Barry Don Brooks

Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2 study.

BACKGROUND Previous results suggest that docetaxel plus cyclophosphamide improves disease-free survival (DFS) and overall survival compared with doxorubicin plus cyclophosphamide in early stage breast cancer. We assessed the addition of 1 year of trastuzumab to a non-anthracycline regimen, docetaxel plus cyclophosphamide, in patients with HER2-amplified early stage breast cancer and examined whether this regimen was equally effective in patients with TOP2A-amplified and TOP2A-non-amplified disease. METHODS This was an open-label, single-group, phase 2 study. Eligible patients were aged 18-75 years; had Eastern Cooperative Oncology Group performance status of 1 or less; HER2-amplified early stage breast cancer; operable, histologically confirmed, invasive carcinoma of the breast; adequate tumour specimen available for FISH analysis of TOP2A status; and adequate haematological, renal, hepatic, and cardiac function. Patients received four 21-day cycles of intravenous docetaxel 75 mg/m(2), plus intravenous cyclophosphamide 600 mg/m(2), plus intravenous trastuzumab 4 mg/kg (loading dose) on day 1 and 2 mg/kg on days 1, 8, and 15 during chemotherapy, followed by trastuzumab 6 mg/kg every three weeks for the remainder of 1 year. The primary endpoint was 2-year DFS in TOP2A-amplified and TOP2A-non-amplified patients; the primary analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00493649. FINDINGS 493 patients were enrolled between June 15, 2007, and Aug 5, 2009. After a median follow-up of 36·1 months (IQR 35·5-36·7), 2-year DFS was 97·8% (95% CI 94·2-99·2) and 2-year overall survival was 99·5% (95% CI 96·2-99·9) for the 190 patients with TOP2A-amplified disease; 2-year DFS was 97·9% (95% CI 94·9-99·1) and 2-year overall survival was 98·8% (95% CI 96·2-99·6) for the 248 patients with TOP2A-non-amplified disease; 55 patients were not assessable for TOP2A status. In the 486 patients who received at least one dose of study drug, the most common adverse events of any grade were fatigue (284 patients, 58·4%), neutropenia (250, 51·4%), and nausea (217, 44·7%). The most common grade 3-4 toxic effects were neutropenia (229, 47·1%), febrile neutropenia (30, 6·2%), fatigue (21, 4·3%), and diarrhoea (16, 3·3%). Cardiac dysfunction occurred in 29 (6·0%) patients (12 [2·5%] grade 1, 15 [3·1%] grade 2, and two [0·4%] grade 3). 23 patients had at least one study-related serious adverse event. 16 patients stopped trastuzumab because of cardiac dysfunction. INTERPRETATION A short, four-cycle regimen of docetaxel and cyclophosphamide combined with trastuzumab could be an option for adjuvant treatment of women with lower risk HER2-amplified early breast cancer, irrespective of TOP2A status. FUNDING Sanofi.

Benchmarks for Value in Cancer Care: An Analysis of a Large Commercial Population

PURPOSE Cancer costs are increasing at an unprecedented rate. Key cost drivers include chemotherapy, hospital admissions/emergency room visits, and aggressive end-of-life care. We sought to evaluate these costs in a commercial payer population in collaboration with consultants from Milliman. PATIENTS AND METHODS We used a retrospective analysis of Medstat 2007 to evaluate chemotherapy costs and use. Included patients had a cancer diagnosis; received chemotherapy during the evaluation period; had at least 1 day of coverage between January 1 and December 31, 2007 (medical and prescription coverage); was younger than age 70, and had active employment or was the spouse of an active employee. Costs are allowed amounts and are trended until 2009. Admission rates and emergency room visits are reported. Hospice use and chemotherapy during the last 14 and 30 days of life were also evaluated. RESULTS In this commercial population of 14 million patients, 0.68% had claims for a cancer diagnosis; approximately 22% of those received chemotherapy during the study time period. Patients with cancer receiving chemotherapy averaged

Bridging to survivorship in breast cancer: How BMI weighs in.

111,000 per year in total medical and pharmacy costs. The average hospitalization rate for any reason was 1 admission/yr. Approximately 40% (or 0.4 admits/year) were identified as being chemotherapy related. Of the 3.5% of patients who died in the hospital, 51% received chemotherapy within 30 days of death. CONCLUSION Understanding the costs of cancer care offers opportunities to formulate a strategic plan to control cancer costs and maintain quality care. Comprehensive cancer solutions to address the full spectrum of care will facilitate improved quality and patient outcomes.

Five-year results of a phase II trial of preoperative 5-fluorouracil, epirubicin, cyclophosphamide followed by docetaxel with capecitabine (wTX) (with trastuzumab in HER2-positive patients) for patients with stage II or III breast cancer

32 Background: Obesity and depression complicate survivorship in early stage breast cancer (BC) by having a direct impact on survival and morbidity among patients (pts) who complete treatment (tx). The prevalence of obesity after BC tx in the community and concordance with BC tx type is poorly described, but important as we characterize risks of tx and optimize goals for survivorship care planning. METHODS We queried the electronic health record (EHR), iKnowMed, from a large network of community oncology practices for pts diagnosed with stage I-III BC from 2007-2010 with at least 5 office visits and follow up through 11-2012 for our retrospective study. We excluded pts who developed metastatic disease or died. We stratified pts by chemotherapy (CT) utilization (yes/no), hormone receptor (HR) status, age, and documented body mass index (BMI) at first office visit and annually. We evaluated changes in BMI characteristics by tx cohort. RESULTS We identified 8,506 pts with a documented BMI at first office visit and 1, 2, and 3 years (yrs) thereafter. 4,369 (51% of the total) pts received adjuvant CT and 4,137 (49%) did not. 6,897 pts (81%) were HR positive. Baseline BMI between tx cohorts were similar, though the prevalence of overweight (31%) and overweight or obese (68%) is high. Percent change of BMI at 3 yrs varied significantly between T cohorts (p<0.01) with greater rise among the cohorts who received CT in comparison to those who did not. Pts receiving CT were 46% more likely to have a 5 point or more increase in BMI at 3 yrs compared to pts that did not receive CT (OR 1.46, CI[1.08-1.96]). A stronger association for BMI increase of at least 0.5 points at 3 yrs (OR 1.53, CI [1.4-1.7]) was also observed amongst pts who received CT compared to those that did not. HR positive pts were less likely than HR negative or unknown pts to increase their BMI by at least 0.5 points (OR 0.84, p<0.01), but there was no difference at detecting a difference of 5 points in BMI (OR 0.88, p=0.49). CONCLUSIONS With 3 yrs of follow up, overweight and obese status is remarkably common among BC survivors in the community and appears to be more prevalent after CT tx. Determinants of obesity require further study and point to necessary intervention to improve the health of early stage BC pts.

Pathways impact on chemotherapy administration before death.

We aimed to increase pathologic complete response (pCR) in patients with invasive breast cancer by adding preoperative capecitabine to docetaxel following 5‐fluorouracil, epirubicin, cyclophosphamide (FEC) (with trastuzumab for patients with HER2‐positive disease) and to evaluate 5‐year disease‐free survival (DFS) associated with this preoperative regimen. Chemotherapy included four cycles of FEC100 (5‐fluorouracil 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2 IV on Day 1 every 21 days) followed by 4 21‐day cycles of docetaxel (35 mg/m2 days 1 and 8) concurrently with capecitabine (825 mg/m2 orally twice daily for 14 days followed by 7 days off) (wTX). For HER2‐positive patients, treatment was modified by decreasing epirubicin to 75 mg/m2 and adding trastuzumab (H) in standard doses (FEC75‐H →wTX‐H). The study objective was to achieve a pCR rate in the breast and axillary lymph nodes of 37% in patients with HER2‐negative breast cancer and of 67% in patients with HER2‐positive breast cancer treated with preoperative trastuzumab. A total of 186 patients were enrolled on study. In an intent‐to‐treat analysis, the pCR rate was 31% (37/118, 95% CI: 24–40%) in the HER2‐negative patients, 24% (15/62, 95% CI: 14–37%) in ER‐positive/HER2‐negative patients, 39% (22/56, 95% CI: 27–53%) in the ER‐negative/HER2‐negative patients, and 46% (29/63, 95% CI: 34–48%) in the HER2‐positive patients. The pCR rate in the 40 trastuzumab‐treated patients was 53% (21/40, 95% CI: 38–67%). Grade 3 and 4 adverse events included neutropenia, leukopenia, diarrhea, and hand‐foot skin reactions. One trastuzumab‐treated patient developed grade 3 cardiotoxicity, and 4 others experienced grade 1–2 decrements in left ventricular function; all five patients’ cardiac function returned to their baseline upon completion of trastuzumab. At 5 years, disease‐free survival was 70% in the HER2‐negative population (78% in ER‐positive/HER2‐negative and 62% in the ER‐negative/HER2‐negative patients) and 80% in the HER2‐positive patients (87% in the trastuzumab‐treated HER2‐positive patients). At 5 years, overall survival was 80% in the HER2‐negative population (88% in ER‐positive/HER2‐negative and 71% in the ER‐negative/HER2‐negative patients) and 86% in the HER2‐positive patients (94.5% in the trastuzumab‐treated HER2‐positive patients). FEC100 (FEC75 with trastuzumab) followed by weekly docetaxel plus capecitabine, with or without trastuzumab is a safe, effective preoperative cytotoxic regimen. However, the addition of capecitabine to docetaxel following FEC, with or without trastuzumab, did not increase pCR rates nor 5‐year DFS over the rates that have been reported with standard preoperative doxorubicin/cyclophosphamide (AC) followed by paclitaxel, with or without trastuzumab. Therefore, the use of capecitabine as part of preoperative chemotherapy is not recommended.

Bridging to survivorship in breast cancer: Learning how treatment impacts mental health among early-stage breast cancer survivors.

86 Background: Continuing IV chemotherapy (chemo) in patients (pts) with advanced cancer near death does not extend survival or improve quality, but does increase costs. Pathways (PW) programs have compared treatment (tx) costs but have not evaluated the impact on chemo given near death. The primary goal is to evaluate IV chemo administered in the last 14 and 30 days of life in pts treated On vs. Off-PW. METHODS Eligibility: in US Oncologys (USO) iKnowMed (iKM) EHR 7/1/09-6/30/12; diagnosis (dx) of breast, colon, NSCLC, SCLC or pancreas cancer; >/=3 visits to a USO clinic; assessed for Level I PW compliance in the last 12 mths of life; and a date of death. IV chemo received in the last year of life was assessed. Pts were defined On-PW if all tx was On-PW or if pts did not receive IV chemo 12 mths before death (best supportive care). Pts were Off-PW if any tx received was Off-PW. PW-status, age, sex, dx, and last line of therapy (LOT) received were assessed. Multivariate logistic regression analysis was used to assess if PW status predicted likelihood of chemo within 14 and 30 days of death. RESULTS 12,551 pts met inclusion criteria. PW status was independently associated with chemo 14 and 30 days before death. Pts treated Off-PW had 2-fold higher odds of receiving IV chemo within 14, 30 days of death vs. pts treated On-PW (OR: 2; 95% CI: 1.8-2.3, OR: 2.2, 95% CI: 2-2.4), see Table. Findings were similar for each dx. Tx for pts On-PW vs Off-PW showed lower mean last LOT overall (1 vs. 2) and by dx. CONCLUSIONS Pts On-PW were less likely to receive IV chemo within 14 and 30 days of death and had fewer LOT. This suggests adherence to Level I PWs is associated with improved quality metrics. [Table: see text].

Policy prescriptions to fix our ailing delivery system

33 Background: Depression (D) and anxiety (A) complicate survivorship in breast cancer (BC) patients (pts). The prevalence of D and A after BC treatment (Tx) in the community and concordance with BC Tx type is poorly described, but vitally important to characterize risks of Tx and optimize support for BC pts and goals for survivorship care planning. METHODS We queried the electronic health record (EHR), iKnowMed, from a a large network of community oncology practices for pts treated with stage I-III breast cancer from 2007-2010 with at least 5 visits and follow up through 2012 for our retrospective study. We excluded pts who developed metastatic disease or died. We stratified pts by chemotherapy (CT) utilization (yes/no),hormone receptor (HR) status, age, and documented body mass index (BMI) at diagnosis, and post diagnosis development of D (y/n), A (y/n) or utilization of venlafaxine (E) like antidepressants (Ads), non-E like Ads or anti-A medications within the study period. Time to onset of A or D was analyzed using Cox proportional hazard methodology. RESULTS We identified 8,506 patients with a documented BMI at 1, 2, and 3 years (yrs) post diagnosis. 4,369 (51%) of patients received adjuvant CT and 4,137 (49%) did not. Baseline characteristics were similar between tx groups, and active D or A was low at the time of dx, but as a whole rose to 41% during the study period. Pts with pre-existing D or A at the time of diagnosis were excluded. CT increases the risk of D or A (HR: 1.23, CI: 1.15-1.33). HR+ status also increases the risk of D or A (HR: 1.21, CI:1.11-1.32). Age conveyed a small diminished risk of D or A (HR: 0.98, CI: 0.98-0.99) while baseline BMI conveyed a small increased risk (HR: 1.02, CI 1.01-1.3). When excluding E like compounds that are often used to treat hot flashes in BC pts, CT was still found to have an increased risk of D or A (HR: 1.28, CI: 1.18-1.39), and HR+ was still associated with higher risk of D or A as well (HR: 1.11, CI: 1.01-1.22). CONCLUSIONS Mental health disorders such as D and A are common among BC survivors, and more prevalent among BC survivors who received CT and have HR+ disease. This warrants further investigation on how to evaluate and support the mental health needs of BC survivors.

Risk of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after adjuvant chemotherapy (CT) for early breast cancer (BC) in the community setting.

We are proud to represent the principal contributors to the world’s most effective and successful cancer care delivery system: oncologists and allied medical professionals who care for Americans who are battling cancer in community clinics throughout the United States. The success of these women and men on the frontlines is clear: after nearly 100 years of increasing cancer death rates in the United States, cancer mortality has fallen 20% from its 1991 peak. Cancer patients from around the world seek care here because Americans enjoy the best cancer survival rates in the world. Yet we still have not realized our potential to eradicate cancer. The American Cancer Society has estimated that 1.6 million Americans were diagnosed with cancer in 2013 and that more than 580,000 will die of the disease during that time. As has been the case for decades, only cardiovascular disease will kill more Americans. To win this important fight, we need a stable and sustainable cancer care delivery system. That’s where Medicare and community-based cancer clinics are so important. Community cancer clinics provide patients with convenient, comprehensive, state-of-theart cancer treatment facilities close to home. And more than 60% of cancer patients rely on Medicare to pay their medical bills. As the single largest payer of cancer care, Medicare has inordinate influence on the health care delivery system and often guides how private insurers pay for cancer care. As a result, Medicare policies have an impact on cancer care for all Americans, not just those who are covered by Medicare.

Low Proliferative Rate of Invasive Node-Negative Breast Cancer Predicts for a Favorable Outcome: A Prospective Evaluation of 669 Patients

62 Background: AML and MDS complicate adjuvant CT in BC. Incidence Rates of MDS/AML with pegfilgrastim (PGCSF) use and newer adjuvant regimens in large patient (pt) populations are not widely characterized. METHODS We queried the iKnowMed electronic health record from a large network of community oncology practices for pts diagnosed with stage I-III BC from 2007-2010 with at least 5 visits and follow up (f/u) through 2/2012 for our retrospective study. We stratified pts by adjuvant CT utilization (yes/no), regimen type, PGCSF use, age, and characterized the incidence of MDS/AML captured as a secondary diagnosis. Fishers exact test and student t-test were used for categorical and continuous variables, respectively; Cox proportional hazard model was used to estimate hazard ratios (HR) for risk factors associated with AML/MDS development. RESULTS We identified 20,900 pts with median f/u of 2.8 years (yrs) (1.2-5.2 yrs). 11,295 pts (54%) received CT, 41% of whom received anthracyclines (A); 9,605 (46%) did not receive CT. Median age of diagnosis in the CT and non-CT arms was 54 and 64 yrs, respectively (p < 0.01). Among the CT-treated group, 12 pts or 0.11% (95% CI, 0.06-0.19) developed AML/MDS with median time to onset of 1.8 yrs and median f/u of 2.7 yrs. Of these 12 pts, 8 received A and 11 PGCSF. In the non-CT group, 18 pts or 0.19% (95% CI, 0.11-0.30) developed AML/MDS with median time to onset of 2.2 yrs and median f/u of 3 yrs (p=NS). Multivariate analysis of pts who received CT revealed pts ≥70 vs. <70 yrs and those that received A-containing vs. alternate regimens were more likely to develop AML/MDS. CONCLUSIONS Adjuvant CT did not increase risk of AML/MDS compared with those that did not receive CT. However, our findings confirm that increased age and A-containing CT regimens are associated with increased risk. The low event rate in our study population may be due to short f/u, younger age in the CT treated arm, and high utilization of non-A CT. Association with PGCSF warrants further evaluation. [Table: see text].