High-risk Node-negative Breast Cancer Research Articles

Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer (UK TACT2; CRUK/05/19): quality of life results from a multicentre, phase 3, open-label, randomised, controlled trial

Adjuvant chemotherapy for patients with early breast cancer improves outcomes but its toxicity affects patients' quality of life (QOL). The UK TACT2 trial investigated whether accelerated epirubicin improves time to recurrence and if oral capecitabine is non-inferior to cyclophosphamide, methotrexate, and fluorouracil (CMF) for efficacy with less toxicity. Results showed no benefit for accelerated epirubicin and capecitabine was non-inferior. As part of the QOL substudy, we aimed to assess the effect of chemotherapies on psychological distress, physical symptoms, and functional domains. TACT2 was a multicentre, phase 3, open-label, parallel-group, randomised, controlled trial done in 129 UK centres. Participants were aged 18 years or older with histologically confirmed node-positive or high-risk node-negative invasive primary breast cancer, who had undergone complete excision, and due to receive adjuvant chemotherapy. Patients were randomly assigned (1:1:1:1) to four cycles of 100 mg/m2 epirubicin either every 3 weeks (standard epirubicin) or every 2 weeks with 6 mg pegfilgrastim on day 2 of each cycle (accelerated epirubicin), followed by four 4-week cycles of either CMF (600 mg/m2 cyclophosphamide intravenously on days 1 and 8 or 100 mg/m2 orally on days 1-14; 40 mg/m2 methotrexate intravenously on days 1 and 8; and 600 mg/m2 fluorouracil intravenously on days 1 and 8 of each cycle) or four 3-week cycles of 2500 mg/m2 capecitabine (1250 mg/m2 given twice daily on days 1-14 of each cycle). The randomisation schedule was computer generated in random permuted blocks, stratified by centre, number of nodes involved (none vs 1-3 vs ≥4), age (≤50 years vs >50 years), and planned endocrine treatment (yes vs no). QOL was one of the secondary outcomes and is reported here. All patients from a subset of 44 centres were invited to complete QOL questionnaires (Hospital Anxiety and Depression Scale [HADS] and European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire 30-item core module [QLQ-C30] and Quality of Life Questionnaire breast module [QLQ-BR23]) at baseline, end of standard or accelerated epirubicin, end of CMF or capecitabine, and at 12 and 24 months after randomisation. The QOL substudy prespecified two coprimary QOL outcomes assessed in the intention-to-treat population: overall QOL (reported elsewhere) and HADS total score. Prespecified secondary QOL outcomes were EORTC QLQ-C30 subscales of physical function, role function, and fatigue and EORTC QLQ-BR23 subscales of sexual function and systemic therapy side-effects. This trial is registered with ISRCTN, ISRCTN68068041, and ClinicalTrials.gov, NCT00301925. From Dec 16, 2005, to Dec 5, 2008, 4391 patients (20 [0·5%] of whom were male) were enrolled in TACT2; 1281 (85·8%) of 1493 eligible patients were included in the QOL substudy. Eight (0·6%) participants in the QOL substudy were male and 1273 (99·4%) were female. Median follow-up was 85·6 months (IQR 80·6-95·9). Analysis was performed on the complete QOL dataset (as of Sept 15, 2011) when all participants had passed the 24-month timepoint. Prerandomisation questionnaires were completed by 1172 (91·5%) patients and 1179 (92·0%) completed at least one postrandomisation questionnaire. End-of-treatment HADS depression score (p=0·0048) and HADS total change score (p=0·0093) were worse for CMF versus capecitabine. Accelerated epirubicin led to worse physical function (p=0·0065), role function (p<0·0001), fatigue (p=0·0002), and systemic side-effects (p=0·0001), but not sexual function (p=0·36), compared with standard epirubicin during treatment, but the effect did not persist. Worse physical function (p=0·0048), sexual function (p=0·0053), fatigue (p<0·0001), and systemic side-effects (p<0·0001), but not role functioning (p=0·013), were seen for CMF versus capecitabine at end of treatment; these differences persisted at 12 months and 24 months. Accelerated epirubicin was associated with worse QOL than was standard epirubicin but only during treatment. These findings will help patients and clinicians make an informed choice about accelerated chemotherapy. CMF had worse QOL effects than did capecitabine, which were persistent for 24 months. The favourable capecitabine QOL compared with CMF supports its use as an adjuvant option after neoadjuvant chemotherapy in patients with triple-negative breast cancer. Cancer Research UK, Amgen, Pfizer, and Roche.

Toxicity and Efficacy of Hypofractionated Regional Nodal Irradiation

Hypofractionated whole-breast irradiation (HF-WBI) has been widely adopted. However, there are still limited data on whether hypofractionated regional nodal irradiation (HF-RNI) is safe and effective. We report toxicity and cancer outcomes with our HF-RNI approach. This retrospective study included 154 patients with node-positive or high-risk node-negative breast cancer treated with HF-RNI with curative intent at a single academic institution from 2008-2020. Median dose to the breast or chest wall/reconstructed breast was 40 Gy in 16 fractions (interquartile range [IQR], 40-45 Gy in 16-18 fractions). Median dose to the regional nodes was 40 Gy in 16 fractions (IQR, 40-40 Gy in 16-16 fractions). The primary end-point was the rate of chronic toxicity. Secondary endpoints were local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), disease-free survival (DFS), and overall survival (OS). Toxicities were scored using the Common Terminology Criteria for Adverse Events v5.0 and Radiation Therapy Oncology Group scale where appropriate. This study was approved by the Institutional Review Board. Median follow-up was 46 months (IQR 33-63 mo). Median age at diagnosis was 58 years. Sentinel lymph node biopsy (SLNB) was performed in 49% of patients, 16% underwent both SLNB and axillary lymph node dissection (ALND), 32% underwent ALND alone, and 3% had no axillary surgery; 79% had partial mastectomy and 21% had total mastectomy with or without reconstruction. The nodal target included the supraclavicular and axillary Level 1-3 nodes in 66% of patients and supraclavicular and Level 3 nodes in 34%. The crude incidence of grade 1 chronic brachial plexopathy was 2%, grade 1 chronic limited range of motion (LROM) of the upper extremity was 3%, and chronic upper extremity lymphedema was 8% (11 patients with grade 1 toxicity and 1 patient with grade 2 toxicity). The only grade 3+ chronic toxicity was hyperpigmentation (1%). The median time to the development of the highest-grade toxicity was 10 months for brachial plexopathy, 10 months for LROM, and 11 months for lymphedema, respectively. Five-year actuarial rates of LRFS, RRFS, DFS, and OS were 98%, 99%, 90%, and 88%, respectively. HF-RNI resulted in low rates of chronic toxicities and excellent disease control in this study. Results of randomized trials of HF-RNI are needed for definitive evidence, but these retrospective data support wider adoption of HF-RNI.

Adjuvant Docetaxel in Node-Negative Breast Cancer Patients: A Randomized Trial of AGO-Breast Study Group, German Breast Group, and EORTC-Pathobiology Group

In node-negative breast cancer (NNBC), a high risk of recurrence is determined by clinico-pathological or tumor-biological assessment. Taxanes may improve adjuvant chemotherapy. NNBC 3-Europe, the first randomized phase-3 trial in node-negative breast cancer (BC) with tumor-biological risk assessment, recruited 4146 node-negative breast cancer patients from 2002 to 2009 in 153 centers. Risk assessment was performed by clinico-pathological factors (43%) or biomarkers (uPA/PAI-1, urokinase-type plasminogen activator/its inhibitor PAI-1). High-risk patients received six courses 5-fluorouracil (500 mg/m2), epirubicin (100 mg/m2), cyclophosphamide (500 mg/m2) (FEC), or three courses FEC followed by three courses docetaxel 100 mg/m2 (FEC-Doc). Primary endpoint was disease-free survival (DFS). In the intent-to-treat population, 1286 patients had received FEC-Doc, and 1255 received FEC. Median follow-up was 45 months. Tumor characteristics were equally distributed; 90.6% of tested tumors had high uPA/PAI-1-concentrations. Planned courses were given in 84.4% (FEC-Doc) and 91.5% (FEC). Five-year-DFS was 93.2% (95% C.I. 91.1-94.8) with FEC-Doc and 93.7% (91.7-95.3) with FEC. Five-year-overall survival was 97.0% (95.4-98.0) for FEC-Doc and 96.6% % (94.9-97.8) for FEC. With adequate adjuvant chemotherapy, even high-risk node-negative breast cancer patients have an excellent prognosis. Docetaxel did not further reduce the rate of early recurrences and led to significantly more treatment discontinuations.

Evaluation of booster injections in maintaining peak immunity in a phase IIb study evaluating HER2/neu peptide GP2 (GLSI-100) versus GM-CSF alone after adjuvant trastuzumab in women with HER2-positive breast cancer.

LBA550 Background: Injection site reactions (ISR) of booster injections in the randomized, active-controlled, single-blinded, multicenter Phase IIb trial of GLSI-100 (GP2+GM-CSF) administered in the adjuvant setting to node-positive and high-risk node-negative breast cancer patients with tumors expressing HER2 have been analyzed. It was demonstrated that GLSI-100 safely elicited a potent immune response versus placebo, along with data showing ISRs correlate to immune response data such as Delayed Type Hypersensitivity (DTH). Methods: Patients were randomized and received GLSI-100 (500 mcg GP2: 125 mcg GM-CSF) or control (GM-CSF) via 6 intradermal injections every 3-4 weeks as part of the Primary Immunization Series (PIS) for 6 months and 4 booster injections every 6 months thereafter. Injection site reactions were assessed 48-72 hours after the injection. Booster injections were introduced mid-trial so not all patients were dosed with boosters. The largest perpendicular diameters of induration were measured, and the orthogonal mean was calculated to quantify ISRs, providing potential assessments of peak and nadir immunity during the PIS and booster phases of treatment. Results: The study enrolled 180 patients who were HER2 3+ positive and low HER2 expressors (1-2+). After 5 years of follow-up, the Kaplan-Meier estimated 5-year DFS rate in the 46 HER2 3+ patients treated with GLSI-100, who were in the efficacy population, was 100% versus 89.4% (95% CI:76.2, 95.5%) in the 50 patients treated with GM-CSF (p = 0.0338). A patient is in the efficacy population if they were treated, followed, and remained disease free over the first 6 months. Boosters were administered to 53 HER2 3+ patients (54%). The median peak ISR during the PIS in GLSI-100 treated patients was 92.1 mm versus 60.5 mm in the GM-CSF only treated control patients. Peak ISR in GLSI-100 treated patients occurred throughout the 10-dose dosing period, including during boosters. During the 6 dose PIS, 84% of the peak ISRs occurred between doses 3 through 6. Each booster is administered 6 months after the last injection, thus the booster ISR is likely measuring the nadir immune response. When comparing the peak ISR during PIS to the boosters, the nadir ISRs of the boosters were approximately 20 mm smaller. Conclusions: Administering GLSI-100 boosters at 6 month intervals to patients produced a consistent nadir ISR approximately 20 mm lower than the maximum PIS ISR of 92.1 mm which is still larger than the maximum ISR in GM-CSF only patients of 60.5 mm. A patient’s immune response a month after booster dosing would theoretically be the peak ISR, which will be measured in future trials by measuring T-cell response and DTH one month after booster injections, further helping to evaluate booster strategies to sustain peak immunity over longer periods of time. Clinical trial information: 00524277.

Baseline GP2 immune response as an independent prognostic factor in a phase IIb study evaluating HER2/neu peptide GP2 (GLSI-100) versus. GM-CSF alone after adjuvant trastuzumab in HER2-positive women with breast cancer.

e12519 Background: Delayed type hypersensitivity (DTH) skin tests to GP2 were conducted in the randomized, active-controlled, single-blinded, multicenter Phase IIb trial investigating GLSI-100 (GP2+GM-CSF) administered in the adjuvant setting to node-positive and high-risk node-negative breast cancer patients with tumors expressing HER2. Previously it has been reported that subjects with baseline response to GP2 by DTH were more likely to experience a recurrence sooner than those without a positive baseline response. It was of interest to determine if this response was independent of other known prognostic factors. Methods: Patients were randomized and received GLSI-100 (500 mcg GP2: 125 mcg GM-CSF) or control (GM-CSF only) via 6 intradermal injections every 3-4 weeks as part of the Primary Immunization Series (PIS) for 6 months and 4 booster injections every 6 months thereafter. GP2 DTH skin tests were placed at baseline and after the 6th dose. After 48-72 hours, the largest perpendicular diameters of induration were measured and the orthogonal mean was calculated. Induration of over 5mm was considered a positive response. The relationship between prognostic factors such as demographic and disease characteristics and the baseline DTH response were investigated by logistic regression. Results: The study enrolled 180 patients who were HER2 3+ positive and low HER2 expressors (1-2+). After 5 years of follow-up, the Kaplan-Meier estimated 5-year DFS rate in the 46 HER2 3+ patients treated with GLSI-100, if completing the PIS, was 100% versus 89.4% (95% CI:76.2, 95.5%) in the 50 patients treated with GM-CSF (p = 0.0338). Just under 23% of subjects experienced an immune response to GP2 by DTH at baseline. The incidence was similar in patients who were HER2/neu positive and those considered low expressors and was equally distributed across GLSI-100 and placebo-treated subjects. Known prognostic factors such as hormone receptor status, stage at presentation, node status, etc. were evenly distributed across subjects that experienced a baseline DTH response to GP2 and those who did not. Each prognostic factor was investigated in a logistic model to determine if it predicted baseline DTH immune status. The prognostic factors did not predict baseline DTH immune response in the logistic models. There appears to be no correlation between baseline immune response to GP2 and known prognostic factors. Conclusions: Baseline GP2 immune response as measured by the delayed-type hypersensitivity test may be an independent prognostic factor for recurrence. Knowledge of this GP2 immune response may identify a patient with increased risk of rapid recurrence. Clinical trial information: 00524277.

Validation of a nuclear grading system for resected stage I–IIIA, high-risk, node-negative invasive breast carcinoma in the N·SAS-BC 01 trial

BackgroundThis retrospective observational study validated nuclear grading criteria developed to identify a high-risk group with recurrence rate ≥20–30% and local pathology diagnosis used in a previous multi-institutional randomized N·SAS-BC 01 trial, where the efficacy of adjuvant chemotherapy regimens was evaluated in 733 high-risk node-negative invasive breast cancer patients.MethodsOf 545 patients with long-term follow-up data (median 12.1 years), pathology slides, and local pathology diagnosis, 530 eligible patients were subjected to central pathology review (CPR) for histological type and nuclear grade (NG). Concordance in NGs was compared with local diagnosis. The 10/15-year recurrence-free survival (RFS) and overall survival (OS) rates stratified by NG and histological type were calculated.ResultsLocal diagnoses were invasive ductal carcinoma (IDC)-NG2, IDC-NG3, invasive lobular carcinoma (ILC), and metaplastic carcinoma (MC) in 158/327/38/7 patients, respectively. The 10/15-year RFS rates were 87.2/82.6% for IDC-NG2 and 81.8/75.0% for IDC-NG3 (p = 0.061), and OS rates were 95.0/92.8% for IDC-NG2 and 90.8/85.7% for IDC-NG3 (p = 0.042). CPR graded 485 locally diagnosed IDCs as IDC-NG1/NG2/NG3/unknown in 98/116/267/4 patients, respectively. No significant difference was found among survival curves for the three NG groups. Although the agreement level between local and CPR diagnoses was low (κ = 0.311), both diagnoses identified a patient group with a 15-year recurrence rate ≥ 20%. The 10/15-year RFS rates were 79.4/63.5% for ILC and 68.6%/unknown for MC.ConclusionsThe N·SAS grading system identified a patient group with high-risk node-negative invasive breast cancer, suggesting that local diagnosis was performed efficiently in the N·SAS-BC 01 trial.Trial registration number: UMIN000022571.Date of registration: June 1, 2016.

Abstract P2-13-29: Analysis of GP2 immune response and relationship to recurrence in a prospective, randomized, placebo-controlled, single-blinded, multicenter, phase IIb study evaluating the reduction of recurrences using HER2/neu peptide GP2 (GLSI-100) vs. GM-CSF alone after adjuvant trastuzumab in HER2 positive women with operable breast cancer

Abstract Background: Delayed type hypersensitivity (DTH) skin tests in the randomized, active-controlled, single-blinded, multicenter Phase IIb trial investigating GLSI-100 (GP2+GM-CSF) administered in the adjuvant setting to node-positive and high-risk node-negative breast cancer patients with tumors expressing any degree of HER2 (immuno-histochemistry [IHC] 1-3+) (NCT00524277) have been analyzed. The trial enrolled HLA-A*02 patients randomized to receive GLSI-100 versus GM-CSF alone. The trial's primary objective was to determine if treatment with GLSI-100, a HER2-derived peptide, reduces recurrence rates. Analyses for this trial showing GLSI-100 to be efficacious, safe and immunogenic have been previously reported by Patel et al. and Mittendorf et al.. Methods: Consented patients were randomized and scheduled to receive GLSI-100 (500 mcg GP2: 125 mcg GM-CSF) or control (GM-CSF only) via 6 intradermal injections every 3-4 weeks as part of the Primary Immunization Series (PIS) for the first 6 months and 4 booster intradermal injections every 6 months thereafter. Boosters were introduced during the trial, thus some patients did not receive all 4 boosters. DTH skin tests were assessed at baseline and after the 6th dose with the orthogonal mean of each skin reaction measured 48-72 hours after injection using the sensitive ballpoint-pen method.. Results: The study enrolled 180 patients across 16 clinical sites with both HER2 3+ positive and low HER2 expressors (1-2+). After 5 years of follow-up, the Kaplan-Meier estimated 5-year DFS rate in the 46 HER2 3+ patients treated with GLSI-100, if the patient completed the PIS, was 100% versus 89.4% (95% CI:76.2, 95.5%) in the 50 placebo patients treated with GM-CSF (p = 0.0338). GLSI-100 was shown to be well tolerated with no SAEs deemed related to study medication and elicited a potent immune response measured by local skin tests and immunological assays. Injection site reactions were common, occurring in almost 100% of patients treated with either GLSI-100 or GM-CSF alone. Previous publications have reported the increase in DTH response reported among patients after treatment with GLSI-100. However, it was of interest to understand the positive DTH responses to GP2 noted at baseline. 22.8% of patients reacted to GP2 at baseline with induration of 5mm or greater. In the subgroup of patients who later experienced a breast cancer recurrence, 36.4% (8/22) had such a baseline response. Analysis of the time to recurrence among those recurring found that the median time to recurrence was 0.6 years for those with a baseline response while those that did not have a positive baseline DTH response to GP2 took 1.2 years to recur.. Conclusions: This study demonstrated that GLSI-100 safely elicited a potent immune response as evidenced by increased DTH skin responses with treatment paired with improved disease-free survival. It is theorized that a positive baseline DTH skin test to GP2 may be evidence of an existing immune response to GP2 associated with residual disease, impending recurrence, or prior treatments. Further studies assessing if GP2 immune response is an important prognosticator of cancer disease state or recurrence are planned. Citation Format: Snehal S Patel, David B McWilliams, Mira S Patel, Christine T Fischette, Jaye Thompson, F. Joseph Daugherty. Analysis of GP2 immune response and relationship to recurrence in a prospective, randomized, placebo-controlled, single-blinded, multicenter, phase IIb study evaluating the reduction of recurrences using HER2/neu peptide GP2 (GLSI-100) vs. GM-CSF alone after adjuvant trastuzumab in HER2 positive women with operable breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-29.

Adjuvant Capecitabine for Early Breast Cancer: 15-Year Overall Survival Results From a Randomized Trial.

Few data are available regarding the influence of adjuvant capecitabine on long-term survival of patients with early breast cancer. The Finland Capecitabine Trial (FinXX) is a randomized, open-label, multicenter trial that evaluates integration of capecitabine to an adjuvant chemotherapy regimen containing a taxane and an anthracycline for the treatment of early breast cancer. Between January 27, 2004, and May 29, 2007, 1,500 patients with axillary node-positive or high-risk node-negative early breast cancer were accrued. The patients were randomly allocated to either TX-CEX, consisting of three cycles of docetaxel (T) plus capecitabine (X) followed by three cycles of cyclophosphamide, epirubicin, and capecitabine (CEX, 753 patients), or to T-CEF, consisting of three cycles of docetaxel followed by three cycles of cyclophosphamide, epirubicin, and fluorouracil (CEF, 747 patients). We performed a protocol-scheduled analysis of overall survival on the basis of approximately 15-year follow-up of the patients. The data collection was locked on December 31, 2020. By this date, the median follow-up time of the patients alive was 15.3 years (interquartile range, 14.5-16.1 years) in the TX-CEX group and 15.4 years (interquartile range, 14.8-16.0 years) in the T-CEF group. Patients assigned to TX-CEX survived longer than those assigned to T-CEF (hazard ratio 0.81; 95% CI, 0.66 to 0.99; P = .037). The 15-year survival rate was 77.6% in the TX-CEX group and 73.3% in the T-CEF group. In exploratory subgroup analyses, patients with estrogen receptor-negative cancer and those with triple-negative cancer treated with TX-CEX tended to live longer than those treated with T-CEF. Addition of capecitabine to a chemotherapy regimen that contained docetaxel, epirubicin, and cyclophosphamide prolonged the survival of patients with early breast cancer.

Prognosis of Patients With Early Breast Cancer Receiving 5 Years vs 2 Years of Adjuvant Bisphosphonate Treatment

Bisphosphonate treatment in patients with early breast cancer has become part of care, but the optimal treatment duration is still unclear. To compare 2 vs 5 years of zoledronate treatment following adjuvant chemotherapy in patients with early breast cancer. The SUCCESS A phase 3 multicenter randomized open-label clinical trial with a 2 × 2 factorial design enrolled 3754 patients from September 21, 2005, to March 12, 2007 (last patient out, May 7, 2014). Final data analysis was conducted from September 2019 to October 2020. In 250 German study centers, patients were eligible for participation in the SUCCESS A trial if they had either node-positive or high-risk node-negative (defined as at least 1 of the following: tumor size ≥ pT2, histologic grade 3, negative hormone receptor status, or age ≤35 years) primary invasive breast cancer. Patients were first randomized to adjuvant chemotherapy with 3 cycles of fluorouracil, epirubicin, and cyclophosphamide followed by 3 cycles of docetaxel with or without gemcitabine (not presented in this report). After chemotherapy, patients underwent a second randomization of 5 years of zoledronate treatment (4 mg intravenously every 3 months for 2 years, followed by 4 mg intravenously every 6 months for 3 years) vs 2 years of zoledronate treatment (4 mg intravenously every 3 months for 2 years). The primary end point of the study was disease-free survival; secondary end points were overall survival, distant disease-free survival, and the incidence of skeletal-related adverse events. Survival times were measured from 2 years after the start of zoledronate treatment (landmark analysis). Overall, data on 2987 patients were available for analysis; median age was 53 (range, 21-86) years. Disease-free survival, overall survival, and distant disease-free survival did not differ significantly between the 2 treatment arms (5 vs 2 years) as shown by adjusted multivariable Cox proportional hazards regression models (disease-free survival: hazard ratio [HR], 0.97; 95% CI, 0.75-1.25; P = .81; overall survival: HR, 0.98; 95% CI, 0.67-1.42; P = .90; distant disease-free survival: HR, 0.87; 95% CI, 0.65-1.18; P = .38). Adverse events were observed more often in the 5-year (46.2%) vs 2-year (27.2%) zoledronate treatment arm, which was particularly true for the skeletal-related events bone pain (5 years, 8.3% vs 2 years, 3.7%) and arthralgia (5 years, 5.1% vs 2 years, 3.1%). The results of this phase 3 randomized clinical trial indicate that extending the zoledronate treatment beyond 2 years does not improve the prognosis of high-risk patients with early breast cancer receiving chemotherapy, suggesting that the currently recommended bisphosphonate treatment duration of 3 to 5 years could be reduced. ClinicalTrials.gov Identifier: NCT02181101.

Final five-year median follow-up safety data from a prospective, randomized, placebo-controlled, single-blinded, multicenter, phase IIb study evaluating the use of HER2/neu peptide GP2 + GM-CSF vs. GM-CSF alone after adjuvant trastuzumab in HER2-positive women with operable breast cancer.

542 Background: The final analysis of the GP2 prospective, randomized, placebo-controlled, single-blinded, multicenter Phase IIb trial investigating GP2+GM-CSF administered in the adjuvant setting to node-positive and high-risk node-negative breast cancer patients with tumors expressing any degree of HER2 (immuno-histochemistry [IHC] 1-3+) ( NCT00524277) is now complete with 5 year follow-up. The trial enrolled HLA-A02 patients randomized to receive GP2+GM-CSF versus GM-CSF alone. It was previously reported that completion of the GP2+GM-CSF Primary Immunization Series (PIS) reduced recurrence rates to 0% over a 5 year follow-up period in HER2 3+ patients, who received a standard course of trastuzumab after surgery. Methods: Each enrolled and consented patient was randomly scheduled to receive a total of 6 GP2+GM-CSF (500 mcg GP2: 125 mcg GM-CSF) or GM-CSF only intradermal injections every 3-4 weeks as part of the PIS for the first 6 months and 4 GP2+GM-CSF or GM-CSF only booster intradermal injections every 6 months thereafter. Boosters were introduced during the trial, thus some patients did not receive all 4 boosters. Injection sight reactions were measured. Results: Safety data was analyzed to assess local and systemic toxicity of each treatment arm. Most subjects completed the planned PIS, 81 (91.0%) GP2+GM-CSF and 86 (94.5%) GM-CSF only. In addition, 77 GP2+GM-CSF and 80 GM-CSF only subjects received all 4 booster injections. The most common local toxicities were erythema, induration and pruritis and they occurred with similar frequency in the two treatment arms. Local reactions were reported by almost all subjects over the course of vaccinations. Occurring in a smaller percentage of subjects, the most common systemic toxicities were fatigue, headache, and myalgia/arthralgia, again with similar incidence by treatment group. The majority of all events reported were of Grade 1 mild severity (GP2+GM-CSF 92.5%, GM-CSF only 90.6%). Only 5 events in 4 subjects were considered Grade 3: induration and maculopapular rash/pruritis, in two GP2+GM-CSF subjects and chest pain and hypersensitivity reaction in two GM-CSF only subjects. The incidence of local reactions minimally increased with subsequent vaccinations however, the types of events remain unchanged. No serious adverse events were reported over the full 5 year treatment and follow-up periods. Conclusions: The study confirms the finding from the Phase I trial evaluating GP2+GM-CSF that the vaccine is safe and well-tolerated. The majority of patients experienced only mild local and systemic toxicities. Importantly, toxicities in the GP2+GM-CSF group were comparable to those seen in the GM-CSF only group, suggesting the toxicities are attributable to GM-CSF. Clinical trial information: NCT00524277.

Abstract PD12-01: Evaluation of sleep problems and their association with febrile neutropenia, leucopenia and infections in women receiving adjuvant chemotherapy for breast cancer in the Canadian Cancer Trials Group MA.21 trial

Abstract BackgroundInsomnia is a frequent complaint in patients with cancer. Sleep problems can affect immune functioning in healthy individuals. Our aim was to evaluate the association between sleep disturbance and the risk of febrile neutropenia, leukopenia and infections in patients treated with chemotherapy in an adjuvant setting for breast cancer.MethodologyThis is a retrospective study using the Canadian Cancer Trial Group data collected for the MA.21 trial, in which three adjuvant chemotherapy regimens (CEF, EC-T dose dense or AC-T) were compared in 2104 patients with node positive or high-risk node negative breast cancer. A total of 1731 patients had completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and 1727 patients had completed the Breast Cancer Chemotherapy Questionnaire (BCQ) quality of life questionnaires, which both include a question about sleep difficulties. The primary definition for patients with insomnia was a score of three (quite a bit) or greater at Question 11 (Have you had trouble sleeping? with answers ranging from one (not at all) to four (very much)) on the EORTC QLQ-C30 questionnaire. We compared patients classified as having “clinical insomnia” based on their response to this question with patients considered “good sleepers”. The primary endpoint was the risk of febrile neutropenia. Secondary endpoints were the risks of grade one or more leukopenia, neutropenia and infection. ResultsFebrile neutropenia was more frequent in patients with sleep problems compared with those without, with 16.3% and 12.2% of patients having at least one episode in each group respectively (p value = 0.01 in the univariate analysis (table 1)). However, after adjustment for potential confounders in the multi-variate analysis, it was not statistically significant with an odds ratio of 1.07, a 95% confidence interval of 0.76-1.50 and a p value of 0.71. Similarly, no statistically significant difference in the risk of leukopenia could be demonstrated in the multi-variate analysis for patients with sleep problems with an odds ratio of 0.92 a 95% confidence interval of 0.69-1.24 and a p value of 0.59. No significant association could be found between sleep problems and neutropenia and infections. In an unplanned exploratory analysis, chemotherapy dose reductions were significantly more frequent in patients with sleep problems with 30.6% in this group compared to 21.8% in good sleepers, with a p value &amp;lt;0.0001. ConclusionWhile our univariate analysis suggested an increased risk of febrile neutropenia and leucopenia in patients with sleep problems, after adjustment for confounders, we could not show a statistically significant association in women undergoing adjuvant chemotherapy for high-risk locoregional breast cancer. Table 1: Univariate analysis of primary and secondary outcomes in patients with sleep problems and good sleepersCharacteristicsSleep problem= yesSleep problem = noFebrile neutropeniaNo781 (83.7%)701 (87.8%)Yes152 (16.3%)97 (12.2%)P-value0.01White blood cell count (WBC)Grade 0157 (16.8%)141 (17.7%)Grade 1135 (14.5%)138 (17.3%)Grade 2184 (19.7%)186 (23.3%)Grade 3214 (22.9%)173 (21.7%)Grade 4243 (26.1%)160 (20.1%)P-value0.02NeutropeniaGrade 0778 (83.4%)700 (87.7%)Grade 10 (0%)1 (0.1%)Grade 22 (0.2%)0 (0%)Grade 3152 (16.3%)96 (12.0%)Grade 41 (0.1%)1 (0.1%)P-value0.014InfectionGrade 0619 (66.4%)564 (70.7%)Grade 168 (7.3%)62 (7.8%)Grade 2158 (16.9%)110 (13.8%)Grade 387 (9.3%)61 (7.6%)Grade 41 (0.1%)1 (0.1%)P-value0.24Chemotherapy delayNo1 (0.1%)12 (1.5%)Yes932 (99.9%)786 (98.5%)P-value0.0008Chemotherapy dose reductionNo648 (69.4%)624 (78.2%)Yes285 (30.6%)174 (21.8%)P-value&amp;lt; 0.0001 Citation Format: Audreylie Lemelin, Josée Savard, Michelle Chen, Margot Burnell, Mark N Levine, Lois Shepherd, Bingshu E Chen, Julie Lemieux. Evaluation of sleep problems and their association with febrile neutropenia, leucopenia and infections in women receiving adjuvant chemotherapy for breast cancer in the Canadian Cancer Trials Group MA.21 trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD12-01.

Abstract PS10-23: Five year median follow-up data from a prospective, randomized, placebo-controlled, single-blinded, multicenter, phase IIb study evaluating the reduction of recurrences using HER2/neu peptide GP2 + GM-CSF vs. GM-CSF alone after adjuvant trastuzumab in HER2 positive women with operable breast cancer

Abstract Background: The final analysis of the GP2 prospective, randomized, placebo-controlled, single-blinded, multicenter Phase IIb trial investigating GP2+GM-CSF administered in the adjuvant setting to node-positive and high-risk node-negative breast cancer patients with tumors expressing any degree of HER2 (immuno-histochemistry [IHC] 1-3+) (NCT00524277) is now complete with 5 year follow-up. The trial enrolled HLA-A02 patients randomized to receive GP2+GM-CSF versus GM-CSF alone. The trial's primary objective was to determine if treatment with GP2, a HER2-derived peptide, reduces recurrence rates. Three and 4 year interim analyses for this trial and 3 Phase I studies showing GP2 to be safe and immunogenic have been previously reported by Mittendorf et al. Methods: Each enrolled and consented GP2-treated patient was scheduled to receive a total of 6 GP2+GM-CSF (500 mcg GP2: 125 mcg GM-CSF) intradermal injections every 3-4 weeks as part of the Primary Immunization Series (PIS) for the first 6 months and 4 GP2+GM-CSF booster intradermal injections every 6 months thereafter. Boosters were introduced during the trial, thus some patients did not receive all 4 boosters. Each enrolled and consented placebo patient was scheduled to receive a total of 6 GM-CSF only intradermal injections every 3-4 weeks for the first 6 months and 4 GM-CSF only booster intradermal injections every 6 months thereafter. Results: This 168 patient (ITT: n=180) basket trial across 16 clinical sites explored 96 HER2 3+ patients, who received a standard course of trastuzumab after surgery and subsequently completed the full PIS or placebo, starting the PIS at median 17.1 months after surgery, and 72 HER2 1-2+ patients, who did not receive trastuzumab after surgery and subsequently completed the full PIS or placebo, starting the PIS at median 10.8 months after surgery. Since GP2 is synergistic with trastuzumab, and the HER2 1-2+ patients did not receive trastuzumab, it was prespecified to compare recurrence rates ITT versus per protocol in these 2 distinct, independently reported populations, excluding those patients who did not complete the PIS. GP2 was shown to be well tolerated with no SAEs and elicited a potent immune response measured by local skin tests and immunological assays, which suggest peak immunity is reached at 6 months upon completion of the PIS. After 5 years of follow-up, the Kaplan-Meier estimated 5-year DFS rate in the 46 HER2 3+ patients treated with GP2+GM-CSF, if the patient completed the PIS, was 100% versus 89.4% (95% CI:76.2, 95.5%) in the 50 placebo patients treated with GM-CSF (p = 0.0338). The treated versus placebo HER2 3+ patients were well-matched, where 53% were stage T1, 41% were stages T2-T4, 55% were node positive, 58% were HR positive and received endocrine therapy, 77% received adjuvant radiation, 77% received adjuvant chemotherapy, and 89% received trastuzumab. After 5 years of follow-up, the Kaplan-Meier estimated 5-year DFS rate in the 35 HER2 1-2+ patients treated with GP2+GM-CSF, if the patient completed the PIS, was 77.1% (95% CI:59.5, 87.9%) versus 77.6% (95% CI:60.1, 88.2%) in the 37 placebo patients treated with GM-CSF (p = 0.9142). Conclusions: This study demonstrated that completion of the GP2+GM-CSF PIS safely elicited a potent immune response and reduced recurrence rates to 0% in HER2 3+ patients, who received a standard course of trastuzumab after surgery. A pivotal Phase III trial is being initiated to treat HER2 3+ patients in the neoadjuvant setting. GP2 also may be effective when used in parallel to trastuzumab based therapeutics or in combination with trastuzumab based therapeutics in HER2 1-2+ or other HER2 expressing cancers. Citation Format: Snehal S Patel, David B McWilliams, Marisa S Patel, Christine T Fischette, Jaye Thompson, F Joseph Daugherty. Five year median follow-up data from a prospective, randomized, placebo-controlled, single-blinded, multicenter, phase IIb study evaluating the reduction of recurrences using HER2/neu peptide GP2 + GM-CSF vs. GM-CSF alone after adjuvant trastuzumab in HER2 positive women with operable breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-23.

Leukocyte nadir as a predictive factor for efficacy of adjuvant chemotherapy in breast cancer. Results from the prospective trial SBG 2000–1

Background: Retrospective studies have suggested that chemotherapy-induced leukopenia is associated with improved recurrence-free or overall survival. The SBG 2000–1 trial was designed to verify the favorable prognosis associated with chemotherapy-induced leukopenia in early breast cancer. Patients not experiencing chemotherapy-induced leukopenia were randomized into standard dosed or individually escalated chemotherapy doses based on the grade of leukopenia after a first standard dose.Patients and methods: 1452 women in Sweden and Denmark with operable node-positive or high-risk node-negative breast cancer aged 18–60 years were recruited to participate in this trial. Participants received a first FEC cycle at standard doses (600/60/600 mg/m2). Patients (n = 1052) with nadir leukopenia grade 0–2 after the first cycle were randomized between either 6 standard FEC or 6 tailored FEC courses with doses of epirubicin and cyclophosphamide escalated during courses 2 and 3 and thereafter aimed at achieving grade 3 leukopenia. Patients with nadir leukopenia grade 3–4 after the first course continued treatment with standard FEC. Results of the randomized comparison has been published previously. The present study focuses on chemotherapy-induced leukopenia as a covariable with outcome in randomized and non-randomized patients. The prognostic value of leukopenia after course 3, was studied in a Cox model adjusted for cumulative doses of epirubicin and cyclophosphamide. The association of chemotherapy-induced leukopenia with prognosis was a preplanned secondary endpoint for this trial.Results: The eight-year distant disease-free survival was 73%, 77%, 78% and 83% for patients with leucocyte nadir grade 0, 1, 2 and 3–4, respectively. Higher degree of leukopenia was highly significantly associated to improved distant disease-free survival (HR 0.84, 95% CI 0.74–0.96, p = .008) and overall survival (HR 0.87 (0.76–0.99, p = .032).Conclusion: This prospective study confirms that chemotherapy-induced leukopenia is a covariable with outcome in primary breast cancer, even after adjustment for chemotherapy doses.

Prospective, randomized, single-blinded, multi-center phase II trial of two HER2 peptide vaccines, GP2 and AE37, in breast cancer patients to prevent recurrence

PurposeAE37 and GP2 are HER2 derived peptide vaccines. AE37 primarily elicits a CD4+ response while GP2 elicits a CD8+ response against the HER2 antigen. These peptides were tested in a large randomized trial to assess their ability to prevent recurrence in HER2 expressing breast cancer patients. The primary analyses found no difference in 5-year overall disease-free survival (DFS) but possible benefit in subgroups. Here, we present the final landmark analysis.MethodsIn this 4-arm, prospective, randomized, single-blinded, multi-center phase II trial, disease-free node positive and high-risk node negative breast cancer patients enrolled after standard of care therapy. Six monthly inoculations of vaccine (VG) vs. control (CG) were given as the primary vaccine series with 4 boosters at 6-month intervals. Demographic, safety, immunologic, and DFS data were evaluated.Results456 patients were enrolled; 154 patients in the VG and 147 in CG for AE37, 89 patients in the VG and 91 in CG for GP2. The AE37 arm had no difference in DFS as compared to CG, but pre-specified exploratory subgroup analyses showed a trend towards benefit in advanced stage (p = 0.132, HR 0.573 CI 0.275–1.193), HER2 under-expression (p = 0.181, HR 0.756 CI 0.499–1.145), and triple-negative breast cancer (p = 0.266, HR 0.443 CI 0.114–1.717). In patients with both HER2 under-expression and advanced stage, there was significant benefit in the VG (p = 0.039, HR 0.375 CI 0.142–0.988) as compared to CG. The GP2 arm had no significant difference in DFS as compared to CG, but on subgroup analysis, HER2 positive patients had no recurrences with a trend toward improved DFS (p = 0.052) in VG as compared to CG.ConclusionsThis phase II trial reveals that AE37 and GP2 are safe and possibly associated with improved clinical outcomes of DFS in certain subgroups of breast cancer patients. With these findings, further evaluations are warranted of AE37 and GP2 vaccines given in combination and/or separately for specific subsets of breast cancer patients based on their disease biology.

Long-term (up to 16\xa0months) health-related quality of life after adjuvant tailored dose-dense chemotherapy vs. standard three-weekly chemotherapy in women with high-risk early breast cancer

PurposeTo prospectively compare HRQoL effects of two modern adjuvant chemotherapy breast cancer treatment regimens at six time-points up to 16 months after random assignment.MethodsThe open-label, randomized, Phase 3 “Panther trial” was conducted between February 2007 and September 2011. 760 women, aged 65 years and younger, after surgery for non-metastatic node-positive or high-risk node-negative breast cancer were randomized 1:1 to the experimental group (four cycles of tailored and dose-dense adjuvant epirubicin and cyclophosphamide/2 weeks followed by four cycles of tailored dose-dense docetaxel/2 weeks) or standard group (three cycles of fluorouracil and epirubicin-cyclophosphamide/3 weeks followed by three cycles of docetaxel/3 weeks). HRQoL was assessed at all Swedish centres using EORTC QLQ-C30 and EORTC QLQ-BR23 at six points during 16 months before randomization.ResultsResponse rates to questionnaires were highest at baseline 728/780 (93%) and lowest 16 months after randomization, 557/750 (74%). HRQoL declined during treatment in both groups. At the end of treatment, the experimental group reported statistically significantly lower HRQoL (P < 0.001) than the standard group on global health status, physical functioning, role functioning, social functioning, fatigue, sexual functioning, and systemic therapy effects. No differences were found for emotional functioning, body image, and arm and breast symptoms. There were no statistically significant differences between the groups at the first follow-up and at subsequent assessments. HRQoL levels at the 16-month follow-up were similar to baseline values.ConclusionsNegative HRQoL impact of the dose-dense and tailored strategy appears to be prominent during treatment, but HRQoL recover once treatment ends.Trial Registration clinicaltrials.gov Identifier: NCT00798070; isrctn.org Identifier:ISRCTN39017665.

Tailored dose-dense chemotherapy in combination with trastuzumab as adjuvant therapy for HER2-positive breast cancer: A secondary analysis of the phase III PANTHER trial.

553 Background: Dose-dense (DD) adjuvant chemotherapy improves outcomes in early breast cancer (BC). However, there are no data to inform on the combination of DD chemotherapy with trastuzumab for patients with HER2-positive disease. Methods: This is a protocol predefined secondary analysis of the randomized phase 3 PANTER trial. Women 65 years old or younger with node-positive or high-risk node negative BC were randomized 1:1 to either tailored according to hematologic nadirs and DD epirubicin/cyclophosphamide (4 cycles) followed by 4 cycles of docetaxel (tDD EC/D) or standard 3-weekly 5-fluorouracil/E/C (3 cycles) and D (3 cycles); Patients with HER2-positive disease received 1 year of adjuvant trastuzumab. In addition, HER2-positive and an equal number of matched for age, treatment group and institution, HER2-negative patients that were enrolled in Swedish sites were enrolled in a predefined study of cardiac safety and underwent echocardiography or MUGA and electrocardiography at baseline and at four and six years of follow-up. The primary endpoint was BC relapse-free survival (BCRFS). Results: There were 342 HER2-positive patients; 335 received at least one dose of trastuzumab, while 29 patients discontinued trastuzumab prematurely. BCRFS was not statistically significantly in favor of tDD EC/D (HR = 0.68, 95% CI 0.37 – 1.27, P= 0.231). Cardiac outcomes after four and six years of follow-up did not differ significantly between HER2-positive and HER2-negative patients, nor between tDD and standard treatment. Conclusions: To our knowledge, these are the only data on combining DD adjuvant chemotherapy and trastuzumab in BC. The combination decreased the risk for BC relapse by 32% compared to standard treatment, a statistically non-significant difference. Its efficacy and safety merit further evaluation as part of both escalation and de-escalation strategies. Clinical trial information: NCT00798070.

Abstract P1-13-09: Long-term follow-up of two randomized controlled trials (N-SAS-BC01 trial and CUBC trial) comparing oral tegafur-uracil (UFT) versus classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) as adjuvant therapy in early breast cancer

Abstract Background: Two randomized controlled trials comparing the efficacy of oral tegafur-uracil (UFT) (2 years) with that of classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) (6 courses) were conducted in patients with resected early breast cancer. UFT is an oral fluoropyrimidine that combines tegafur, a prodrug of 5-fluorouracil, with uracil in a 1:4 molar ratio. One study was the N-SAS-BC01 trial (Watanabe et al, J Clin Oncol 2009), which was conducted in patients with high-risk node-negative breast cancer (n=733). The other was the CUBC trial (Park et al, Br J Cancer 2009), which was performed in patients with node-positive breast cancer (n=377). We reported the pooled analysis of these two randomized control trials using individual patient data (Ohashi et al, Breast Cancer Res Treat 2010). This pooled analysis showed that UFT was non-inferior to CMF in terms of inhibiting recurrence of estrogen receptor (ER)-positive early breast cancer. In addition, an exploratory subgroup analysis showed that UFT may be more effective in ER-positive patients who were 50 years or older. The present study was conducted to investigate the long-term efficacy of UFT or CMF in patients with early breast cancer. Methods: Long-term follow-up data for disease recurrence and survival were collected. Hazard ratios (HR) were determined using the Cox model stratified by study and adjusted for clinical characteristics, namely age, tumor size, nodal status, histological type, ER, and progesterone receptor (PgR). Survival curves were estimated by the Kaplan-Meier method. Hochberg multiplicity adjustment was applied in the previous pooled analysis, and non-inferiority of UFT versus CMF was shown in terms of relapse-free survival (RFS) in the ER-positive patient group. We investigated the non-inferiority of UFT in the same patient group with updated data. Restricted mean survival time (RMST) was calculated to consider the relative efficacy of UFT. This study is registered with JapicCTI-163321. Results: In total, 1,057 patients were analyzed (CMF, n=528; UFT n=529). The median follow-up time was 11.1 years (12.1 years in the N-SAS-BC 01 trial and 8.3 years in the CUBC trial). Table 1 shows the 10-year RFS and overall survival (OS) in all patients and ER-positive patients. The difference in RMST between arms at 20 years in terms of RFS was -2.7 months in all patients and 3.4 months in ER-positive patients. Table 2 shows the HR for RFS according to ER status and age. UFT (%)CMF (%)UFT to CMF; HR (95% CI)10-year RFSall patients74.477.11.02 (0.81–1.30)ER-positive patients75.075.10.91 (0.66–1.27)10-year OSall patients86.886.90.98 (0.72–1.34)ER-positive patients89.987.90.86 (0.54–1.37) Age &amp;lt;50 yearsAge ≥50 yearsER negative1.76 (0.95–3.26)0.93 (0.58–1.51)ER positive1.29 (0.74–2.23)0.76 (0.50–1.16) Conclusion: This study shows that UFT was shown to be non-inferior to CMF in terms of RFS in ER-positive early breast cancer. This result is similar to that of the previous pooled analysis. Sponsor: Taiho Pharmaceutical Co., LTD Citation Format: Yonemori K, Ohsumi S, Takao S, Tokuda Y, Ito Y, Nakagami K, Takahashi M, Yoshidome K, Nakayama T, Yamaguchi Y, Ohashi Y, Inaji H, Watanabe T. Long-term follow-up of two randomized controlled trials (N-SAS-BC01 trial and CUBC trial) comparing oral tegafur-uracil (UFT) versus classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) as adjuvant therapy in early breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-13-09.

Use of Granulocyte-colony Stimulating Factor During Chemotherapy and Its Association With CA27.29 and Circulating Tumor Cells—Results From the SUCCESS A Trial

BackgroundLittle is known about the effect of granulocyte colony-stimulating factor (G-CSF) treatment during adjuvant chemotherapy on prognostic markers. The present study explored the association between G-CSF and changes in cancer antigen (CA)27.29 and circulating tumor cell (CTC) levels during therapy. Patients and MethodsA total of 3754 node-positive or high-risk node-negative early-stage breast cancer patients were treated within the SUCCESS-A trial (simultaneous study of gemcitabine-docetaxel combination adjuvant treatment, as well as extended bisphosphonate and surveillance-trial). CA27.29 and CTCs were determined before the start and within 6 weeks after the end of chemotherapy. ResultsOverall, 1324 of the 2646 patients (50.0%) available for analysis had ≥ 1 G-CSF applications during chemotherapy. G-CSF application was significantly associated with CA27.29 status before and after chemotherapy (χ2 = 30.6, df = 3; P < .001), because 238 patients (18.0%) with G-CSF treatment but only 146 (11.0%) without G-CSF treatment switched from a negative CA27.29 status before to a positive CA27.29 status after chemotherapy. In addition, patients with G-CSF application showed a significantly greater increase in CA27.29 levels after chemotherapy compared with patients without any G-CSF application during chemotherapy (Mann-Whitney U test; Z = −7.81, P < .001). No significant association was found between G-CSF application and CTC status before or after chemotherapy (χ2 = 1.2, df = 3; P = .75). ConclusionCautious interpretation is needed regarding elevated levels of MUC-1–derived tumor markers such as CA27.29 shortly after adjuvant chemotherapy when G-CSF has been given, because G-CSF treatment was associated with increased CA27.29 levels after chemotherapy.

Abstract GS1-02: NSABP B-47 (NRG oncology): Phase III randomized trial comparing adjuvant chemotherapy with adriamycin (A) and cyclophosphamide (C) → weekly paclitaxel (WP), or docetaxel (T) and C with or without a year of trastuzumab (H) in women with node-positive or high-risk node-negative invasive breast cancer (IBC) expressing HER2 staining intensity of IHC 1+ or 2+ with negative FISH (HER2-Low

Abstract Background: Adjuvant trastuzumab (H) reduces cancer recurrence and improves survival in patients (pts) with HER2-amplified or overexpressing (IHC 3+ staining intensity) IBC. Two of the landmark trials that demonstrated the efficacy of H-based eligibility on HER2 testing performed at local site laboratories were found to contain a cohort of pts without amplification or IHC overexpression on tissue submitted for central testing. These HER2-low cohorts appeared to benefit from the addition of H, and efforts at external HER2 testing validation and laboratory explorations did not negate these findings. NSABP B-47 was performed to determine if these findings would be confirmed in a large prospective randomized trial. The primary aim was to determine whether the addition of H to chemotherapy (CT) regimens of AC→WP or TC (choice per investigator discretion) would improve invasive disease-free survival (IDFS). Methods: From 2/8/2011 to 2/10/2015, 3270 women were enrolled with 1630 pts randomly assigned to Arm 1 [TC: docetaxel 75mg/m2, cyclophosphamide 600 mg/m2 every 3 weeks x 6 cycles; or AC→WP: doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 2 or 3 weeks x 4 cycles followed by paclitaxel 80 mg/m2 every week x 12], and 1640 pts to Arm 2 [same CT regimens + 12 months of H]. Pts were stratified by IHC score (1+ vs 2+), number of positive nodes (0-3, 4-9, ≥10), hormone receptor status (ER or PgR positive vs both negative), and CT (TC vs AC→WP). Overall 58.5% were ≥50 years, 57% had tumors with IHC 1+, 17.3% were ER- and PgR-, 19.9% were node negative, and 27.4% had ≥4 positive nodes. TC was the intended CT regimen for 44.2%. Results: As of 7/31/2017, the median follow-up time was 46.1 months. We observed 264 IDFS events, which triggered the definitive analysis for the primary endpoint. The addition of H to CT showed a 5-year IDFS of 89.6% compared to 89.2% for CT alone (HR 0.98; 95%CI 0.77-1.26; P=0.90). The findings did not differ by level of HER2 IHC expression, level of lymph node involvement, or hormone receptor status. 5-year point estimates for RFI were 92.0% for CT+H compared to 92.2% for CT alone (HR 0.995; 95%CI 0.75-1.32; P=0.97). 5-year estimates for DRFI were 92.7% for CT+H and 93.5% for CT alone (HR 1.10; 95%CI 0.81-1.49; P=0.55). The addition of H did not change OS significantly with 5-year point estimates of 94.8% in CT+H vs 96.2% in CT alone (HR 1.33; 95%CI 0.91-1.94; P=0.14). 4.3% of women in the CT arm experienced Grade 4 or 5 toxicities compared to 5.0% in CT+H. Conclusion: The addition of H to CT did not demonstrate a reduction in IDFS, RFI, or DRFI in women with non-overexpressing but IHC measurable HER2 IBC. This prospective study did not confirm the retrospective findings in NSABP B-31 or N9831. The threshold of HER2 expression or genetic amplification for H benefit remains unchanged. Support: NCI U10-180868, -180822, -44066, UG1-189867, and Genentech, Inc. Citation Format: Fehrenbacher L, Cecchini RS, Geyer CE, Rastogi P, Costantino JP, Atkins JN, Polikoff J, Boileau J-F, Provencher L, Stokoe C, Moore TD, Robidoux A, Borges V, Albain KS, Swain SM, Paik S, Mamounas EP, Wolmark N. NSABP B-47 (NRG oncology): Phase III randomized trial comparing adjuvant chemotherapy with adriamycin (A) and cyclophosphamide (C) → weekly paclitaxel (WP), or docetaxel (T) and C with or without a year of trastuzumab (H) in women with node-positive or high-risk node-negative invasive breast cancer (IBC) expressing HER2 staining intensity of IHC 1+ or 2+ with negative FISH (HER2-Low IBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS1-02.

Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial

SummaryBackgroundAdjuvant chemotherapy for early breast cancer has improved outcomes but causes toxicity. The UK TACT2 trial used a 2×2 factorial design to test two hypotheses: whether use of accelerated epirubicin would improve time to tumour recurrence (TTR); and whether use of oral capecitabine instead of cyclophosphamide would be non-inferior in terms of patients' outcomes and would improve toxicity, quality of life, or both.MethodsIn this multicentre, phase 3, randomised, controlled trial, we enrolled patients aged 18 years or older from 129 UK centres who had histologically confirmed node-positive or high-risk node-negative operable breast cancer, had undergone complete excision, and were due to receive adjuvant chemotherapy. Patients were randomly assigned to receive four cycles of 100 mg/m2 epirubicin either every 3 weeks (standard epirubicin) or every 2 weeks with 6 mg pegfilgrastim on day 2 of each cycle (accelerated epirubicin), followed by four 4-week cycles of either classic cyclophosphamide, methotrexate, and fluorouracil (CMF; 600 mg/m2 cyclophosphamide intravenously on days 1 and 8 or 100 mg/m2 orally on days 1–14; 40 mg/m2 methotrexate intravenously on days 1 and 8; and 600 mg/m2 fluorouracil intravenously on days 1 and 8 of each cycle) or four 3-week cycles of 2500 mg/m2 capecitabine (1250 mg/m2 given twice daily on days 1–14 of each cycle). The randomisation schedule was computer generated in random permuted blocks, stratified by centre, number of nodes involved (none vs one to three vs four or more), age (≤50 years vs >50 years), and planned endocrine treatment (yes vs no). The primary endpoint was TTR, defined as time from randomisation to first invasive relapse or breast cancer death, with intention-to-treat analysis of standard versus accelerated epirubicin and per-protocol analysis of CMF versus capecitabine. This trial is registered with ISRCTN, number 68068041, and with ClinicalTrials.gov, number NCT00301925.FindingsFrom Dec 16, 2005, to Dec 5, 2008, 4391 patients (4371 women and 20 men) were recruited. At a median follow-up of 85·6 months (IQR 80·6–95·9) no significant difference was seen in the proportions of patients free from TTR events between the accelerated and standard epirubicin groups (overall hazard ratio [HR] 0·94, 95% CI 0·81–1·09; stratified p=0·42). At 5 years, 85·9% (95% CI 84·3–87·3) of patients receiving standard epirubicin and 87·1% (85·6–88·4) of those receiving accelerated epirubicin were free from TTR events. 4358 patients were included in the per-protocol analysis, and no difference was seen in the proportions of patients free from TTR events between the CMF and capecitabine groups (HR 0·98, 95% CI 0·85–1.14; stratified p=0·00092 for non-inferiority). Compared with baseline, significantly more patients taking CMF than those taking capecitabine had clinically relevant worsening of quality of life at end of treatment (255 [58%] of 441 vs 235 [50%] of 475; p=0·011) and at 12 months (114 [34%] of 334 vs 89 [22%] of 401; p<0·001 at 12 months) and had worse quality of life over time (p<0·0001). Detailed toxicity and quality-of-life data were collected from 2115 (48%) of treated patients. The most common grade 3 or higher adverse events in cycles 1–4 were neutropenia (175 [16%]) and fatigue (56 [5%]) of the 1070 patients treated with standard epirubicin, and fatigue (63 [6%]) and infection (34 [3%]) of the 1045 patients treated with accelerated epirubicin. In cycles 5–8, the most common grade 3 or higher adverse events were neutropenia (321 [31%]) and fatigue (109 [11%]) in the patients treated with CMF, and hand-foot syndrome (129 [12%]) and diarrhoea (67 [6%]) in the 1044 patients treated with capcitabine.InterpretationWe found no benefit from increasing the dose density of the anthracycline component of chemotherapy. However, capecitabine could be used in place of CMF without significant loss of efficacy and with improved quality of life.FundingCancer Research UK, Amgen, Pfizer, and Roche.