NSABP Protocol Research Articles

TNM stage at diagnosis is more predictive of prognosis than pathological complete response in young breast cancer treated with neoadjuvant chemotherapy.

TNM stage at diagnosis is more predictive of prognosis than pathological complete response in young breast cancer treated with neoadjuvant chemotherapy.

Long-Term Follow-Up of Cardiac Function and Quality of Life for Patients in NSABP Protocol B-31/NRG Oncology: A Randomized Trial Comparing the Safety and Efficacy of Doxorubicin and Cyclophosphamide (AC) Followed by Paclitaxel With AC Followed by Paclitaxel and Trastuzumab in Patients With Node-Positive Breast Cancer With Tumors Overexpressing Human Epidermal Growth Factor Receptor 2

Purpose Early cardiac toxicity is a risk associated with adjuvant chemotherapy plus trastuzumab. However, objective measures of cardiac function and health-related quality of life are lacking in long-term follow-up of patients who remain cancer free after completion of adjuvant treatment. Patients and Methods Patients in NSABP Protocol B-31 received anthracycline and taxane chemotherapy with or without trastuzumab for adjuvant treatment of node-positive, human epidermal growth factor receptor 2-positive early-stage breast cancer. A long-term follow-up assessment was undertaken for patients who were alive and disease free, which included measurement of left ventricular ejection fraction by multigated acquisition scan along with patient-reported outcomes using the Duke Activity Status Index (DASI), the Medical Outcomes Study questionnaire, and a review of current medications and comorbid conditions. Results At a median follow-up of 8.8 years among eligible participants, five (4.5%) of 110 in the control group and 10 (3.4%) of 297 in the trastuzumab group had a > 10% decline in left ventricular ejection fraction from baseline to a value < 50%. Lower DASI scores correlated with age and use of medications for hypertension, cardiac conditions, diabetes, and hyperlipidemia, but not with whether patients had received trastuzumab. Conclusion In patients without underlying cardiac disease at baseline, the addition of trastuzumab to adjuvant anthracycline and taxane-based chemotherapy does not result in long-term worsening of cardiac function, cardiac symptoms, or health-related quality of life. The DASI questionnaire may provide a simple and useful tool for monitoring patient-reported changes that reflect cardiac function.

Adjuvant or neoadjuvant chemotherapy in early stage triple negative breast cancer (TNBC) comparison of outcomes in both BRCA positive and BRCA negative patients.

576 Background: NSABP Protocol B-18 was a randomized trial which found no statistically significant difference in overall survival (OS) in patients (pts) receiving neoadjuvant (NAC) or adjuvant chemotherapy (AC), however outcome was not analyzed by breast cancer subtypes. Subsequent retrospective studies in TNBC reported conflicting results with an initial study showing a significant OS benefit with AC and later studies showing a trend toward improved survival with NAC. Furthermore, studies have not included a significant number of pts with BRCA mutations. This study aims to analyze outcomes of AC versus NAC in pts with early stage TNBC with and without BRCA germline mutations. Methods: Pts with stage I or II TNBC who had BRCA testing were identified from a prospective cohort study of 4027 pts at MD Anderson Cancer Center. Clinical, demographic, genetic test results, chemotherapy, recurrence, survival data were collected. OS and disease free survival (DFS) were estimated using the Kaplan-Meier method, and log-rank tests were used to compare groups. Results: 305 pts with stage I and II TNBC who met eligibility criteria were included in the analysis. Pts who received both NAC and AC or no chemotherapy were excluded. 181 received AC (59.3%) and 124 received NAC (40.7%). The majority of the pts were less than 50 years old (236, 77.4%) and white (194, 63.8%). 134 were BRCA positive (44.1%) and 170 were BRCA negative (55.9%). The majority of the pts received an anthracycline and taxane regimen (223, 73.1%). There was no significant association between OS or DFS and treatment with NAC versus AC in the overall cohort. Furthermore, there were no significant differences between pt subgroups (NAC BRCA positive, NAC BRCA negative, AC BRCA positive, and AC BRCA negative) with respect to either OS or DFS. Conclusions: NAC versus AC with standard anthracycline and taxane containing regimens results in similar DFS and OS survival amongst pts with stage I and II TNBC regardless of BRCA status. Further studies are needed to evaluate whether similar results are observed with newer agents, such as platinums, PARP inhibitors and other targeted agents.

Quality of life and symptoms in long-term survivors of colorectal cancer: results from NSABP protocol LTS-01.

Little is known about health-related quality of life (HRQL) in long-term survivors (LTS) of colorectal cancer (CRC). Long-term CRC survivors (≥5years) treated in previous National Surgical Adjuvant Breast and Bowel Project trials were recruited from 60 sites. After obtaining consent, a telephone survey was administered, which included HRQL instruments to measure physical health (Instrumental Activities of Daily Living [IADL], SF-12 Physical Component Scale [PCS], SF-36 Vitality Scale), mental health (SF-12 Mental Component Scale [MCS], Life Orientation Test, and Impact of Cancer), and clinical symptoms (Fatigue Symptom Inventory [FSI], European Organization for Research and Treatment of Cancer Colorectal Module [EORTC-CR38], and Brief Pain Inventory). A multivariable model identified predictors of overall quality of life (global health rating). Participants (N=708) had significantly higher HRQL compared with age group-matched non-cancer controls with higher mean scores on SF-12 PCS (49.5 vs. 43.7, p=<0.05), MCS (55.6 vs. 52.1, p=<0.05), and SF-36 Vitality Scale (67.1 vs. 59.9, p=<0.05). Multivariable modeling has demonstrated that better overall physical and mental health (PCS and MCS), positive body image (EORTC-CR38 scale), and less fatigue (FSI), were strongly associated with overall quality of life as measured by the global health rating. Interestingly, ability to perform IADLs, experience of cancer, gastrointestinal complaints, and pain, were not important predictors. In long-term CRC survivors, overall physical and mental health was excellent compared with general population. Other disease-related symptoms did not detract from good overall health. LTS of CRC within the setting of a clinical trial have higher HRQL than the general population, and treatment regimens do not appear to be associated with any significant late effects on quality of life. NSABP LTS-01: NCT00410579.

Evaluation of lapatinib as a component of neoadjuvant therapy for HER2+ operable breast cancer: 5-year outcomes of NSABP protocol B-41.

501Background: The primary aim of this randomized trial of neoadjuvant therapy in operable, HER2-positive breast cancer (BC) was to determine the effect on pathologic complete response (pCR) rates of substituting lapatinib (L) for trastuzumab (T) in combination with weekly paclitaxel (WP) following AC as well as adding L to T with WP following AC. Previously reported results showed pCR breast 52.5% for AC→WP+T, 53.2% for AC→WP+L, and 62% for AC→WP+TL. Planned secondary endpoints included 5-year recurrence-free interval (RFI) and overall survival (OS) and are reported here. Methods: All patients received standard AC q3wks x 4 cycles followed by WP (80 mg/m2) on days 1, 8, and 15 q28 days x 4 cycles. Concurrently with WP, patients received either T (4 mg/kg load, then 2 mg/kg) weekly until surgery, L (1250 mg) daily until surgery, or weekly T plus L (750 mg) daily until surgery. Following surgery, all patients received T to complete 52 wks of HER2-targeted therapy. 529 pts were randomized and 522 had follow...

Abstract S6-04: Patient-reported outcome (PRO) results, NRG Oncology/NSABP B-35: A clinical trial of anastrozole (A) vs tamoxifen (tam) in postmenopausal patients with DCIS undergoing lumpectomy plus radiotherapy

Abstract Background The clinical results of NSABP B-35, phase III trial comparing 1 mg/day A to 20 mg/day tam, each given for 5 years, were reported at ASCO 2015. B-35 demonstrated a statistically significant benefit in breast cancer free interval for women assigned to A, primarily in women &amp;lt;60 years. A secondary endpoint of B-35 was quality of life (QOL) and symptom (SX) outcomes in the two treatment groups. The primary hypotheses of the PRO study were that there would be no differences in QOL between the two treatments, and that patients receiving A would report higher rates of hot flashes compared to patients receiving tam. Other SX comparisons were secondary endpoints. Methods QOL and SX were assessed at baseline (prior to randomization), and every 6 months thereafter for 5 years of treatment and in the following 12 months. QOL was measured with the SF-12 Physical Component Summary (PCS) and Mental Component Summary (MCS). SX were measured with selected scales from the BCPT symptom-checklist, and other standardized instruments. Stratification was by age (&amp;lt;60 v ≥60) as in the main trial. Study hypotheses and endpoints were examined by comparing PROs in the two treatment arms using a mixed model for repeated measures analysis with adjustment for the baseline scores, time point and age category, using an intention-to-treat principle and including only patients who completed the baseline and at least one follow-up questionnaire. Patients with protocol events were censored. Only data through 60 months are reported here. The accrual goal for the sub-study was 1,150 consecutive patients. Results Between January 6, 2003 and June 15, 2006, a total of 3,104 patients were entered and randomly assigned to NSABP Protocol B-35. Accrual to the PRO study of B-35 closed on December 28, 2004, at which time 1,275 patients were entered, with 1,193 patients included in this analysis. There were no medical or demographic differences between patients assigned to A or tam in the PRO sub-study, and they reflected the characteristics of the parent trial. Adherence to data collection across the 60 months was 87%. There were no significant differences in QOL outcomes by treatment for the PCS (p=0.16) or the MCS (p=0.38). SX subscales: hot flash scale was greater in tam group and this difference varied over time (p=0.001); musculoskeletal pain was significantly greater in A group for time points 6-24 months (all p&amp;lt;.001); vaginal problems were greater in A group (p=0.03). Hot flash and vaginal problems were significantly worse in women &amp;lt;60 years. Additional SX outcomes (depression, fatigue, sexual function) will be reported at presentation. Conclusion In this large, double-blind, placebo-controlled trial comparing A to tam in patients with DCIS, there was no significant difference in QOL between the two treatments. However, there were important treatment differences in SX outcomes, which should be considered as part of treatment decision-making discussions, along with the clinical breast cancer outcome results. Support: CA-180868, 180822, 189867, 196067, 114732; AstraZeneca Pharmaceuticals LP. Citation Format: Ganz PA, Cecchini RS, Julian TB, Margolese RG, Costantino JP, Vallow LA, Albain KS, Whitworth PW, Cianfrocca ME, Brufsky A, Gross HM, Soori GS, Hopkins JO, Fehrenbacher L, Sturtz K, Wozniak TF, Seay TE, Mamounas EP, Wolmark N. Patient-reported outcome (PRO) results, NRG Oncology/NSABP B-35: A clinical trial of anastrozole (A) vs tamoxifen (tam) in postmenopausal patients with DCIS undergoing lumpectomy plus radiotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S6-04.

Abstract PD2-1: The effect on overall and disease-free survival (OS &amp; DFS) by adding bevacizumab and/or antimetabolites to standard neoadjuvant chemotherapy: NSABP Protocol B-40

Abstract Purpose The NSABP B-40 study was designed to determine whether the addition of capecitabine (X) or gemcitabine (G) to neoadjuvant docetaxel (T) followed by AC increased pathologic complete response (pCR) rates and improved outcomes of women with operable, HER2-negative breast cancer. In addition, B-40 was to determine whether the addition of neoadjuvant plus adjuvant bevacizumab (Bev) to T-based regimens followed by AC would increase pCR and improve outcomes. The pCR results and toxicities have been reported previously. The DFS and OS results are reported here for the first time. Methods Patients (Pts) received one of three T-based regimens for 4 cycles: T 100 mg/m2 day 1; T 75 mg/m2 day 1 and X 825 mg/m2 BID days 1-14; or T 75 mg/m2 day 1 and G 1000 mg/m2 days 1 and 8. Pts then received preoperative AC x 4 cycles. Pts randomly assigned to the Bev groups received Bev at 15mg/kg, q3wks x 6 with the first 6 courses of neoadjuvant chemotherapy and were to resume Bev post-operatively for 10 doses. 1,206 pts were assigned and 1,163 of them were clinically eligible and had follow-up. The cutoff date for data presented here was March 31, 2014. The median follow-up was 4.7 years. Results Neither X nor G added to neoadjuvant chemotherapy increased DFS or OS. 50% of Bev pts for whom treatment data were available (577) completed 10 doses of post-op Bev; 26% did not start Bev post-op. Addition of Bev significantly increased OS (HR=0.70, p=0.01) and marginally increased DFS (HR=0.81, p=0.06). The effect of Bev was most notable in women with hormone receptor positive (HR+) breast cancers (DFS HR=0.71, p=0.04; OS HR=0.63, p=0.03). Conclusions Addition of G or X to neoadjuvant T + AC had no significant impact on DFS or OS. Bev added to neoadjuvant chemotherapy and continued post-operatively marginally increased DFS in the overall cohort, with a significant increase in DFS in the HR+ subset. The addition of bevacizumab significantly improved OS for women with operable HER-2-negative breast cancer. In agreement with previously reported results for pCR, the improvement in DFS and OS was seen preferentially in women with HR+ breast cancers. Support NCI PHS grants U10-CA-37377, -69974, -12027, -69651, -44066, and -44066-26, Genentech Inc, Roche Laboratories Inc, Eli Lilly, and Precision Therapeutics, Inc. Citation Format: Harry D Bear, Gong Tang, Priya Rastogi, Charles E Geyer, Qing Liu, André Robidoux, James N Atkins, Luis Baez-Diaz, Adam M Brufsky, Rita S Mehta, Louis Fehrenbacher, James A Young, Francis M Senecal, Rakesh Gaur, Richard G Margolese, Paul T Adams, Howard M Gross, Joseph P Costantino, Soonmyung Paik, Sandra M Swain, Eleftherios P Mamounas, Norman Wolmark. The effect on overall and disease-free survival (OS &amp; DFS) by adding bevacizumab and/or antimetabolites to standard neoadjuvant chemotherapy: NSABP Protocol B-40 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD2-1.

Final results from NSABP protocol R-04: Neoadjuvant chemoradiation (RT) comparing continuous infusion (CIV) 5-FU with capecitabine (Cape) with or without oxaliplatin (Ox) in patients with stage II and III rectal cancer.

3603 Background: The two primary aims of NSABP R-04 were 1) Can the oral fluoropyrimidine, Cape be substituted for the standard of care in the curative setting of Stage II & III rectal cancer namely, CIV 5-FU, during neoadjuvant RT; and 2) Can the addition of Ox enhance the activity of fluoropyrimidine sensitized RT? Methods: Pts with clinical stage II or III rectal cancer undergoing preoperative RT (4,500cGy in 25 fractions over 5 wks + boost of 540cGy-1080cGy in 3-6 daily fractions) were randomly assigned to one of four chemotherapy regimens in a 2x2 design: CVI 5-FU (225mg/m2 5 days/wk), with or without intravenous Ox (50mg/m2 /wk x 5) or oral Cape (825 mg/m2 BID 5 days/wk), with or without Ox (50mg/m2/wk x 5). The primary endpoint was local-regional (L-R) tumor control that included L-R tumor recurrence, less than a complete surgical resection, and no surgery for any reason. Results: From July 2004 to August 2010, 1,608 patients were randomly assigned and 99.2% were eligible for analysis. There were n...

Neoadjuvant therapy for rectal cancer: Mature results from NSABP protocol R-04.

390 Background: The primary aims were to: 1) compare capecitabine (Cape) and continuous intravenous infusion (CVI) 5-FU combined with pelvic radiation therapy (RT) given preoperatively for patients (pts) with stage II or III rectal cancer; 2) determine whether the addition of oxaliplatin (Ox) would improve pt outcomes. Preliminary results focusing on pathologic complete response, sphincter-sparing surgery, surgical downstaging, and toxicity were presented at ASCO 2011 (Roh: J Clin Oncol 29: 2011 Ab 3503). Methods: Pts with clinical stage II or III rectal cancer undergoing preoperative RT (4,500cGy in 25 fractions over 5 wks + boost of 540cGy-1080cGy in 3-6 daily fractions) were randomly assigned to one of four chemotherapy regimens in a 2x2 design: CVI 5-FU (225mg/m2 5 days/wk), with or without intravenous Ox (50mg/m2 /wk x 5) or oral Cape (825 mg/m2 BID 5 days/wk), with or without Ox (50mg/m2/wk x 5). The primary endpoint of local-regional (L-R) tumor control included L-R tumor recurrence, less than an R0 resection (complete surgical resection), and no surgery. Results: From July 2004 to August 2010, 1608 patients were randomly assigned and 99.2% were eligible. There were no significant differences in L-R tumor control, DFS, or OS between regimens for either the 5-FU-Cape (L-R p=0.98) or the Ox-none (L-R p=0.70) comparisons. The addition of Ox was associated with significantly more grade 3-4 diarrhea (p&lt;0.0001). Analysis of the primary endpoint showed 3-yr rates of L-R tumor control ranged from 87.4%-88.2%. 3-yr rates of L-R recurrence among pts who underwent R0 resection ranged from 2-4 % for stage II pts, and from 4-11% for stage III pts. 16% of stage II and 26% of stage III pts developed distant metastases by 5 yrs. From 84% to 97% of pts received &gt;80% of the ideal chemotherapy dose in combination with preoperative RT. Conclusions: CVI 5-FU or oral Cape combined with RT produced similar outcomes and toxicity profiles. Because use of oral Cape avoids the need for central venous catheters and ambulatory infusion pumps, it can be considered a new standard of care in this setting. The addition of Ox provided no improvement in outcomes but did add significant toxicity. Clinical trial information: NCT00058474.

Comparison of planning techniques when air/fluid is present using the strut‐adjusted volume implant (SAVI) for HDR‐based accelerated partial breast irradiation

The presence of air/fluid surrounding implantable devices used for partial breast irradiation may significantly impact dose coverage to at‐risk tissue. Of the 67 total patients retrospectively evaluated for this study, 32 (48%) had greater than 1 cc volume of air/fluid extending outside of the strut‐adjusted volume implant (SAVI) device surface and were selected for comparison of planning approaches. The planning approaches utilized two different definitions of PTV_EVAL. One definition of a PTV_EVAL (PTV_EVALSAVI) was based on expanding 1 cm beyond the SAVI device only while accounting for the air/fluid using the NSABP Protocol B‐39/RTOG Protocol 0413. The second PTV_EVAL definition (PTV_EVALCAV) was based on expanding 1 cm beyond the cavity (SAVI device plus air/fluid volume). The results indicate use of the B‐39 formalism to account for air/fluid displacing the PTV_EVAL may overestimate the dose coverage to the at‐risk tissue, especially for large contiguous volumes of air/fluid. Using the SAVI device to optimize dose covering the PTV_EVALCAV volume surrounding the cavity improves dosimetric coverage to at‐risk tissue by 11.3% and 8.7% for V100 and V90, respectively, while the average V150 and V200 indices for PTV_EVALCAV increased by 9.1 cc and 5.0 cc, respectively, and the average maximum rib and skin doses increased by 11. 1% and 6.1%, respectively. The maximum skin dose, rib dose, V150, and V200 all met the planning objectives despite any increase in these parameters.PACS number: 87.55.kh

Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial

We studied the effect on tumour response to neoadjuvant therapy of the substitution of lapatinib for trastuzumab in combination with weekly paclitaxel after doxorubicin plus cyclophosphamide treatment, and of the addition of lapatinib and trastuzumab combined after doxorubicin plus cyclophosphamide treatment in patients with HER2-positive operable breast cancer to determine whether there would be a benefit of dual HER2 blockade in these patients. For this open-label, randomised phase 3 trial we recruited women aged 18 years or older with an ECOG performance status of 0 or 1 with operable HER2-positive breast cancer. Each received four cycles of standard doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) intravenously on day 1 every 3 weeks followed by four cycles of weekly paclitaxel (80 mg/m(2)) intravenously on days 1, 8, and 15, every 4 weeks. Concurrently with weekly paclitaxel, patients received either trastuzumab (4 mg/kg load, then 2 mg/kg intravenously) weekly until surgery, lapatinib (1250 mg orally) daily until surgery, or weekly trastuzumab plus lapatinib (750 mg orally) daily until surgery. After surgery, all patients received trastuzumab to complete 52 weeks of HER2-targeted therapy. Randomisation (ratio 1:1:1) was done centrally with stratification by clinical tumour size, clinical nodal status, hormone-receptor status, and age. The primary endpoint was the pathological complete response in the breast, and analysis was performed on an intention-to-treat population. Patient accrual started on July 16, 2007, and was completed on June 30, 2011; 529 women were enrolled in the trial. 519 patients had their pathological response determined. Breast pathological complete response was noted in 93 (52·5%, 95% CI 44·9-59·5) of 177 patients in the trastuzumab group, 91 (53·2%, 45·4-60·3) of 171 patients in the lapatinib group (p=0·9852); and 106 (62·0%, 54·3-68·8) of 171 patients in the combination group (p=0·095). The most common grade 3 and 4 toxic effects were neutropenia (29 [16%] patients in the trastuzumab group [grade 4 in five patients (3%), 28 [16%] in the lapatinib group [grade 4 in eight patients (5%)], and 29 [17%] in the combination group [grade 4 in nine patients (5%)]) and grade 3 diarrhoea (four [2%] patients in the trastuzumab group, 35 [20%] in the lapatinib group, and 46 [27%] in the combination group; p<0·0001). Symptomatic congestive heart failure defined as New York Heart Association Class III or IV events occurred in seven (4%) patients in the trastuzumab group, seven (4%) in the lapatinib group, and one (<1%) in the combination group; p=0·185). Substitution of lapatinib for trastuzumab in combination with chemotherapy resulted in similar high percentages of pathological complete response. Combined HER2-targeted therapy produced a numerically but insignificantly higher pathological complete response percentage than single-agent HER2-directed therapy; these findings are consistent with results from other studies. Trials are being undertaken to further assess these findings in the adjuvant setting.

DCIS Treated with Excision Alone Using the National Comprehensive Cancer Network (NCCN) Guidelines

In 2008, the NCCN published guidelines allowing low-risk DCIS patients to be treated by excision alone. The goal of this study was to determine local and distant recurrence and breast-cancer specific survival in patients with DCIS that meet NCCN criteria and are treated with excision alone. A prospective, single institution database was analyzed for patients with the following: pure ductal carcinoma in situ (no microinvasion), tumor extent 20 mm or less, age ≥50 years, margin width ≥2 mm, and nuclear grade 1 or 2 (non-high grade). Patients were treated with excision alone. Kaplan-Meier analysis was used to determine recurrence and survival rates. A total of 205 patients were treated with excision alone. The median age was 59 years. The median time of follow-up was 51 months. The median extent of disease was 8 mm. There were a total of nine local recurrences. The 6-year probability of local recurrence was 6.6 %. The 12-year probability of local recurrence was 7.8 %. The 12-year breast cancer-specific survival probability was 100 %. The 12-year local recurrence rate for DCIS patients in NSABP Protocol B-17 treated with excision alone was 32 %, and for excision plus radiation therapy, it was 16 %. In this study, retrospectively applying the NCCN Guidelines to our patients, the 12-year local recurrence rate for excision alone was 7.8 %. Patients with a low risk of local recurrence, if treated by excision alone, can be safely selected using the NCCN Guidelines.

Relationship Between Arm Morbidity and Patient-Reported Outcomes Following Surgery in Women with Node-Negative Breast Cancer: NSABP Protocol B-32

The impact of arm morbidity following breast cancer surgery on patient-observed changes in daily functioning and health-related quality of life (HRQoL) has not been well-studied. To examine the association of objective measures such as range of motion (ROM) and lymphedema, with patient-reported outcomes (PROs) in the arm and breast, upper extremity function, activities, and HRQoL. The National Surgical Adjuvant Breast and Bowel Project Protocol B-32 was a randomized trial comparing sentinel node resection (SNR) with axillary dissection (AD) in women with node-negative breast cancer. ROM and arm volume were measured objectively. PROs included symptoms; arm function; limitations in social, recreational, occupational, and other regular activities; and a global index of HRQoL. Statistical methods included cross-tabulations and multivariable linear regression models. In all, 744 women provided at least 1 postsurgery assessment. About one-third of the patients experienced arm mobility restrictions. A similar number of patients avoided the use of the arm 6 months after surgery. Limitations in work and other regular activities were reported by about a quarter of the patients. In this multivariable analysis, arm mobility and sensory neuropathy were predictors of patient-reported arm function and overall HRQoL. Predictors for activity limitations also included side of surgery (dominant vs nondominant). Edema was not significant after adjustment for sensory neuropathy and ROM. Arm mobility and edema were measured simultaneously only once during the follow-up (6 months). Clinical measures of sensory neuropathy and restrictions in arm mobility following breast cancer surgery are associated with self-reported limitations in activity and reductions in overall HRQoL.

Evaluation of lapatinib as a component of neoadjuvant therapy for HER2+ operable breast cancer: NSABP protocol B-41.

LBA506 Background: The purposes of this trial are to determine the effect of substituting lapatinib (L) for trastuzumab (T) in combination with weekly paclitaxel (WP) following AC as well as adding L to T with WP following AC on pathologic complete response (pCR) rates. Methods: Women with HER2-positive operable breast cancer received standard AC q3wks x 4 cycles followed by WP (80 mg/m2) on days 1, 8, and 15 q28 days x 4 cycles. Concurrently with WP, patients received either T (4 mg/kg load, then 2 mg/kg) weekly until surgery, L (1250 mg) daily until surgery, or weekly T plus L (750 mg) daily until surgery. Following surgery, patients received trastuzumab to complete 52 wks of HER2-targeted therapy. The primary endpoint is pCR breast. For each of the two primary comparisons, the Fisher’s exact test was used to test the equality of pCR rates. A Hochberg-type step-up procedure was applied to address multiple testings and to control the family-wise error rate at 0.05. Results: 51% were clinically node positive and 63% had HR+ tumors. pCR assessments were available from 519 of 529 patients. pCR percentage was 52.5% for AC→WP+T, 53.2% (p=0.9) for AC→WP+L, and 62% (p=0.075) for AC→WP+TL. pCR percentages in the HR+ subset were 46.7%, 48% (p=0.85), and 55.6% (p=0.18), respectively, and were 65.5%, 60.6% (p=0.57), and 73% (p=0.37) in the HR- cohort. The corresponding pCR breast and nodes percentages were 49.1%, 47.4% (p=0.74), and 60.4% (p=0.04). Grade 3/4 toxicities include diarrhea in 2%, 20%, 27% (p&lt;0.001), and symptomatic Gr 3/4 left ventricular systolic dysfunction in 4%, 4%, and 2% (p=0.49). Conclusions: Substitution of lapatinib for trastuzumab in combination with the chemotherapy program employed in this study resulted in similar high percentages of pCR in both HR+ and HR- cohorts. Combined HER2-targeted therapy produced a numerically higher pCR percentage than single agent HER2-directed therapy, but the difference was not statistically significant. Central review of HER2 and ER is being conducted to determine if subsets benefiting from the combined HER2-targeted therapy can be identified. Funding: GlaxoSmithKline.

Evaluation of lapatinib as a component of neoadjuvant therapy for HER2+ operable breast cancer: NSABP protocol B-41.

LBA506 The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Sunday, June 3, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.

Statin polyp prevention trial in patients with resected colon cancer: NSABP protocol P-5.

TPS1615 Background: HMG-CoA reductase inhibitors (statins) are effective lipid-lowering agents that are used for treating hyperlipidemia. Results from cell culture, animal experiments, and epidemiologic studies indicate that statins may be active chemopreventive agents against colorectal cancer (CRC). However, the clinical studies come largely from retrospective, observational studies originally designed to investigate lipid-lowering or cardiovascular endpoints rather than tumor endpoints. Methods: NSABP P-5 is a randomized, prospective placebo-controlled, double-blind study of rosuvastatin (10 mg per day x 5 years) or placebo for the prevention of adenomatous polyps of the colon or rectum, metachronous colorectal carcinoma, and colon cancer recurrence. Additional secondary endpoints include the size, number and features of the colorectal adenomas as well as health-related quality of life and self-reported symptoms. Selected Eligibility: (1) Patients who have undergone complete resection of AJCC Stage I or II colon cancer within 1 year before randomization. (2) Colonoscopy within 180 days before randomization. Selected Ineligibility: (1) Hyperlipidemia, (2) Familial Adenomatous Polyposis, (3) Lynch Syndrome. Sample Size:1,740 patients will be entered, and as of January 23, 2012, 163 (9.37%) have been randomized. The study is open at NSABP and CTSU sites in North America. Funded by NCI PHS grants U10-CA-37377 and U10-CA-6974, with additional funding from AstraZeneca Pharmaceuticals, LP.

Censored quantile regression for residual lifetimes

We propose a regression method that studies covariate effects on the conditional quantiles of residual lifetimes at a certain followup time point. This can be particularly useful in cancer studies, where more patients survive cancers initially and a patient's residual life expectancy is used to compare the efficacy of secondary or adjuvant therapies. The new method provides a consistent estimator that often exhibits smaller standard error in real and simulated examples, compared to the existing method of Jung et al. (2009). It also provides a simple empirical likelihood inference method that does not require estimating the covariance matrix of the estimator or resampling. We apply the new method to a breast cancer study (NSABP Protocol B-04, Fisher et al. (2002)) and estimate median residual lifetimes at various followup time points, adjusting for important prognostic factors.

PD07-08: The Effect on Surgical Complications of Bevacizumab Added to Neoadjuvant Chemotherapy: NSABP Protocol B-40.

Abstract The NSABP trial B-40 was designed to determine whether adding capecitabine or gemcitabine to docetaxel followed by AC would increase the pathologic complete response (pCR) rates in patients with operable HER2−negative breast cancer and to determine whether the addition of bevacizumab to three docetaxel-based regimens followed by AC would increase pCR rates. Secondary endpoints include the percentage of surgical complications after mastectomy, lumpectomy, and axillary staging procedures in the patients who received chemotherapy versus those who received chemotherapy and bevacizumab. Methods: Women with HER2−negative operable breast cancer received one of the following docetaxel-based regimens with or without bevacizumab (15mg/kg) every 3 weeks for four cycles: docetaxel 100 mg/m2 IV; docetaxel 75 mg/m2 and capecitabine 825 mg/m2 po BID days 1–14; and docetaxel 75 mg/m2 day 1 and gemcitabine 1000 mg/m2 IV days 1 and 8. These regimens were followed by preoperative standard AC on day 1 every 21 days for four cycles with or without bevacizumab 15 mg/kg given with the initial 2 cycles of AC. Treatment groups randomized to receive bevacizumab resumed postoperative bevacizumab 15 mg/kg IV every 3 weeks for an additional 10 doses. Assessment of surgical complications was performed from the date of surgery through 24 months following study entry. Results: Planned analysis for surgical complications will be conducted in October 2011 and will be presented along with breast reconstruction data. Funded by NCI PHS grants U10-CA-37377, U10-CA-69974, U10-CA-12027, U10-CA-69651, and U10-CA-52667, with additional support from F. Hoffmann La-Roche, Ltd., Genentech, USA, and Eli Lilly and Company. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD07-08.

S2-3: NSABP Protocol B-34: A Clinical Trial Comparing Adjuvant Clodronate vs. Placebo in Early Stage Breast Cancer Patients Receiving Systemic Chemotherapy and/or Tamoxifen or No Therapy – Final Analysis.

Abstract Bisphosphonates reduce the incidence of skeletal-related events (fractures, pain, hypercalcemia) in patients (pts) with bone metastases from breast cancer. By inhibiting osteoclast function and subsequent bone turnover they may inhibit the growth of bone (and other) metastases. Their role in preventing or delaying the development of bone (or other) metastases in pts with early breast cancer is uncertain. Three previous trials of oral clodronate have given mixed results. The largest trial (placebo-controlled) and a smaller open-label trial suggested that oral clodronate benefitted pts with improved bone metastases-free survival (BMFS) and overall survival (OS), but a third open-label study showed no benefit with an apparent detrimental effect on survival. Studies of IV zoledronate in open-label trials in early breast cancer have also shown mixed results: the AZURE trial in pts with node positive breast cancer showed no benefit in disease-free survival (DFS) or OS with a possible effect in pts aged over 60. The ABCSG-12 trial in GnRH (plus tamoxifen or anastrozole) treated women with early breast cancer showed a small DFS benefit for those receiving IV zoledronate but no BMFS or OS benefit. Methods: B-34 is a prospective, randomized, double-blind, phase III clinical trial in pts with stage 1, 2 or 3 breast cancer assessing oral clodronate 1600mg daily for 3 years compared to placebo given alone or in addition to adjuvant chemo- or hormone therapy. Stratification is by age (&amp;lt;50, +50), number of positive nodes (0, 1–3, 4+) and ER/PR status. The primary end-point is DFS. Secondary endpoints are the incidence of skeletal metastases, OS, relapse-free survival, incidence of non-skeletal metastases, and incidence of skeletal morbid events. Results: 3323 patients were accrued — 1662 in Group A and 1661 in Group B. As of March 31, 2011, 54 pts were declared ineligible: 23 in Group A and 31 in Group B. The average time on study is 101.3 months. Patient characteristics were evenly distributed throughout both groups. Approximately 75% of pts in each group had negative axillary lymph nodes and some 78% in each group were ER and/or PR positive. About 64% of pts were age 50 or over. Oral clodronate was generally tolerable, toxicities observed being mainly due to the concomitant systemic chemotherapy. One pt in Group A had a 1 mm area of osteonecrosis on the palatal taurus. Compliance, as expected with trials of oral medications, has been a problem. 1910 pts completed 3 years of therapy. Event rates were slower than anticipated. This final analysis assesses a total of 598 events in the two arms. Conclusions: This trial is the largest placebo-controlled study of an oral bisphosphonate in patients with early breast cancer and will provide further information on the role of bisphosphonates in breast cancer management. Supported for NSABP by NCI U10CA12027, −37377, 69651, 69974; and Bayer Schering Pharma Oy; for ECOG by U10CA021115; for NCCTG by U10CA25224; for SWOG by U10CA38926. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S2-3.

The effect on pCR of bevacizumab and/or antimetabolites added to standard neoadjuvant chemotherapy: NSABP protocol B-40.

LBA1005 Background: The addition of capecitabine (X), gemcitabine (G), and bevacizumab (B) to taxanes have each improved PFS in metastatic breast cancer. The primary aims of this trial were to determine if adding X or G to docetaxel (T) → AC will increase breast pathologic complete response (pCR) rates in operable, HER2-negative breast cancer and if adding B to T-based regimens →AC will increase pCR rates. Secondary aims included assessment of clinical complete response (cCR) rates. Methods: Pts received one of 3 T-based regimens, with or without B, 15mg/kg, q3wks x 4: T 100 mg/m2 day 1; T 75 mg/m2 day 1 and X 825 mg/m2 BID days 1-14; or T 75 mg/m2 day 1 and G 1000 mg/m2 days 1 and 8. Pts then received preoperative AC x 4, with or without B for the initial 2 cycles of AC. Pts randomized to B resumed B for 10 postop doses. The primary endpoint was pCR in the breast. The maximum of the standardized pairwise differences between pCR rate for the T → AC regimen and for the other 2 T-based regimens was used as the test statistic to adjust for multiple comparisons. Fisher’s exact test was used to compare the arms with and without B. Results: The groups were balanced, with 47% clinically node+, 56% poorly differentiated, and 59% HR+. Assessments for pCR were available from 1180 of 1206 randomized patients. pCR for TX and TG were 29.7% and 32% vs. 32.7% for T. Neither TX nor TG increased cCR rates relative to T (58.3% and 60.4% vs. 61.5%). TX and TG increased toxicity. Addition of B increased the pCR rate (28.4 vs. 34.5%, p=0.027) and the cCR rate (55.8 vs. 64.3%, p=0.007). The effect of B was predominantly in the HR+ subset (15.2 vs. 23.3%, p=0.008) with minimal effect in the HR- subset (47.3% vs. 51.3%, p=0.44). Grades 2/3/4 toxicities increased with B were HTN (1/&lt;1/0% vs. 13/9/&lt;1%), HFS (11/7/0% vs. 15/11/0%), and mucositis (10/3/0% vs. 20/5/0%). Conclusions: The addition of B to neoadjuvant chemotherapy improved pCR and cCR rates, but the addition of X or G to T did not improve outcomes. Follow-up for wound healing issues and DFS will help define the role of B in the treatment of early breast cancer. Funded by NCI PHS grants U10-CA-37377, U10-CA-69974, U10-CA-12027, U10-CA-69651, and U10-CA-44066, and F. Hoffmann La-Roche, Ltd., Genentech, USA, and Eli Lilly.