Risk Node Negative Breast Cancer Research Articles

Abstract P5-11-02: Survival benefit needed to undergo chemotherapy: Patients and physicians preferences

Abstract Background: Data regarding patients (pts) and physicians' preferences for modern adjuvant chemotherapy (CT) are limited. Prior studies suggested that most pts with early stage breast cancer were willing to receive 6 months of adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) for modest survival benefits (e.g. most women would have accepted 3-6 months extension of life). Methods: E5103 was a phase III trial which randomized node positive or high risk node negative breast cancer pts to receive adjuvant CT (doxorubicin, cyclophosphamide and paclitaxel) with either placebo or bevacizumab. Telephone based surveys were administered to all pts enrolled on E5103 between 01/Jan/10 and 08/Jun/10, as part of a Decision-Making/Quality of Life component. Results presented here are part of the 18 months post-enrollment follow-up. Pts were asked to rate the survival benefit needed to justify 6 months of CT. A complementary survey was sent to all physicians who registered at least one pt on E5103. Results: 465 out of 519 eligible pts (90%) responded to this survey at 18 months. Main reasons for non response were: inability to reach the patient (6%) or patient refusal (2%). Median pts age was 51 (25-76); 42% of pts had at least a college degree. The majority had at least Stage II cancer. 179 (16%) physicians participated, among whom median age was 50 (35-70). The median years in practice was 17 (3-38); 78% of physicians worked on large size practices, 72% saw at least 5 new breast cancer pts/month, and 77% enroll between 1-4 pts on trials/month. We found considerable variation in pts preferences particularly for modest survival benefits: a substantial minority of pts (24%) would consider 6 months of CT definitely worthwhile for 1 month survival benefit, 18% would possibly consider it and 56% would not. The percentage considering CT definitely worthwhile increased with greater benefit, but did not reach 100%, even with 24 months survival benefit. About half of pts considered 6 months of CT definitely worthwhile for 9 months benefit, 70% for 12 months and 84% for 24 months. Physicians were less likely to accept CT for a small chance of benefit (34% of pts vs. 5% of physicians would definitely consider CT worthwhile for 2 months of benefit). For longer benefit, pts and physicians choices were similar (84% of pts vs. 92% of physicians would definitely consider CT worthwhile for 24 months benefit). Table Yes, definitely worthwhileYes, maybeNo, not worthwhileNo answerConsider 6 months of CT to live:PtsPhysiciansPtsPhysiciansPtsPhysiciansPts/Physicians*1 month longer24%3%18%15%56%80%2%2 months longer34%5%23%32%41%60%2%6 months longer44%32%35%54%19%12%2%9 months longer53%51%34%42%11%5%2%12 months longer70%75%23%22%5%1%2%24 months longer84%92%12%5%2%1%2%n Pts= 465; n Physicians= 179; * equal results in both groups Conclusions: This subgroup of pts who had undergone modern adjuvant CT in a large multicenter randomized controlled trial and these physicians who registered pts on the same trial had different cutoffs for acceptable levels of benefits and risks when considering adjuvant chemotherapy. It is important to engage pts in determining whether CT is or is not a "reasonable" option for treatment. Citation Format: Vaz Luis I, O'Neill A, Sepucha K, Miller KD, Baker E, Dang CT, Northfelt DW, Winer EP, Sledge GW, Schneider BP, Partridge A. Survival benefit needed to undergo chemotherapy: Patients and physicians preferences. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-11-02.

NSABP B-47: A randomized phase III trial of adjuvant therapy comparing chemotherapy alone to chemotherapy plus trastuzumab in women with node-positive or high-risk node-negative HER2-low invasive breast cancer.

TPS1139 Background: Adjuvant trastuzumab trials in HER2+ breast cancer (BC) demonstrated a large reduction in recurrence and death. Central testing showed HER2 non-amplified participants derived similar benefit. Among HER2-amplified patients (pts), multiple studies showed no effect on benefit by degree of amplification. Blinded internal and external review confirmed the non-amplified nature of the HER2 normal group. Based on these findings, NSABP B-47, sponsored by the NCI, was activated January 2011 and is actively accruing. The study is NCI central IRB approved, open via the CTSU, and endorsed by SWOG, ECOG, and RTOG. Methods: Study: Chemotherapy treatment is by physician choice: The non-anthracycline regimen is TC (docetaxel 75 mg/m2, cyclophosphamide (C) 600 mg/m2) IV q 3 wks for 6 cycles; the anthracycline regimen is AC → WP (doxorubicin 60 mg/m2 and C 600 mg/m2 IV either q 3 wks or q 2 wks [investigator discretion] for 4 cycles → paclitaxel 80 mg/m2 IV wkly for 12 doses). Pts are randomly assigned to chemotherapy with or without trastuzumab for 1 year. Pts receive adjuvant radiation therapy and endocrine therapy, as clinically indicated. Detailed menstrual history, concurrent medications, weight changes, and biomarkers (estrogen, stress, inflammation), are being collected. Eligibility: Eligibility includes: node positive or high risk node negative BC pts; HER2 IHC 1+ or 2+ scores, but non amplified by FISH; normal cardiac, renal, and liver function. Detailed eligibility will be provided. Statistical Design: The primary aim is to determine whether the addition of trastuzumab to chemotherapy improves invasive disease-free survival (IDFS). 3,260 pts will be enrolled to provide statistical power of 0.9 to detect a 33% reduction in the hazard rate of IDFS using a one-sided alpha level of 0.025. Progress: Protocol was activated in January 2011. First pt was entered in February 2011. As of January 23, 2013, 1,416 of 3,260 (43.4 %) pts have been enrolled. Updated information on enrollment and study background will be provided. Support: NCI U10-12027, -37377, 69651, 69974, and Genentech, Inc. Clinical trial information: NCT01275677.

Abstract P1-13-01: A randomized trial of CEF versus dose dense EC followed by paclitaxel versus AC followed by paclitaxel in women with node positive or high risk node negative breast cancer, NCIC CTG MA.21: Results of the final relapse free survival analysis.

Abstract Background: In 2000, cyclophosphamide(C), epirubicin(E) and fluorouracil (F) (CEF) and doxorubicin (A) and C followed by paclitaxel (T) (AC/T) given every three weeks were commonly used regimens in Canada and the USA to treat women with node positive or high risk node negative operable breast cancer. In a previous trial in women with locally advanced breast cancer, 3 months of dose-dense EC was equivalent to six months of CEF. We hypothesized that the addition of 3 months of a taxane following dose-dense EC would be superior to CEF alone or AC/T. In a randomized trial in women with early breast cancer we compared CEF, dose dense EC/T and AC/T. An interim analysis (JCO, 2010) conducted when 50% of the events for the relapse-free-survival (RFS) analysis were observed, demonstrated that AC/T administered every 3 weeks was significantly inferior to CEF or EC/T. The results of the final RFS including CEF versus EC/T will be presented. Methods: Women, 60 years or younger, with operable axillary node positive or high risk node negative breast cancer were randomized to adjuvant CEF, EC/T or AC/T. CEF was given for 6 cycles and consisted of: C 75 mg/m2 orally on Days 1–14, and E 60 mg/m2 and F 500 mg/m2, IV on Days 1 and 8. CEF patients received concurrent antibiotic prophylaxis. EC/T consisted of 6 cycles of EC every 14 days; E 120 mg/m2 and C 830 mg/m2, both IV on Day 1 with filgrastim 5 [ug]/kg/day subcutaneous from Days 2–13 and epoetin alpha 40,000 units subcutaneous once weekly. After completion of EC, 4 cycles of T 175 mg/m2 every 21 days with filgrastim and epoetin alpha were given. The AC/T regimen consisted of A 60 mg/m2 and C 600 mg/m2 IV every 21 days for 4 cycles. This was followed by T 175 mg/m2 every 21 days for 4 cycles. The final analysis for RFS was planned when 453 events were observed permitting the detection of a hazard ratio (HR) of 1.43 between CEF and AC/T and a HR of 1.43 between EC/T and the best of the other two arms. Quality of Life data using the EORTC C-30 and the Breast Cancer Chemotherapy questionnaires were collected throughout the study. The results will be available at the time of the presentation. Results: A total of 2104 women were enrolled between December 2000 and April 2005. The required 453 events for the RFS analysis were observed by the clinical cut-off date of March 30, 2012. At this point 369 deaths had been observed. The median follow-up is 87.5 months. Outstanding data and queries are currently being collected and reviewed with an expected database lock and final analysis mid August, 2012. Febrile neutropenia remains higher on the CEF and EC/T arms while more neuropathy was seen in the taxane containing regimens. Conclusions: Although the two regimens considered a standard of care at the time the study was initiated are no longer widely used, the trial results will enhance our understanding of the magnitude of benefit of taxane following an anthracycline, the significance of cumulative anthracycline dose, and the role of dose density/ intensity as backbone of conventional chemo regimens. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-13-01.

Abstract P1-13-04: Optimal duration of adjuvant chemotherapy for high risk node negative breast cancer patients: 6-year results of the prospective randomized phase III trial PACS 05.

Abstract BACKGROUND: In 2000, the NIH Consensus meeting concluded that 4 to 6 cycles of adjuvant chemotherapy appeared to provide an optimal benefit; So, we underwent a prospective randomized trial comparing 4 and 6 cycles of FEC 100 (JCO 2005; 23: 2686–2693) for high risk node negative breast cancer patients. METHODS: This study enrolled 18–65 y women with operable breast cancer, without axillary lymph node involvement, or presence of isolated tumor cells, with size superior to 1 cm and another poor prognostic factor: T > 2 cm, HR –, SBR grade II or III, age < 35 y. After adequate breast surgery and axillary lymph node dissection or sentinel node technique, they were randomized between arm A, 6 cycles of FEC 100, and arm B, 4 cycles, every three weeks. The local regional treatment was completed following usual recommendations. All HR+ patients received hormonal therapy for 5 years. After August 2005, patients with HER2+ tumors were excluded from this study. The primary end point was PFS at 5 years. This study was powered to detect a 6% difference in favour of 6 cycles. Between August 2002 and September 2006, 1516 patients were randomized; 1515 are analysed in ITT. Three patients in the B group did not receive any chemotherapy. There is no significant difference between the two arms for tumor and patient characteristics. RESULTS At a median follow-up of 73 months we observed regarding PFS a low event rate, 197 for the entire population (13%) 91 in arm A median PFS, vs. 106 in arm B median PFS, without any difference between the two groups for DFS, DDFS, local relapse, overall survival. There was no unexpected toxicity. In the arm A we observed more grade III and IV neutropenia, without congestive heart failure. CONCLUSION At a follow-up of 73 months, we observed a low relapse rate, with no significant difference between the two arms. Duration of FEC100 does not induce different outcomes in this population. Question of length of adjuvant treatment is still open with and without taxanes. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-13-04.

Early efficacy analysis of the AE37 vaccine in patients with HER2 low-expressing and triple-negative breast cancer.

109 Background: Peptide vaccines comprised of HLA class II epitopes, which elicit CD4+ T cell responses, play a critical role in potentiating immune responses. We are conducting a randomized phase II trial of AE37, a hybrid peptide created by the addition of the Ii-Key moiety (LRMK) to the HER2 helper epitope, AE36 (HER2 aa776-790). Here, we present efficacy data focusing on outcomes in patients with low HER2 (IHC 1+ or 2+) expression and triple negative breast cancer (TNBC). Methods: The trial is enrolling node positive or high risk node negative breast cancer patients with any degree of HER2 expression (IHC 1+, 2+ or 3+ or FISH > 1.2) rendered disease-free following standard of care therapy. Patients are randomized to receive either AE37+GM-CSF or GM-CSF alone in 6 monthly intradermal inoculations followed by booster inoculations administered every 6 months. Results: The trial has enrolled 254 patients; 105 in the vaccine group (VG) and 149 in the control group (CG). After a median follow-up of 22.3 months, the disease-free survival (DFS) rate in the VG is 90.3% vs 81.1% in the CG (p=.46), a 49% risk reduction. Evaluating patients with low HER2 expression (IHC 1+ or 2+), there are 53 VG patients and 77 CG patients. The groups are well-matched with respect to the percentage of patients with high grade tumors, tumors > 2cm, the rate of node positivity and ER/PR status (all p>.5). The DFS rate in the VG of low HER2 expressers is 89.8% vs 68.2% in the CG (p=.12), a 68% risk reduction. When limiting analyses to patients with TNBC (ER/PR negative, HER2 1+ or 2+), there are 13 VG patients and 23 CG patients. The groups are again well-matched with the exception of control patients having a larger percentage of tumors > 2 cm (70% vs 31%; p=.02). The DFS rate in the VG of TNBC patients is 83.3% vs 47.6% in the CG (p=.23), a 68% risk reduction. Conclusions: Early analyses suggest clinical benefit to vaccination with AE37, particularly in patients with low HER2-expressing tumors. Importantly, the benefit appears to persist in TNBC patients. Patients will continue to be followed per protocol for 5 years; however, these data suggest that a subsequent phase III trial should evaluate the vaccine in patients with low HER2-expressing disease to include TNBC.

An assessment of disease features and immune response in breast cancer patients that did not recur after receiving HER2 peptide, AE37 vaccine in a randomized phase II trial.

625 Background: In a phase I trial of AE37, the Ii-Key hybrid of HER2 derived peptide AE36 (776-790), administered with immunoadjuvant GMCSF demonstrated the vaccine to be safe and capable of stimulating CD4+helper T cells with HER2 specific anti-tumor activity. Here we present analysis of immune markers and patient feature that may impact recurrence from an ongoing prospective, randomized, single-blinded Phase IIb trial of AE37+GMCSF v GMCSF alone in adjuvant high risk breast cancer (BC) patients. Methods: After completion of standard therapy; disease-free, node positive or high risk node negative BC patients (pts) were randomized to receive either AE37+GMCSF or GMCSF in 6 monthly intradermal inoculations. Immunologic responses were measured using [3H]-thymidine incorporation assay (in vitro), delayed-type hypersensitivity (DTH) reactions (in vivo) and T regulatory cells (Tregs). Among those vaccinated recurrent pts (VR) are compared to non recurrent (VNR) pts. Results: We have vaccinated 109 pts with 8.3% recurrence rate at 2 year median follow up. VR v VNR were younger (44 v 50 yo p=0.11), had higher grade (67% v 44% p=0.32), more ER/PR- (44% v 38% p=0.75), larger tumors (89% v 50% p=0.06), and node positive (89% v 70% p=0.37). No difference for HER2 status (IHC 3+, 44% v 49% p=0.64). Both VR and VNR responded to vaccine though the mean DTH and proliferative stimulation index was approximately 10% less in VR pts (18 v 20 p=0.73; 1.96 v 2.2 p=0.77 respectively). The most predictive measure was change in Tregs with VR pts less likely to decrease their Tregs levels (50% v 76% p=0.17) after vacination and more likely experience increased Tregs (17% v 8% p=0.48). A decrease in Tregs had an inverse trend towards recurrence (p=0.17). Conclusions: Preliminarily, it appears most pts immunologically respond to vaccine though slightly less for VR in most assays. The changes of Tregs appear to correlate best with disease recurrence. Whether this reflects an association with disease status or a failure of the vaccine is yet to be seen. These levels may become important in predicting risk for clinical recurrence in future vaccine trials.

Abstract LB-218: Immune response assessment in a phase II trial of AE37 HER2 peptide vaccine

Abstract Introduction: AE37 is the Ii-Key hybrid of the HER2 derived peptide AE36 (776-790). A phase I trial administering AE37 with the immunoadjuvant GMCSF demonstrated the vaccine to be safe and capable of stimulating CD4+helper T cells with HER2 specific anti-tumor activity. Here we present an analysis of our immunologic testing of our prospective, randomized, single-blinded, phase II trial of the AE37+GMCSF vs. GMCSF alone for the prevention of breast cancer recurrence. Methods: After completion of indicated standard therapy; disease-free, node positive or high risk node negative breast cancer patients were randomized to receive either AE37+GMCSF (VG) or GMCSF (CG) in 6 monthly intradermal inoculations. Patients were enrolled with any level of HER2 expression (IHC 1+ 2+ or 3+). Specific immunologic responses to both AE36 and AE37 were evaluated. In vitro responses were measured using [3H]-thymidine incorporation assay and in vivo responses using delayed-type hypersensitivity (DTH) reactions. T regulatory cells (Tregs) were measured throughout vaccination series. Data was analyzed using Pearson chi-squared tests. Results: To date 217 patients have enrolled (VG=109, CG=108). HER2 over-expression was present in 54 (49.5%) VG and 51 (47.2%) CG, p=0.783. VG had 59 (51.4%) ER positive and CG had 58 (53.7%, p=0.985). The in vitro proliferation responses with a stimulation index (SI) ≥2 were classified as high responders VG 36 (33.0%) vs CG 8 (7.4%, p<0.001), SI 1.5-2 were classified as low responders VG 19 (17.4%) vs CG 16 (14.8%, p=0.600) or SI <1.5 as non responders VG 54(49.5%) vs CG 84(77.8%, p<0.001). The in vivo DTH reactions measured in 149 (VG n=86, CG n=63) were stratified as responders with ≥5mm (VG 74(86.0%) vs CG 17(27.0%) p<0.0001) or non responders with <5mm (VG 12 (14.0%) vs CG 46(73.0%) p<0.001). Tregs responses were measured in 107 patients (VG n=56, CG=51) and categorized according to percent change from pre-vaccination baseline as an increase >110% (5(8.9%) VG vs 10 (19.6%) CG, p=0.112), no change 90-110% (10 (17.9%) VG vs 13 (25.5%) CG, p=0.337), or decrease <90% (41 (73.2%) VG vs 28 (54.9%), p=0.048). Conclusion: VG patients had significant immunologic responses compared to CG. VG had a statistical decrease in Tregs compared to CG. Monitoring immunologic tests and Tregs throughout the vaccination process may stratify patients into responders and non responders and thus assist in identifying patients that will have recurrence. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-218. doi:1538-7445.AM2012-LB-218

P1-13-01: An Update of a Phase II Trial of the HER2 Peptide AE37 Vaccine in Breast Cancer Patients To Prevent Recurrence.

Abstract Introduction AE37 is the Ii-Key hybrid of the HER2−derived peptide AE36 (HER2:776–790). A phase I trial administering AE37 with the immunoadjuvant GM-CSF demonstrated the vaccine to be safe and capable of stimulating CD4+helper T-cells with HER2−specific anti-tumor activity. Here we present an update of our prospective, randomized, single-blinded, phase II trial of the AE37 vaccine for the prevention of breast cancer recurrence in disease-free, high risk patients. Methods After completion of standard therapy, disease-free, node positive or high risk node negative breast cancer patients were randomized to receive either AE37+GM-CSF (vaccine) or GM-CSF alone (control) in six monthly intradermal inoculations. Patients were enrolled with any level of HER2 expression, (IHC 1+ 2+ or 3+). Specific immunologic responses to both AE36 and AE37 were evaluated in all patients at pre-determined intervals: before (RO), mid-series (R3), upon completion (R6), and at six (RC6) and 12 (RC12) months after completion of the vaccine series. In vitro responses were measured using the [3H]-thymidine incorporation assay and in vivo responses using delayed-type hypersensitivity (DTH) reactions. The trial's primary endpoint is disease recurrence. Results To date, 215 patients have enrolled (vaccine=92, control=123). 99% of local and systemic toxicities were ≤grade 2 or less. There were no grade 4–5 local or systemic toxicities and no difference between toxicity profiles of vaccine and control groups. Vaccine patients exhibited a statistically significant increase from baseline in AE36 and AE37 proliferative responses at each time point, including maintenance of this response up to 12 months post-vaccination (AE36 (cpm): R0=0, R3=1335, R6=1242, RC6=1586, RC12=1360; AE37: R0=0, R3=2859, R6=2300, RC6=3235, RC12=3279, p<0.001) while there have been no proliferative changes for control patients (AE36: R0=91, R3=95, R6=97, RC6=126, RC12=48; AE37: R0=291, R3=399, R6=319, RC6=103, RC12=0). Vaccine patients also had statistically significant increases in DTH reactions to both AE36 and AE37 (AE36 (mm): R0=0, R6=15, RC6=15, RC12=15; AE37: R0=0, R6=24, RC6=17, RC12=20 p=<0.001) while controls had no response (AE36: R0, R6, RC6, RC12=0; AE37: R0, R6, RC6, RC12=0). With a median follow up of 17 months, breast cancer recurrences were reduced by 42% in vaccine patients compared to control patients (7.6% vs. 13.2%, p=0.15). In an analysis of patients with low HER2 expression (IHC 1 or 2+), vaccine patients experienced a 49% reduction in recurrence compared to controls (9.5% vs. 18.6%, p=0.16) with no reduction seen in HER2 over-expressing patients (6.0% vs. 7.9%, p=0.49). Conclusions The AE37 vaccine is safe and well tolerated with only mild toxicity, which is attributable to the GM-CSF immunoadjuvant. The AE37 vaccine elicits strong peptide specific in-vivo and ex-vivo immune responses, which are maintained for 12 months after completion of the vaccine series. While the number of recurrences are still low, the recurrence rate appears to decrease in vaccinated patients. Administration of the AE37 vaccine may reduce the risk of breast cancer recurrence with the greatest benefit in patients with low levels of HER2 expression. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-13-01.

The SUCCESS-C trial: Interim analysis of toxicity evaluating the role of an anthracycline-free chemotherapy regimen in the adjuvant treatment of HER2/neu-negative breast cancer.

1070 Background: Taxane-based anthracycline containing chemotherapy has been established as treatment option in the adjuvant setting of early breast cancer. Indication was recently enlarged for high risk node negative breast cancer. Promising retrospective data indicate equi-efficacy of anthracycline-free chemotherapy in Her2/neu-negative patients (Gennari et al., Slamon et al.). Anthracycline-free regimens are probably associated with less long-term toxicities, especially cardiac toxicities. Methods: The SUCCESS-C trial is an open-label, multicenter, 2x2 factorial design, randomized controlled, phase III study comparing the disease free survival in patients treated with 3 cycles fluorouracil 500mg/m2-epirubicine 100mg/m2-cyclophosphamide 500mg/m2 (FEC) chemotherapy, followed by 3 cycles docetaxel 100mg/m2 (D) chemotherapy, versus 6 cycles docetaxel 75mg/m2-cyclophosphamide 600mg/m2 (DC) chemotherapy. Monitored toxicity data after end of treatment are available from 1,452 patients. Results: Chemotherapy was prematurely stopped in 51 pts (7.2%) receiving FEC-D and in 57 pts (7.7%) with DC (p=0.71). Dose reductions occurred significantly more often in the FEC-D arm (2.7%) than in the DC arm (1.9%, p=0.024), reasons did not differ significantly between both arms (p=0.093). Incidence of treatment-postponement was significantly higher for FEC-D (9.4% FEC-D vs. 7.6% DC; p=0.0008). Haematological toxicity as a reason for treatment-postponement occurred significantly more frequent within the FEC-D-arm (FEC-D: 18.1%, DC: 6.6%, p<0,0001); non-haematological toxicity as a reason for treatment postponement was nearly equal within both arms (8.6% FEC-D vs. 8.8% DC, p=0.9). G-CSF support was applied in 22.7% of all chemotherapy cycles (FEC-D: 22.2% vs. DC: 23.2%, p=0.21). Severe toxicities (NCI-grade > 2) were reported in 910 cases for FEC-D and in 848 cases for DC arm (p= 0.02). Conclusions: Significantly more dose-reductions of chemotherapy and a significant higher incidence of treatment-postponement occurred in the FEC-D arm. The toxicity profiles of both treatment arms differ discretely and support the continuation of the trial until target recruitment (n=3,547).

Dose-volumetric Parameters for Predicting Severe Radiation Pneumonitis and Skin Toxicity in Breast Cancer Patients Treated with Three Dimensional Conformal Radiation Therapy and Paclitaxel

Delaying the initiation of adjuvant radiation therapy (RT) adversely affects local-regional control and RT given concomitantly with chemotherapy may increase rates of radiation pneumonitis (RP) and skin toxicity (ST). For this reason, it is important to identify dosimetric parameters that would permit the safe administration of this treatment. Our aim was to identify potential clinical factors and dosimetric factors for RP and ST following concomitant paclitaxel and RT. Records of 57 patients treated with weekly paclitaxel at 80 mg/m2 for 12 cycles and 50 Gy RT plus a boost to the surgical bed of 16-20 Gy between January 2005 and December 2007 were reviewed. All patients had either node positive or high risk node negative breast cancer. RP and ST were graded according to the RTOG criteria. Factors including performance status, comorbidities, smoking status, tamoxifen use, body mass index (BMI), plastic cup (PC) use, breast volume (BV), dose-volume parameters (V5, V20, V25, V30), MLD (mean lung dose), and radiation fields were analyzed and correlated with clinical toxicity. Median follow-up was 30 months (range, 7.87-56 months). Twenty-six and 31 patients, respectively, received two-field radiotherapy (2FRT) and three-field radiotherapy (3FRT). In no case was the internal mammary chain irradiated. Grade ≥2 RP was observed in 14% of cases. All cases of RP resolved without any clinical sequelae. The mean time to develop RP after RT was 50 days. The mean ipsilateral V5, V20, V25, V30, MLD were 22.55%, 8.9%, 8.07%, 7.3%, and 6.35 Gy, respectively, for patients with 2FRT group and 41.7%, 21.6%, 19.64%, 17.8%, 11.97 Gy, respectively, for patients with 3FRT group. These values were significantly correlated. There was no significant association between specific RT fields and RP. By univariate analyses, MLD (p = 0.03), V5 (p = 0.003), V20 (p = 0.03), V25 (p = 0.04), V30 (p = 0.04), V25 cc (p = 0.03), and V30 cc (p = 0.04) were found to be significantly associated with RP. By multivariate analysis, only V20 (p = 0.01) and V30 (p = 0.001) were significant factors. There was a significant trend for increasing RP with V20 values ≥17% (p = 0.05) and V30 ≥14% (p = 0.043). Using ST scoring criteria, 21 patients (37%) experienced grade 3-4 toxicity. By univariate analysis, mean BMI (p = 0.01), BV (p = 0.009) and use of PC (p = 0.011) were predictors of grade 3-4 ST. Multivariate analysis revealed the BMI (p = 0.004) and BV (p = 0.002) to be significant predictors of ST. Given the high rate of RP observed with concomitant paclitaxel and RT, the V20 and V30 ipsilateral constraints should be adhered to closely in order to decrease the risk of RP. BMI and BV are the main predictors of ST in these patients.

A phase III adjuvant trial of sequenced EC + filgrastim + epoetin-alpha followed by paclitaxel compared to sequenced AC followed by paclitaxel compared to CEF in women with node-positive or high-risk node-negative breast cancer (NCIC CTG MA.21)

550 Background: CEF and AC followed by paclitaxel (AC/T) are commonly used adjuvant regimens in women with early breast cancer. In a trial conducted by the EORTC, NCIC CTG, and SAKK three months of dose-dense EC was equivalent to six months of CEF in women with locally advanced breast cancer. We hypothesized that three months of a taxane following dose-dense EC would be superior to CEF alone or AC/T. The results of a planned interim analysis were presented in San Antonio 2006 (Abstract #53). We now present more detailed results on efficacy and toxicity. Methods: Women 60 years of age or younger, with axillary node positive or high risk node negative breast cancer were randomized to CEF, EC/T or AC/T for six months. Results: Between December 2000 and April 2005, 2104 patients were enrolled. The median follow-up is 30.4 months. Hazard ratios for recurrence are: AC/T vs. CEF, 1.49 (95% CI, 1.12–1.99), p=0.005; AC/T vs. EC/T, 1.68 (95% CI, 1.25–2.27), p=0.0006; and EC/T vs. CEF, 0.89 (95% CI, 0.64–1.22), p=0.46. Three year recurrence-free survival rates for CEF, EC/T, and AC/T are 90.1, 89.5 and 85.0%, respectively. There was no significant interaction between ER status and treatment. Multivariate analysis of predictive factors will be presented. The numbers of deaths are 50 (CEF), 47 (EC/T) and 65 (AC/T). There was more toxicity in CEF and EC/T compared to AC/T. Conclusion: AC/T given every three weeks, although less toxic is significantly inferior to CEF or EC/T in terms of relapse-free survival. It is too early to detect any difference between CEF and dose-dense EC/T. Our results indicate that there is still room to explore anthracycline and taxane adjuvant chemotherapy regimens. Supported by: NCI Canada and Canadian Cancer Society, Pfizer, Bristol-Myers Squibb, Amgen, Janssen Ortho, Ortho Biotech, and NCI US. [Table: see text] No significant financial relationships to disclose.

Efficacy and safety of mitoxantrone-based chemotherapy as adjuvant treatment in elderly patients (EP) with node positive and high risk node negative breast cancer (BC)

10738 Background: Breast cancer is a very frequent malignancy among EP. Adjuvant chemotherapy improves survival for patients with early breast cancer, but older woman at high risk of recurrence are frequently not offered adjuvant chemotherapy and few data are available on efficacy, compliance and safety of adjuvant chemotherapy when indicated in EP. Objective: the aim of our study was to determine the efficacy, compliance and safety of adjuvant mitoxantone-based chemotherapy (FNC) in high risk BC patients older than 70. Methods and Results: From July 1994 to July 2005 we treated 30 patients &gt;70 years, who had diagnosed with early BC in our institution. The treatment (mitoxantrone 10 mg/m2, 5-Fluorouracil 600 mg/m2, Cyclophosphamide 600 mg/m2, i.v. on day 1 every 3 weeks for 6 cycles) was indicated if patients had no severe comorbidity and a high risk of recurrence. All the patients had undergone mastectomy (56%) or quadrantectomy plus axillary lymphadenectomy (44%). Patients undergoing conservative surgery were scheduled for radiotherapy that was planned immediately after the end of chemotherapy. Study population age ranged from 70–78 years, mean age of 74 years.PS (ECOG) was 0 in 74% of patients, 1 in 26%. Comorbid conditions were detected in 38% of patients (64% hypertension, 8% arythmia, 10% depression syndrome, 14% arthrosis) Main histologic types were invasive ductal carcinoma (87%) and lobular carcinoma (13%). Stage was IIA in 20%, IIB in 37%, IIIA in 43%. Grading was 2 in 51%, G3 in 49%.Sixty-seven percent of tumors were ER+ PGR+, 20% were ER- PGR-, 8% ER-PGR+, 5% ER+ PGR-. Seventy-five percent of patients received adjuvant endocrine therapy, after the end of chemotherapy. Toxicity was very manageable with grade 3–4 haematological toxicity in 1 patient, nausea and vomiting appeared as grade 0 and 1 severity in 10%, alopecia was extremely mild and appeared as grade 0 and 1 in 12%. Only 1 patient disrupted treatment because of toxicity. The overall and relapse free survival rates were 70% and 73% at the 60-month follow up, respectively. Conclusion: FNC is an effective and well-tolerated combination regimen suitable as adjuvant chemotherapy for high risk breast cancer EP. No significant financial relationships to disclose.

Focal HER2/neu amplified clones partially account for discordance between immunohistochemistry and fluorescence in-situ hybridization results: data from NCCTG N9831 Intergroup Adjuvant Trial

568 Background: Accurately and reliably identifying HER2/neu status is a critical priority in the treatment decision process. Current HER2 testing strategies include immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), but discrepancies between them (3+IHC and FISH-, 0–2+ IHC and FISH+) interfere with interpretation and patient management. We postulate that some of these discrepancies may reflect tumor heterogeneity, derived from focal HER2 amplified clones (FHAC) within a tumor. Methods: As part of the ongoing N9831 “Phase III trial of doxorubicin and cyclophosphamide followed by weekly paclitaxel with or without trastuzumab treatment for women with HER2 overexpressing or amplified node positive or high–risk node negative breast cancer” adjuvant Intergroup trial, breast tumors were evaluated for HER2 status by both IHC and FISH using HercepTest™ and PathVysion™ assays. Samples with FHAC were defined as containing 2% to 40% of cells demonstrating unequivocal amplification (cells with >10 HER2 signals and HER2:CEP17 ratio >5.0), regardless of the overall HER2:CEP17 ratio. HER2/FISH discordant cases were identified and the number with FHAC determined. Results: 2006 samples from 1738 patients were studied. 1169 cases demonstrated FISH amplification (HER2:CEP17 ratio ≥2) and were IHC positive (3+). 114 cases contained FISH amplification, but were IHC negative (0–1+) or equivocal (2+). 2 % of the IHC 3+/FISH amplified, 21% of the IHC 0–1+/FISH amplified, and 30% of the IHC 2+/FISH amplified cases contained FHAC (Table 1). Conclusions: The presence of FHAC seems to be a factor in a substantial number of cases exhibiting discordance between IHC and FISH evaluations of HER2 positivity. The prognosis and response to trastuzumab among patients with FHAC have yet to be determined. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly; Merck; Vysis, Inc.; Wyeth Merck Aventis Genentech

Focal HER2/neu amplified clones partially account for discordance between immunohistochemistry and fluorescence in-situ hybridization results: data from NCCTG N9831 Intergroup Adjuvant Trial

568 Background: Accurately and reliably identifying HER2/neu status is a critical priority in the treatment decision process. Current HER2 testing strategies include immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), but discrepancies between them (3+IHC and FISH-, 0–2+ IHC and FISH+) interfere with interpretation and patient management. We postulate that some of these discrepancies may reflect tumor heterogeneity, derived from focal HER2 amplified clones (FHAC) within a tumor. Methods: As part of the ongoing N9831 “Phase III trial of doxorubicin and cyclophosphamide followed by weekly paclitaxel with or without trastuzumab treatment for women with HER2 overexpressing or amplified node positive or high–risk node negative breast cancer” adjuvant Intergroup trial, breast tumors were evaluated for HER2 status by both IHC and FISH using HercepTest™ and PathVysion™ assays. Samples with FHAC were defined as containing 2% to 40% of cells demonstrating unequivocal amplification (cells with >10 HER2 signals and HER2:CEP17 ratio >5.0), regardless of the overall HER2:CEP17 ratio. HER2/FISH discordant cases were identified and the number with FHAC determined. Results: 2006 samples from 1738 patients were studied. 1169 cases demonstrated FISH amplification (HER2:CEP17 ratio ≥2) and were IHC positive (3+). 114 cases contained FISH amplification, but were IHC negative (0–1+) or equivocal (2+). 2 % of the IHC 3+/FISH amplified, 21% of the IHC 0–1+/FISH amplified, and 30% of the IHC 2+/FISH amplified cases contained FHAC (Table 1). Conclusions: The presence of FHAC seems to be a factor in a substantial number of cases exhibiting discordance between IHC and FISH evaluations of HER2 positivity. The prognosis and response to trastuzumab among patients with FHAC have yet to be determined. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly; Merck; Vysis, Inc.; Wyeth Merck Aventis Genentech