Cycles Of CMF Research Articles

Postmastectomy radiotherapy in high-risk breast cancer patients given adjuvant systemic therapy. A 30-year long-term report from the Danish breast cancer cooperative group DBCG 82bc trial

BackgroundBetween 1982 and 1990 the Danish Breast Cancer Cooperative Group (DBCG) conducted a randomized trial in high-risk pre- and postmenopausal (<70 years) breast cancer patients comparing mastectomy plus adjuvant systemic therapy alone versus the same treatment plus postoperative irradiation. AimTo present a comprehensive analysis of the complete DBCG 82bc study with a 30-year long-term follow-up of the cancer therapeutic effect and survival, together with an additional focus on the potential long-term life-threatening morbidity related to cardiac irradiation and/or the risk of secondary cancer induction. MethodsA total of 3083 patients with pathological stage II and stage III breast cancer were after mastectomy randomly assigned to receive adjuvant systemic therapy and postoperative irradiation to the chestwall and regional lymph nodes (1538 pts), or adjuvant systemic therapy alone (1545 pts). Pre- and menopausal patients (DBCG 82b) received 8–9 cycles of CMF with an interval of 4 weeks, whereas postmenopausal patients (DBCG 82c) received tamoxifen 30 mg daily for one year. The median follow-up time was 34 years. The primary endpoints were loco-regional recurrence (LRR) and overall mortality, and the secondary endpoints were distant metastasis, breast cancer mortality, and irradiation related late morbidity. ResultsOverall the 30-year cumulative incidence of loco-regional recurrence was 9% in irradiated patients versus 37% in non-irradiated patients who received adjuvant systemic therapy alone (HR: 0.21 [95% cfl 0.18–0.26]). Distant metastasis probability at 30 years was 49% in irradiated patients compared to 60% in non-irradiated (HR: 0.77 [0.70–0.84]). Consequently, these figures resulted in a reduced breast cancer mortality: 56% vs 67% (HR: 0.75 [0.69–0.82], and overall mortality (81% vs 86% at 30 years (p < 0.0001), HR: 0.83 [0.77–0.90] in favor of irradiation. Radiotherapy did not result in any significant excess death of other courses, such as ischemic heart disease, HR: 0.82 [0.58–1.18]; nor secondary lung cancer HR: 1.44 [0.92–2.24], or other non-cancer related death HR: 1.15 [0.92–1.45]. ConclusionThe study definitely demonstrate that optimal long-term treatment benefit of high-risk breast cancer can only be achieved if both loco-regional and systemic tumor control are aimed for. Therefore, radiotherapy has an important role in the multidisciplinary treatment of breast cancer. The PMRT treatment did not result in excess ischemic heart damage, nor in other non-breast cancer related death.

Abstract P1-12-01: Dose-dense sequential adjuvant chemotherapy in the trastuzumab era: Final long-term results of the hellenic cooperative oncology group phase III HE10/05 trial

Abstract Background: Dose-dense sequential chemotherapy based on anthracyclines and taxanes has achieved an 18% reduction of recurrence risk in the adjuvant setting of early breast cancer (BC). However, the optimal chemotherapy schedule and the preferable interval between cycles are still under investigation. Methods: A total of 990 eligible BC patients were randomized to receive either 3 cycles of epirubicin (E,110 mg/m2) every 2 weeks followed by 3 cycles of paclitaxel (T, 200 mg/m2) every 2 weeks followed by 3 cycles of intensified CMF (Control Arm A, E-T-CMF; 333 patients) or three cycles of epirubicin followed by 3 cycles of CMF followed by 9 consecutive weekly cycles of docetaxel (wD) 35 mg/m2 (Experimental Arm B, E-CMF-wD; 331) or 9 consecutive weekly cycles of paclitaxel (wT) 80 mg/m2 (Experimental Arm C, E-CMF-wT; 326). Trastuzumab was administered for HER2-positive disease. The primary endpoint was disease-free survival (DFS). Results: At a median follow-up of 13.3 years, 330 DFS events (33.3%) had been reported. DFS and overall survival (OS) did not differ between patients in the combined B and C arms versus control arm A either in the entire cohort (HR=0.90, p=0.38 and HR=0.85, p=0.20) or among HER2-positive, trastuzumab-treated patients (HR=0.69, p=0.13 and HR=0.67, p=0.13). Thirty-four patients (3.4%) developed secondary neoplasms. Conclusions: Overall, no significant differences in DFS or OS were found amongst the studied regimens after a long-term observational period. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12610000151033 Citation Format: Flora Zagouri, Georgia-Angeliki Koliou, Foteinos Dimitrakopoulos, Christos Papadimitriou, Ioannis Binas, Angelos Koutras, Pavlos Papakostas, Christos Markopoulos, Vasileios Venizelos, Grigorios Xepapadakis, Charisios Karanikiotis, Amanda Psyrri, Dimitrios Bafaloukos, Paris Kosmidis, Gerasimos Aravantinos, Eleni Res, Davide Mauri, Anna Koumarianou, Kalliopi Petraki, Anna Tsipoura, Dimitrios Pectasides, Helen Gogas, George Fountzilas. Dose-dense sequential adjuvant chemotherapy in the trastuzumab era: Final long-term results of the hellenic cooperative oncology group phase III HE10/05 trial [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 P1-12-01.

Breast Cancer in Young and Premenopausal Women

Abstract Breast cancer is not a unique disease. In the last 10 years it has become quite clear that breast cancer can be separated into different categories with treatment implications. Patients younger than 40 years of age can be considered as a special population. The bilogicla features are different these women have of special needs. In early breast cancer their tumours are more often hormone-receptor negative, of higher grade and in general more aggressive. Young women with breast cancer tend to have an inferior disease free and overall survival. The use neoadjuvant of chemotherapy results in higher pathological complete response rates than in elderly women. The younger the patients the higher the pCR rate. In data form the TAILOR-X study premenopausal women with an intermediate recurrence score benefit from chemotherapy. One theory might be that these women render menopausal by using chemotherapy . This hypothesis needs to be further examined. Data from the ZORO study in the late 90s confirmed that the DFS in premenopausal women is similar between 2years of LHRH analogues and 6 cycles of CMF. Both treatments are considered not standard of care anymore but underline that a substantial effect of chemotherapy is rendering the women postmenopausal. Young women need to be acknowledged a separate entity.

Abstract PD10-03: Predictive value of a proliferation score (MS) in postmenopausal women with endocrine-responsive breast cancer: results from International Breast Cancer Study Group (IBCSG) Trial IX

Abstract Background: While representing the largest fraction of women diagnosed with primary breast cancer, older postmenopausal women with ER+, HER2− tumors are less responsive to chemoendocrine therapy than younger women and have been underrepresented in molecular profiling of randomized trials. IBCSG Trial IX, a randomized controlled trial in postmenopausal women, median age 61y, with node negative disease, failed to demonstrate the benefit of preceding tamoxifen (T) by 3 cycles of CMF for ER+ tumors. We sought to determine if MS, a proliferation score, could identify a subset of women who differentially benefit from addition of chemotherapy to T in this trial. Methods: From 1988–1999, 1669 eligible patients (1040 with ER+, HER2− tumors) were randomized to CMF→T vs T. Disease-free survival (DFS) was the primary trial endpoint; breast cancer-free interval (BCFI) which excludes second (non-breast) malignancies and censors deaths without prior cancer event was also evaluated. Analysis was limited to the first 7 years of follow-up. From 671 (ER+, HER2−) available subjects, 568 were successfully profiled by RT-PCR. The mRNA expression levels of 14 equally-weighted proliferation genes and 3 normalization genes were used to generate MS; predetermined binary categorization of MS was used. Analysis of this post hoc, pre-specified study used results from centralized laboratory IHC and Cox models to assess the predictive value of MS on DFS and BCFI, adjusting for traditional risk factors of local treatment, age, ER, PR, Ki67, tumor size and grade. Results: Subgroups of MS (low, 169 samples (30%) and high, 399 samples (70%)) were identified. MS by treatment interaction was significant for DFS and BCFI (each p ≤ 0.004). Among patients with low MS, CMF→T improved DFS (HR 0.19, 95% CI 0.06–0.59) and BCFI (HR 0.19, 95% CI 0.05–0.72) vs T; 7y DFS was 95% vs 83% with CMF→T vs T. Among patients with high MS, CMF→T did not improve DFS (HR 1.27, 95% CI 0.79–2.05) or BCFI (HR 1.37, 95% CI 0.80–2.33) and 7y DFS of 81% for CMF→T and T. Continuous MS was moderately correlated with log Ki67 (r = 0.47) but not correlated with ER or PR. The MS by treatment interaction remained significant with Ki67 in the model. Conclusions: Low MS was associated with differential benefit favoring those women receiving CMF→T vs T alone for both DFS and BCFI in the first 7 years. The effect was independent of traditional risk factors including Ki67. Hence this study, which is unconfounded by chemotherapy-induced ovarian ablation in younger women, identifies a subset of postmenopausal women with ER+, HER2− tumors that benefit from CMF chemotherapy. This seemingly incongruous observation is consistent with a) the prior observation that only the low-proliferation subgroup by PAM50 11-gene signature benefits from the addition of weekly paclitaxel to adjuvant FEC (GEICAM/9906), b) the ability of MS to identify a subset of women with tumors with disseminated luminal progenitor cells activated through the agonistic activity of tamoxifen, and c) the repetitive dosing of cyclophosphamide and taxol being hypothesized to act via tumor stroma/anti-angiogenesis. The relative contribution of these factors is under investigation. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD10-03.

246O - Dose-Dense Sequential Adjuvant Chemotherapy With Epirubicin, Paclitaxel and CMF Versus Epirubicin, Cmf and Weekly Docetaxel or Paclitaxel Followed by Trastuzumab for One Year in Patients With Early Breast Cancer

ABSTRACT Background Dose-dense sequential chemotherapy including anthracyclines and taxanes has been well established in the adjuvant setting of high-risk operable breast cancer. However, the preferable taxane and optimal schedule of administration have not been defined, as yet. Patients and methods From July 2005 until November 2008, 1,001 patients (990 eligible) were randomized to receive 3 cycles of epirubicin 110 mg/m2 followed by 3 cycles of paclitaxel 200 mg/m2 followed by 3 cycles of CMF (cyclophosphamide 840 mg/m2; methotrexate 57 mg/m2; fluorouracil 840 mg/m2) with G-CSF support (Group A; 333 patients) or to 3 cycles of epirubicin followed by 3 cycles of CMF, as in Group A, followed 3 weeks later by 9 weekly cycles of docetaxel 35 mg/m2 (Group B; 331 patients) or 9 weekly cycles of paclitaxel 80 mg/m2 (Group C; 328 patients). Radiation and hormonal therapy were given after the completion of chemotherapy. Trastuzumab was administered for 1 year to all HER2-positive patients post radiation. Results At a median follow-up of 60 months, 123 patients had documented disease relapse (51 in Group A, 37 in Group B and 35 in Group C) and 81 deaths (30 in group A, 22 in group B and 29 in group C) had been observed. The 3-year disease-free survival (DFS) rate was 86%, 91% and 89%, with overall survival (OS) rates of 96%, 97% and 96%, respectively. No differences were found in DFS or OS between the three treatment groups (log-rank, p = 0.38 and p = 0.48, respectively). The most frequently reported severe adverse events were neutropenia (29% vs 27% vs 24%, p = 0.31) and leucopenia (12% vs 13% vs 10%, p = 0.66). Febrile neutropenia occurred in fifty patients (6%, vs 5% vs 5%, p = 0.81). Severe mucositis was more frequent in Group B (3% vs 6% vs 1%, p = 0.001), while severe neuropathy was more frequent in Group A (4% vs 0% vs 1%, p Conclusions No significant differences in DFS and OS between the three regimens were identified. Taxane regimen and schedule of administration preferentially influenced the type of severe toxicities. HER2-positive patients demonstrated comparable 3-year DFS and OS rates with those reported in other similar studies. Disclosure All authors have declared no conflicts of interest.

Abstract P5-13-01: Patterns of Breast Cancer Relapse According to Breast Cancer Subtypes in Lymph Node-Negative Breast Cancer — Results from International Breast Cancer Study Group Trials VIII and IX

Abstract Background: To explore the patterns of breast cancer (BC) relapse according to BC subtypes in a lower risk (lymph node (LN)-negative) population we classified pts from two trials according to a molecular classification using IHC surrogates. IBCSG Trial VIII randomized 1109 premenopausal pts with LN-negative BC to sequential treatment with six cycles of CMF followed by 18 months of goserelin, six courses of CMF alone, or 24 months of goserelin alone. The IBCSG Trial IX randomized 1669 postmenopausal pts with LN-negative BC to sequential treatment with 3 courses of CMF followed by tamoxifen for 57 months or tamoxifen alone for 5 years. Retrospective central pathology evaluation including ER, PgR, HER2 and Ki67 was used to define a molecular classification. Patients &amp; Methods: Of the 2778 pts enrolled in both trials the present analysis includes 2033 (824 from trial VIII and 1209 from trial IX) who also had centrally-reviewed pathology data. The BC molecular subtypes were defined as following: Luminal-A (ER and/or PR-present, HER2-negative and Ki67&amp;lt;14%); Luminal-B (ER and/or PR-present, HER2-negative and Ki67 ≥14%); HER2 (HER2-positive independent of ER and PgR status); basal (HER2-, ER-, and PR-negative). Time to the first recurrence in a specific site was calculated from randomization and evaluated using cumulative incidence analysis and competing-risks regression analysis. Wald tests were used to determine the interaction effect of treatment group and molecular subtypes. Results: In the population analyzed (N = 2033), 25.9% had luminal-A (LA) tumors, 40.3% had luminal B (LB) tumors, 17.7% had HER2-positive tumors, and 16.0% had basal tumors. At 12.7 years median follow-up, a total of 699 (34.4%) pts had BC recurrence or non-BC events (secondary malignancy or death): LA = 152 (28.8%), LB = 291 (35.5%), HER2- positive = 134 (37.2%), and Basal = 122 (37.4%). Among 2033 pts, no significant differences were observed among the molecular subtypes for time to local recurrence (LA 6.1%, LB 6.7%, HER2 7.8%, basal 6.7%, p = 0.98), contralateral BC (LA 3.4%, LB 4.1%, HER2 2.5%, basal 4.9%; p = 0.36), and non-BC events (LA 12%, LB 10%, HER2 8.3%, basal 7.7%; p=0.39). Patients with LB disease had more bone recurrences (LB 5.5%, LA 2.5%, HER2 3.3%, basal 1.8%; p=0.004). The patterns over time of soft tissue nodes and visceral recurrence varied according to the adjuvant treatment received (interaction tests P&amp;lt;0.001 and p=0.007, respectively). Among pts receiving chemotherapy (N = 1139), HER2-positive pts had more and earlier visceral recurrence (HER2 11%, Basal 8%, LB 8.5%, LA 3.1%; p=0.005). Among pts not receiving chemotherapy (N=859), basal and HER2-positive pts had more visceral recurrences than luminal pts (HER2 15.3%, Basal 15.0%, LB 4.2%, LA 4.0%; P&amp;lt;0.001). Conclusion: In this large retrospective analysis we observed a higher incidence of bone recurrence among all LB tumors, while among those allocated chemotherapy LB tumors had a similar incidence of visceral recurrence when compared to basal tumors. Patterns of other DFS events were similar in all subtypes. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-13-01.

Phase 2 trial of primary systemic therapy with doxorubicin and docetaxel followed by surgery, radiotherapy, and adjuvant chemotherapy with cyclophosphamide, methotrexate, and 5‐fluorouracil based on clinical and pathologic response in patients with stage IIB to III breast cancer

This study was performed to evaluate the outcomes of patients with locally advanced breast cancer (LABC) who were treated with a multidisciplinary approach including primary systemic chemotherapy and noncross-resistant adjuvant chemotherapy. Patients with LABC received 4 or 6 cycles of doxorubicin and docetaxel (DT) as primary systemic chemotherapy (PST) every 21 days. Patients with adequate response underwent surgery followed by adjuvant chemotherapy according to pathologic response: complete (pCR), 2 more cycles of DT; partial (pPR), 2 more cycles of DT followed by 6 cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU) (CMF); and minor (pMR), 6 cycles of CMF. Patients then received radiation and tamoxifen (hormone receptor-positive patients only). Eighty-eight patients were evaluable. Seventy-four patients had an adequate response to DT and were considered operable, and 72 underwent surgery. Ten patients (13.9%) achieved a pCR, 22 (30.5%) achieved a pPR, and 40 achieved a pMR (55.5%). Fourteen patients were considered nonoperable after DT and underwent salvage CMF therapy. Five of these patients underwent surgery and 1 had achieved a pCR. The estimated 5-year recurrence-free survival (RFS) rates for patients with pCR, pPR, and pMR were 80%, 77%, and 59%, respectively, and the estimated 5-year overall survival (OS) rates were 90%, 91%, and 74%, respectively. The 5-year OS rates were 82% for initially operable and 21% for initially inoperable patients (P < or = .001) Multidisciplinary therapy that includes PST with DT and adjuvant therapy with CMF administered according to the clinical and pathologic response is associated with high long-term RFS and OS rates in patients with LABC. Clinical or pathologic PR or CR to DT predicts improved RFS and OS.

Uracil-tegafur and tamoxifen vs cyclophosphamide, methotrexate, fluorouracil, and tamoxifen in post-operative adjuvant therapy for stage I, II, or IIIA lymph node-positive breast cancer: a comparative study

Background:It has been reported that treatment with uracil-tegafur (UFT) has shown significantly better survival and relapse-free survival (RFS) than surgery alone. Therefore, we compared UFT with a combination therapy of cyclophosphamide, methotrexate, and fluorouracil (CMF) in patients who had undergone curative surgery for axillary lymph node-positive breast cancer.Methods:A total of 377 node-positive patients with stage I, II, or IIIA disease were registered from September 1996 through July 2000 and were randomly assigned to either 6 cycles of CMF or 2 years of UFT. In both arms, tamoxifen (TAM) was concurrently administered for 2 years. The primary end point in this study was the non-inferiority of UFT to CMF.Results:No statistically significant difference between the two groups was observed with regard to the 5-year RFS rate (72.2% in the UFT and 76.3% in the CMF). Adverse event profiles differed between the two groups, with a significantly lower incidence of leukopenia and anaemia in the UFT group, as well as anorexia, nausea/vomiting, stomatitis, and alopecia, which have implications for quality of life.Conclusion:UFT administered in combination with TAM holds promise in the treatment of lymph node-positive early breast cancer. On stratified analysis, the recurrence rate in the UFT group was found to be better in oestrogen receptor (ER)-positive patients. Tegafur-based treatment should be evaluated by a prospective randomised trial conducted in ER-positive patients.

Survival advantage by neoadjuvant radiochemotherapy in locally advanced noninflammatory breast cancer

638 Background: The impact of timing of radiochemotherapy (RCT) relative to surgery has been assessed in terms of ten year survival rate for locally advanced or surgically in terms of breast conserving surgery or simple mastectomy unfavourable, noninflammatory breast cancers (LABC). Methods: A total of 644 women were included in the retrospective study from 1991–1998. Chemotherapy was applied in 166 as neoadjuvant, in 236 simultaneously and in 113 as adjuvant. 119 patients received no chemotherapy. 40% of the patients received four courses of epirubicin/ cyclophosphamide, 26% concurrent mitoxantrone, 5% three cycles of CMF, 3% six cycles of CMF and 15% had no chemotherapy. 315 patients with locally advanced breast cancer (LABC) received neoadjuvant and 329 adjuvant RCT. Preoperative radiotherapy consisted of 50 Gy to the breast and the supra/infraclavicular lymph nodes with a 10 Gy electron or interstitial boost. The mean time interval between the end of radiotherapy and the surgery was 27 weeks (6–89 weeks). Results: Breast conservation was possible in 48% in the preoperative arm and in 52% in the postoperative arm. The rate of pT0 after neoadjuvant RCT was 38% (120/315) and the pCR in breast and axilla 30% (95/315). The ten year survival in the neoadjuvant group (n = 315) compared favourably 68.6% vs. 65% in case of the adjuvant group (n = 329; p = 0.21) in spite of more advanced disease. Patients with cT1- (n = 3) and cT2- (n = 97) categories had a significantly 13.6% better ten year survival rate after neoadjuvant RCT (85.76% vs. 72.19%) compared to cT1- (n = 1) and cT2- (n = 180) after adjuvant RCT (p = 0.0026). Conclusions: This study compares, retrospectively, neoadjuvant RCT vs. adjuvant RCT in LABC. Preoperative RCT achieved a pT0-rate of 38% and a prolonged ten year survival to a degree of 13.6% statistically significant in patients with cT2- category breast cancer compared to adjuvant RCT. No significant financial relationships to disclose.

Dose-dense (DD) cyclophosphamide, methotrexate, and fluorouracil (CMF) at 14-day intervals: A pilot study of every 14- and 10–11-day dosing intervals for women with early-stage breast cancer

590 Background: CMF (C 600 mg/m2, M 40 mg/m2, F 600 mg/m2) is an option for adjuvant therapy for patients with low risk early stage breast cancer. DD regimens as predicted by mathematical models of cancer growth and treatment response are superior. We previously demonstrated the safety of DD EC (epirubicin/cyclophosphamide) followed by paclitaxel at 10–11 day (d) intervals. We investigated the feasibility of administering DD adjuvant CMF every 14 d and then every 10–11 d in a 2-stage phase II trial. Methods: An initial cohort (A) was treated q 14 d with PEG-filgrastim (Neulasta) support. A second cohort (B) was treated every 10–11 d with filgrastim/Neupogen x 5 d and then, based on feasibility, modified (cohort C) to use 7 d filgrastim. The primary end point was feasibility defined as having ANC &gt; 1.5 x 103/uL on day 1 of planned treatment for all 8 cycles with no grade 3 or higher non-hematologic toxicity. All three cohorts were tested using a Simon's two-stage optimal design with type I and type II errors set at 10%. This design would effectively discriminate between true tolerability (as protocol-defined) rates of&lt; 60% and&gt; 80%. Cohort A: 38 pts with early stage breast cancer were accrued from 3/2008 though 6/2008. Cohort B: 7 pts were accrued from June 2008 through August 2008. Cohort C: Is still open with 16 pts accrued from August 2008 through December 5, 2008. Results: Median age 51: range 38 to 78. Cohort A: 29/38 pts completed 8 cycles of CMF. The regimen was considered feasible. 2 other pts completed 7 cycles and were withdrawn for depression and grade 2 transaminitis. The 7 other pts completed between 1 and 6 cycles of CMF were withdrawn as follows: 3 personal, 1 (grade 3) bone pain, 2 allergy unrelated to CMF, and 1 seizure. Cohort B: 7 pts were accrued. 6 out of 7 pts could not complete 8 cycles of chemotherapy secondary to neutropenia and 1 secondary to grade 3 ALT elevation. Cohort C: Accrual has not been completed. 16 pts are currently enrolled. Conclusions: Dose dense adjuvant CMF is feasible at 14 d intervals with PEG-filgrastim support. Adjuvant CMF every 10–11 days with filgrastim given for 5 days beginning day 2 is not feasible. Accrual is ongoing for CMF at 10–11 days with filgrastim x 7 days. Updated results will be available for Cohort C. [Table: see text]

Oral Uracil and Tegafur Compared With Classic Cyclophosphamide, Methotrexate, Fluorouracil As Postoperative Chemotherapy in Patients With Node-Negative, High-Risk Breast Cancer: National Surgical Adjuvant Study for Breast Cancer 01 Trial

The primary aim of this study was to compare the effectiveness of oral uracil-tegafur (UFT) with that of classical cyclophosphamide, methotrexate, and fluorouracil (CMF) given as postoperative adjuvant treatment to women with node-negative, high-risk breast cancer. Women with node-negative, high-risk breast cancer were randomly assigned to receive either 2 years of UFT or six cycles of CMF after surgery. The primary end point was relapse-free survival (RFS). Overall survival (OS), toxicity, and quality of life (QOL) were secondary end points. The hypothesis was that UFT was not inferior to CMF in terms of RFS. Between October 1996 and April 2001, a total of 733 patients were randomly assigned to receive either treatment. The median follow-up time was 6.2 years. The RFS rates at 5 years were 88.0% in the CMF arm and 87.8% in the UFT arm. OS rates were 96.0% and 96.2%, respectively. The hazard ratios of the UFT arm relative to the CMF arm were 0.98 for RFS (95% CI, 0.66 to 1.45; P = .92) and 0.81 for OS (95% CI, 0.44 to 1.48; P = .49). The toxicity profiles differed between the two groups. The QOL scores were better for patients given UFT than those given CMF. RFS and OS with oral UFT were similar to those with classical CMF. Given the higher QOL scores, oral UFT is a promising alternative to CMF for postoperative adjuvant chemotherapy in women with node-negative, high-risk breast cancer.

Neoadjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer: primary efficacy analysis of the NOAH trial.

Abstract Abstract #31 Background: Trastuzumab (Herceptin®; H) improves survival in HER2-positive early and metastatic breast cancer. The Phase III NOAH trial is the largest neoadjuvant study that evaluated the addition of H to an anthracyclines- and taxanes-based chemotherapy (CT) for patients (pts) with HER2-positive locally advanced breast cancer (LABC).&amp;#x2028; Methods: In this multicentre, randomised, open-label trial, women aged ≥18 years with HER2-positive (IHC 3+ or FISH+) LABC (T3N1 or T4; any T + N2 or N3 or + ipsilateral supraclavicular node involvement) were randomised to receive 3 cycles of doxorubicin (60 mg/m²) and paclitaxel (150 mg/m²) q3w, 4 cycles of paclitaxel (175 mg/m² q3w) and 3 cycles of CMF (cyclophosphamide 600 mg/m², methotrexate 40 mg/m², 5-fluorouracil 600 mg/m² q4w) on Days 1 and 8, with or without concomitant H (8 mg/kg loading dose then 6 mg/kg q3w for 1 year) before surgery. In parallel, LABC pts screened as HER2-negative (IHC 0/1+) received the same CT regimen. The primary end point was event-free survival (EFS), defined as the time between randomisation and disease recurrence or progression, or death from any cause. Secondary end points were pathological complete response (pCR), overall response rate (ORR), overall survival (OS) and safety. We report for the first time here the study's primary endpoint.&amp;#x2028; Results: 327 pts were enrolled. Baseline characteristics were balanced for randomised pts. Inflammatory breast cancer was present in 27% of HER2-positive vs 14% of HER2-negative tumours, while 35% vs 64%, respectively, were hormone-receptor positive. EFS was analyzed after 88 events in the HER2-positive group (n=228). EFS rate at 3 years was significantly better in the H + CT arm compared with CT alone: 70.1% vs 53.3%, respectively (HR 0.56; p=0.007). EFS rate in the HER2-negative arm was 67.4%. OS data were immature at this stage. Trastuzumab treatment was the only variable significantly associated with EFS outcome in multivariate analysis which included disease stage and hormonal receptor status. Both ORR and pCR were significantly higher in the H + CT arm compared to CT alone: 89% vs 77% for ORR, respectively (p=0.02); 39% vs 20% for pCR, respectively (p=0.002). Similar results for ORR and pCR were observed between the HER2-positive CT-alone arm and the HER2-negative arm. The addition of H to CT in the neoadjuvant setting was well tolerated with acceptable cardiac safety.&amp;#x2028; Conclusion: Neoadjuvant H significantly increased EFS in pts with HER2-positive LABC. This analysis of the NOAH study establishes neoadjuvant H with CT as a standard treatment option in women with HER2-positive LABC. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 31.

Long-Term Benefit of High-Dose Epirubicin in Adjuvant Chemotherapy for Node-Positive Breast Cancer: 15-Year Efficacy Results of the Belgian Multicentre Study

The 4-year results of this trial demonstrated that a higher dose of epirubicin with cyclophosphamide (HEC) is superior to a lower dose of epirubicin, 60 mg/m(2) (EC), for event-free survival (EFS; 27% reduction), but is not superior to classical oral cyclophosphamide, methotrexate, and fluorouracil (CMF) in the adjuvant treatment of node-positive breast cancer. Herein we report the 15-year data on efficacy and long-term toxicity of this three-arm Belgian multicenter trial. Between March 1988 and December 1996, 777 eligible patients were randomly assigned to six cycles of CMF, eight cycles of EC, or eight cycles HEC. The 15-year EFS was 45% for patients who received CMF, 39% for patients who received EC, and 50% for patients who received HEC. The hazard ratios (HR) were 0.77 for HEC versus EC (95% CI, 0.60 to 0.98; P = .03), 0.90 for HEC versus CMF (P = .39), and 0.86 for EC versus CMF (P = .21). No difference in overall survival (OS) was seen. Cardiac toxicity was more frequent with HEC than with CMF (11 patients v 1 patient; P = .006), but no more than with EC (P = .21). Treatment with HEC demonstrated superior EFS when compared with lower-dose epirubicin. However, we do not recommend the use of HEC regimen in daily clinical practice, mainly because of the higher risk of cardiotoxicity related to the cumulative doses of epirubicin and the lack of superiority of anthracyclines over CMF in our study.

Biomarkers as potential predictors of pathologic complete response (pCR) in the NOAH trial of neoadjuvant trastuzumab in patients (pts) with HER2-positive locally advanced breast cancer (LABC)

504 Background: The NOAH trial evaluated the addition of trastuzumab (H) to chemotherapy (CT) for pts with HER2-positive LABC. A significant improvement in pCR has been reported (Gianni. ASCO 2007; abs 532). Methods: 228 pts were randomized to receive 3 cycles of doxorubicin (60 mg/m2) and paclitaxel (150 mg/m2) q3w, 4 cycles of paclitaxel (175 mg/m2 q3w) and 3 cycles of CMF (C 600 mg/m2, M 40 mg/m2, F 600 mg/m2 d 1+8 q4w) with or without concomitant H (8 mg/kg loading dose then 6 mg/kg q3w for 1 year) before surgery. 171 (75%) core biopsies obtained before treatment were available for assays of c-Myc (by FISH), PTEN (by IHC) and IGF1R (by IHC) in addition to estrogen receptor (ER) and progesterone receptor (PgR). Results: The 171 pts with available biopsies were representative of the overall NOAH population, although with a lower incidence of ER+ tumors. Negative PgR status was strongly associated with pCR in the H group (51% vs 16% in PgR-positive tumors; p=0.008). Overall, 32 pts had c-Myc amplification (cut-off ratio >2). Of these, 11/21 (52%) H pts but only 1/11 (9%) CT pts had pCR. PTEN expression was not predictive of pCR after H but was associated with a higher pCR rate after CT alone (p=0.05). IGF1R membrane staining was significantly lower in H-treated pts with pCR than those with residual disease (24% vs 48%; p=0.05). In logistical regression analysis, PgR status and H treatment were significant predictors of pCR. In the H-treated group, PgR status (p=0.012) was the most significant predictor of pCR; ER and IGF1R membrane staining showed borderline significance (p=0.089 and p=0.075, respectively). Conclusions: PgR-negative status and c- Myc amplification are associated with higher pCR rates after addition of H compared to CT alone. Overexpression of membranous IGF1R is associated with a higher likelihood of residual disease after H-based CT. These results will be combined with those of ongoing studies of additional biomarkers (HER3, p95HER2 and HER2 homodimers) to define a multivariate residual disease predictor. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech™ BioOncology, Roche MGRM Genentech™ BioOncology, Roche Roche

Chemoendocrine Compared With Endocrine Adjuvant Therapies for Node-Negative Breast Cancer: Predictive Value of Centrally Reviewed Expression of Estrogen and Progesterone Receptors—International Breast Cancer Study Group

To centrally assess estrogen receptor (ER) and progesterone receptor (PgR) levels by immunohistochemistry and investigate their predictive value for benefit of chemo-endocrine compared with endocrine adjuvant therapy alone in two randomized clinical trials for node-negative breast cancer. International Breast Cancer Study Group Trial VIII compared cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy for 6 cycles followed by endocrine therapy with goserelin with either modality alone in pre- and perimenopausal patients. Trial IX compared three cycles of CMF followed by tamoxifen for 5 years versus tamoxifen alone in postmenopausal patients. Central Pathology Office reviewed 883 (83%) of 1,063 patients on Trial VIII and 1,365 (82%) of 1,669 on Trial IX and determined ER and PgR by immunohistochemistry. Disease-free survival (DFS) was compared across the spectrum of expression of each receptor using the Subpopulation Treatment Effect Pattern Plot methodology. Both receptors displayed a bimodal distribution, with substantial proportions showing no staining (receptor absent) and most of the remainder showing a high percentage of stained cells. Chemo-endocrine therapy yielded DFS superior to endocrine therapy alone for patients with receptor-absent tumors, and in some cases also for those with low levels of receptor expression. Among patients with ER-expressing tumors, additional prediction of benefit was suggested in absent or low PgR in Trial VIII but not in Trial IX. Low levels of ER and PgR are predictive of the benefit of adding chemotherapy to endocrine therapy. Low PgR may add further prediction among pre- and perimenopausal but not postmenopausal patients whose tumors express ER.

Lessons From the Initial Adjuvant Cyclophosphamide, Methotrexate, and Fluorouracil Studies in Operable Breast Cancer

In 1975, we presented our first report on the efficacy of cyclophosphamide, methotrexate, and fluorouracil (CMF) delivered in 1-month cycles for 12 months as adjuvant treatment for nodepositive breast cancer. These results, along with those reported in a similar patient population by the National Surgical Adjuvant Breast and Bowel Project, raised hopes that chemotherapy could have a more central role in the primary management of this common cancer, and were of seminal importance for all the studies on adjuvant systemic therapy conducted throughout the world. Among the numerous questions to be answered after the first CMF study was the optimal duration of treatment. In fact, a relatively short-term effective adjuvant chemotherapy would spare the patients a considerable amount of toxicity. For this reason, in September 1975, we started a new randomized study with the intent of evaluating the possibility of reducing the duration of CMF without compromising its therapeutic effects. The 5-year results of the study showed that 1-month cycles for 6 months of CMF yielded results that were identical to those obtained with 12 cycles. The long-term analysis after a median follow-up of 25 years confirmed that a longer duration of the same drug regimen was unable to improve treatment outcome. The pattern of relapse-free survival was superimposable in the two treatment groups, the estimated relapse-free survival rates were 39% after 12 cycles and 38% after six cycles of CMF, and the overall survival rates were 40% in both treatment arms. In the multivariate analysis, the only variable able to influence treatment outcome was the extent of axillary node involvement; patients with more than three involved nodes were at a significantly higher risk of disease relapse and death (hazard rate, 2.3; P .0001). Neither estrogen-receptor status nor size of the primary tumor was able to affect therapeutic outcome significantly. In response to the early results observed in the abovementioned study, in the early 1980s our own research group tested in a random fashion whether the inclusion of a non– crossresistant agent such as doxorubicin (DOX) could be of benefit in patients with positive nodes. The choice of DOX was based on its great efficacy in metastatic and locally advanced breast cancer and on the low reported incidence of congestive heart failure when the total dose was less than 400 mg/m of the body-surface area. In women at high risk of disease relapse because of extended axillary involvement ( three positive nodes), we reasoned that DOX, either given first and followed sequentially by CMF or interspersed with CMF, had the potential to improve treatment outcome. A 20-year analysis confirmed the superiority of the sequential delivery of DOX as first treatment for four cycles followed by intravenous CMF (DOXCMF) compared with the alternating delivery of the same regimens (CMF/DOX). In fact, after DOXCMF, the risk of developing disease relapse was reduced by approximately 32% (P .0017) and the risk of dying as a result of all causes was reduced by approximately 26% (P .018). The improved outcome in the sequential arm was not impaired by the occurrence of congestive heart failure. It is important to note that the 5-year joint efficacy analysis of the National Epirubicin Adjuvant Trial and of the Scottish Cancer Trials Breast Group reported a highly significant benefit in favor of the sequential administration of epirubicin for four cycles followed by CMF compared with CMF alone, supporting the hypothesis that single-agent anthracyclines given first, before CMF, can indeed improve treatment outcome. In patients with one to three involved axillary nodes, we randomly assessed whether the addition of single-agent DOX for four cycles administered after intravenous CMF given for approximately 6 months could overcome resistance putatively induced by the alkylating regimen alone. The 20-year analysis showed that approximately half of the patients in this study were alive and disease free regardless of whether they received CMF alone or CMF sequentially followed by DOX. Although available long-term results failed to detect any statistically significant difference from the addition of DOX in the overall population of patients enrolled onto the study, a retrospective analysis on the predictive relevance of the status of human epidermal growth factor receptor (HER2) showed a trend for an increased benefit of the DOX combination in patients with HER2-positive tumors. This observation further emphasizes the need for a priori characterization of markers predicting for response, and for eventually tailoring adjuvant treatment to individual patients—a goal that is currently being pursued, but was inconceivable at the time when the study protocol was designed. JOURNAL OF CLINICAL ONCOLOGY C E L E B R A T I N G 2 5 Y E A R S O F J C O VOLUME 26 NUMBER 3 JANUARY 2

Assessment of different criteria for the pathological complete response (pCR) to primary chemotherapy in breast cancer: standardization is needed

Evaluation of the safety and efficacy of a combination of docetaxel and doxorubicin in breast cancer patients. Evaluation and comparison of the pathological complete response (pCR) to this regimen according to various definitions in different clinical trials. Utilize the data to propose standardization of definitions. Between 1998 and 2001, 141 patients with stage II (tumor size >3.0 cm) or III breast cancer were treated with doxorubicin 50 mg/m(2) followed by docetaxel 60 mg/m(2 )(AT) on day 1. A total of 4 courses of AT were administered as primary chemotherapy with intervals of 3 weeks. Additionally, 2 cycles of the same regimen were administered after surgery when clinical CR or PR was achieved; otherwise, 4 cycles of CMF were added postoperatively. 141 patients were enrolled in this trial. A clinical response rate was 86%. Seven patients (5%) achieved pCR according to the Japanese Breast Cancer Society classification, 14 patients (10%) fulfilled the University of Texas M.D. Anderson Cancer Center trial's pCR criteria, and 19 patients (14%) met the NSABP trial pCR definition. NCI CTC version 2 grade 3/4 toxicities included leucopenia (26%), neutropenia (85%) and febrile neutropenia (12%). Primary chemotherapy with AT induced modest tumor responses with tolerable toxicity. Differences in the definition of pCR among clinical trials caused substantial confusion in interpreting the trial results. Therefore, standardization of the pCR definition after primary chemotherapy is needed.

Preferences for adjuvant chemotherapy (ACT) in early breast cancer: The benefits needed to make extended treatment with docetaxel, doxorubicin, and CMF worthwhile

6528 Background: Small benefits are judged sufficient to make ACT worthwhile by women who have had either 6 cycles of CMF or 4 cycles of AC. We sought to determine the benefits needed to make longer and more intensive regimens worthwhile. Methods: 293 women who completed ACT 3 to 39 months earlier were presented 4 hypothetical scenarios based on known survival times (5 and 15 years) and rates (65% and 85% at 5 years) without ACT using validated, standardised interviews. 179 were in a randomized trial (BIG 02–98) testing addition of docetaxel (T) to a standard regimen including doxorubicin (A) and classical CMF; 114 were treated outside of the trial at the same centres. Women also rated their recollections of health-related quality of life during ACT. Results: The median age was 55 (range 25 to 78), 36% had a college or university degree, and 62% had dependants. The regimens (and their duration) in the trial were: 4 cycles of A or AC then 3 cycles of CMF (24w) in 31% of the women; 4 cycles of AT followed by 4 cycles of CMF (24w) in 29%; and 3 cycles of A then 3 cycles of T then 3 cycles of CMF (30w) in 40%. The regimens outside of the trial were: 4 cycles of AC (12w) in 52%; 6 cycles of CMF (24w) in 20%; and 4 cycles of AC then 3 cycles of CMF (24w) in 23%. A 2% gain in 5-year survival rates or a 6-month gain in survival duration was judged sufficient to make ACT worthwhile by 62–67% of women. Gains of more than 5% in 5-year survival rates or more than 2 years in survival duration were judged necessary to make ACT worthwhile by 10–20% of women. Women's preferences were strongly associated with the aversiveness of their treatment. Women who had more problems with physical well-being, coping with treatment, and nausea or vomiting judged larger benefits necessary to make their ACT worthwhile (p&lt;.0001). Preferences were unaffected by chemotherapy regimen, duration, context in a trial, age, time between treatment and interview, and social circumstances (p&gt;.2). Conclusions: As in previous studies, small benefits were judged sufficient to make ACT worthwhile, even if it lasted 6–7 months, and included docetaxel, doxorubicin and CMF. No significant financial relationships to disclose.

Age of menopause among women who remain premenopausal following treatment for early breast cancer: Long-term results from International Breast Cancer Study Group Trials V and VI

Background The likelihood of premature menopause has not been thoroughly explored in women who remain premenopausal after adjuvant chemotherapy for breast cancer. Methods We used data from the International Breast Cancer Study Group (IBCSG) Trials V and VI. Trial V enrolled 1407 eligible premenopausal women randomised to no systemic therapy (No CT) or 1 cycle of perioperative CMF-based chemotherapy (PeCT) if node negative, and 6 cycles of CMF-based chemotherapy postoperatively (CMF × 6) or 1 cycle perioperative CMF-based chemotherapy plus CMF × 6 postoperatively (CMF × 7) if node positive. From Trial VI (a 2 × 2 factorial designed study of 3 versus 6 initial cycles of CMF and a reintroduction of three additional courses of CMF), we included 375 women randomised to receive only six initial cycles of CMF (CMF × 6). Findings We excluded women who reported no menses during 12–24 months after randomisation ( N = 934), hysterectomy ( N = 16) or bilateral oophorectomy ( N = 8), or missing menses data ( N = 57), creating a cohort of 767 women; 540 women had been randomised to PeCT or no CT, 227 randomised to CMF × 6 or 7. A Cox proportional hazards model revealed that CMF × 6 or 7 (HR = 2.03, p < 0.0001) and temporary amenorrhea (HR = 1.96, p < 0.0001) were associated with premature menopause. Interpretation Women who remain premenopausal after 6 or 7 cycles of CMF-based chemotherapy have a higher likelihood of going through menopause at an earlier age than women who received little or no chemotherapy. Temporary cessation of menses appears to be a marker for earlier onset of menopause. These findings may assist women and clinicians when making treatment and reproductive decisions after a diagnosis of breast cancer.

Effect of adjuvant systemic treatment on cosmetic outcome and late normal-tissue reactions after breast conservation

To investigate whether adjuvant treatment with CMF or tamoxifen predisposes to an unfavorable cosmetic outcome or increased breast morbidity after radiotherapy in breast conservation. Data from 266 patients who entered a randomized breast conservation trial (DBCG-82TM protocol) was analyzed. The patients were treated with lumpectomy and axillary dissection followed by external beam radiotherapy to the residual breast. High-risk patients (n = 94), as well as 31 low-risk patients, received additional radiation to the regional lymph nodes. Adjuvant systemic treatment was given to all high-risk patients: premenopausal patients (n = 67) received eight cycles of CMF intravenously (600/40/600 mg per m2) every fourth week; postmenopausal patients (n = 27) received 30 mg of tamoxifen daily for one year. Clinical assessments included cosmetic outcome, breast fibrosis, skin telangiectasia, and dyspigmentation which were scored on a 4-point categorical scale after median 6.6 years. The observations were analyzed in multivariate logistic regression analysis which included potential risk factors on outcome related to systemic treatment, surgery, radiation technique, tumor, and patient characteristics. In premenopausal patients, systemic treatment with CMF independently predicted a fair/poor cosmetic outcome, RR = 2.2 (95% CI 1.2–4.2), as well as increased skin telangiectasia, RR = 3.3 (1.4–8.2). There was no impact of tamoxifen treatment on cosmetic outcome in postmenopausal patients (p = 0.32). However, univariate analysis showed that tamoxifen was significantly associated with breast fibrosis (p <0.004), as was radiation to the regional lymph nodes (p <0.0001). A strong interaction between axillary irradiation and tamoxifen treatment occurred since 26 of 27 high-risk postmenopausal patients had received both tamoxifen and axillary irradiation. In multivariate regression analysis, axillary irradiation independently predicted moderate/severe breast fibrosis with a relative risk of 5.0 (2.0–12.5) and 9.6 (3.3–27.7) in premenopausal and postmenopausal patients, respectively. To circumvent the strong interaction between tamoxifen treatment and axillary irradiation, a subsequent analysis omitting axillary treatment from the multivariate regression showed a significant effect of both tamoxifen and CMF on the occurrence of breast fibrosis with relative risks of 5.3 (CI 1.8–15.8) and 4.4 (1.8–10.3), respectively. Adjuvant systemic treatment with CMF given sequentially to radiotherapy independently predicted an adverse cosmetic outcome as well as increased skin telangiectasia after breast conserving treatment. Due to a strong interaction between tamoxifen administration and radiation to the regional lymph nodes, the effect of tamoxifen on the development of fibrosis could not be fully discerned in this study. Axillary irradiation increased the incidence of moderate to severe breast fibrosis in both premenopausal and postmenopausal patients.