trial participants may be outpacing the current “supply”. Methods: The ClinicalTrials.gov database, maintained by National Institutes of Health was selected for review on the basis that it is proposed to be the mandated repository for clinical trials information. Over a 2 month period, the database was mined for all active, US recruiting, phase I, I/II, II, and III trials in breast, lung, and prostate cancers. Results: There were 290 breast, 212 lung, and 177 prostate cancer trials with the prespecified criteria. The number of patients needed to complete these trials is 151,311 (breast), 33,498 (lung), and 53,181 (prostate). These represent 19.4% to 71.6% of the American Cancer Society incidence estimates of the studied tumors. NCI, industry, and academia sponsored, either solely or in collaborations, 42.1%, 26.5%, and 45.6% of trials, respectively. Majority of studies were phase II (51%), with 11.5% phase I, and 15.6% phase III. Remaining studies were either combined phase I/II studies or not specified. Significant percentage of trials involved pts with advanced/metastatic disease (54% breast, 51.4% lung, and 44.6% prostate). Conclusions: Although many studies have anticipated enrollment period over several years, the number of trial participants needed to complete these studies is quite daunting. Our results are likely under-estimates as not all studies currently enrolling patients may be included in this registry, and not all studies in the database specified the recruitment goal. Although not all trial participants are drawn from the incidence numbers, it is clear that given the current trial participation rate, demand has outpaced the supply. The medical community has the ethical responsibility to ensure sufficient patient enrollment for clinical trials. In addition to addressing accrual barriers, the authors encourage the establishment of a task force including academia, government, and industry to systematically evaluate and prioritize the types of trials being conducted.

No significant financial relationships to disclose.
21-gene RT-PCR assay in lymph node negative (LN-), estrogen receptor positive (ER+) breast cancer: An economic analysis including prognostic and predictive information
Authors: Cosler L. E. , Kuderer N. M. , Hornberger J. , Lyman G. H.
Published: March 2020

6024

Background: The prognostic accuracy of a 21-gene RT-PCR assay has undergone validation in 668 evaluable LN-, ER+ early stage breast cancer patients receiving tamoxifen on NSABP B-14 (Paik, NEJM 2004) and its economic evaluation (Hornberger, Am J Man Care 2005). Assay predictive accuracy for response to chemotherapy or tamoxifen has also undergone recent validation in 651 patients on NSABP B-20 and 645 patients on NSABP B-14 (Paik, SABCS 2004). Methods: Based on the model recurrence score (RS), women with LN−, ER+ breast cancer with and without adjuvant chemotherapy (C) or tamoxifen (T) were classified as high (RS ≥31), intermediate (RS 18–30) or low (RS <18) risk of distant recurrence at 10 years. Incremental costs ($), life-years (LYs), quality-adjusted LYs (QALYs) and cost-effectiveness (C/E; cost per LY gained) were estimated for: RS-guided treatment (RSGT) with T for low and intermediate risk patients and C+T for high-risk patients, compared to either T alone or C+T for all patients. Results: Under base case assumptions, no significant difference in life expectancy at 10 years is estimated between the RSGT and C+T strategies whereas RSGT is associated with a gain in individual life expectancy of 2.7 LYs compared to T alone. RSGT is estimated to yield a net cost savings of $4,502 compared to C+T with an incremental C/E of $1,059 per LY saved compared to T alone. At a utility of 90% associated with adjuvant chemotherapy, RSGT is associated with a gain in individual QALYs of 1.82 compared to T alone at a cost utility of $1,573/QALY and a gain in 3.21 QALYs compared to C+T. RSGT is associated with lower expected cost than C+T for total chemotherapy costs above $3,998. The gain in LYs with RSGT compared to T alone increases with healthy age-specific life expectancy (years) while the cost per LY gained decreases. Conclusions: Treatment based on the RSGT compared to T alone is associated with acceptable C/E ratios and substantially lower toxicity and cost compared to C+T.

[Table: see text]

[Table: see text]
Timely access to care for colorectal cancer (CRC): A description and analysis of associated factors
Authors: Porter G. A. , Inglis K. M. , Murdoch J. L. , Veugelers P. J.
Published: March 2020

6028

Background: There are multiple points in the presentation, diagnosis and treatment of CRC where access to physicians and/or medical services may affect the timeliness of appropriate care. A single interval, such as time from diagnosis to surgery, may incompletely reflect the timeliness of care in CRC. We describe the various components of access to care for resectable CRC, and identify factors associated with variation in such components. Methods: From 02/15/2002 to 02/15/2004, all patients undergoing surgery for primary CRC within a single health district were enrolled in a prospective consecutive cohort study. A comprehensive, standardized method of ascertaining specific time intervals, including a patient interview, was used to quantify the timeliness of presentation, diagnosis and surgery. Differences in these time intervals according to demographic and clinical factors were examined using multivariate linear regression. Results: Among the 455 patients in the study cohort, the median time intervals (interquartile range) for the various components of access to care were as follows: symptoms to first physician visit - 36 days (12–79); first physician visit to diagnosis - 51 days (15–127); diagnosis to surgery - 23 days (10–39). On multivariate analysis, the interval from initial symptoms to first physician visit was 96% longer for patients < 50 years (p = 0.02) and 144% longer for rectal lesions (p < 0.001). The interval from first physician visit to diagnosis was 190% longer for patients < 50 years (p < 0.001), and was positively correlated with gross household income (p = 0.02). The interval from diagnosis to surgery was 33% longer in females (p = 0.003) and 70% longer for rectal lesions (p < 0.001). None of these intervals were found to vary significantly according to geographic residence, education level, body mass index, number of years with family doctor, smoking history, or previous use of CRC screening. Conclusions: The timeliness of access to care for CRC involves several defined components; the longest interval is from initial physician visit to diagnosis. Although associated factors vary somewhat according to the specific interval, interventions aimed at improving the timeliness of access to care in CRC should address younger patients and those with rectal cancer.

No significant financial relationships to disclose.