Node-negative HER2 Research Articles

Chemotherapy-related amenorrhea after adjuvant paclitaxel-trastuzumab (APT trial).

Chemotherapy-related amenorrhea (CRA) is associated with infertility and menopausal symptoms. Learning how frequently paclitaxel and trastuzumab cause amenorrhea is important. Most other adjuvant breast cancer therapies induce CRA in approximately 50% of all premenopausal recipients [1]. 410 patients enrolled on the APT Trial, a single-arm phase 2 adjuvant study of 12weeks of paclitaxel and trastuzumab followed by nine months of trastuzumab monotherapy. Eligible patients had ≤3cm node-negative HER2+breast cancers. Premenopausal enrollees were asked to complete menstrual surveys every 3-12months for 72months. Women who responded to at least one survey at least 15months after chemotherapy initiation (and who did not undergo hysterectomy and/or bilateral oophorectomy or receive ovarian suppressing medications prior to 15months) were included in this analysis. A participant was defined as having amenorrhea in follow-up if her self-reported last menstrual period at last follow-up was greater than 12months prior to the survey. Among the 64 women in the evaluable population (median age at study entry 44years, range 27-52years), the median time between chemotherapy initiation and last menstrual survey was 51months (range 16-79). 18 of 64 women (28%, 95% CI 18-41%) were amenorrheic at that time point. Amenorrhea rates among premenopausal women treated with adjuvant paclitaxel and trastuzumab for early stage breast cancer appear lower than those seen historically with standard alkylator-based breast cancer regimens. Future studies are needed to understand the impact of this regimen on related issues of fertility and menopausal symptoms.

Preoperative Single-Fraction Partial Breast Radiation Therapy: A Novel Phase 1, Dose-Escalation Protocol With Radiation Response Biomarkers

Women with biologically favorable early-stage breast cancer are increasingly treated with accelerated partial breast radiation (PBI). However, treatment-related morbidities have been linked to the large postoperative treatment volumes required for external beam PBI. Relative to external beam delivery, alternative PBI techniques require equipment that is not universally available. To address these issues, we designed a phase 1 trial utilizing widely available technology to 1) evaluate the safety of a single radiation treatment delivered preoperatively to the small-volume, intact breast tumor and 2) identify imaging and genomic markers of radiation response. Women aged ≥55 years with clinically node-negative, estrogen receptor-positive, and/or progesterone receptor-positive HER2-, T1 invasive carcinomas, or low- to intermediate-grade in situ disease ≤2 cm were enrolled (n=32). Intensity modulated radiation therapy was used to deliver 15 Gy (n=8), 18 Gy (n=8), or 21 Gy (n=16) to the tumor with a 1.5-cm margin. Lumpectomy was performed within 10 days. Paired pre- and postradiation magnetic resonance images and patient tumor samples were analyzed. No dose-limiting toxicity was observed. At a median follow-up of 23 months, there have been no recurrences. Physician-rated cosmetic outcomes were good/excellent, and chronic toxicities were grade 1 to 2 (fibrosis, hyperpigmentation) in patients receiving preoperative radiation only. Evidence of dose-dependent changes in vascular permeability, cell density, and expression of genes regulating immunity and cell death were seen in response to radiation. Preoperative single-dose radiation therapy to intact breast tumors is well tolerated. Radiation response is marked by early indicators of cell death in this biologically favorable patient cohort. This study represents a first step toward a novel partial breast radiation approach. Preoperative radiation should be tested in future clinical trials because it has the potential to challenge the current treatment paradigm and provide a path forward to identify radiation response biomarkers.

Abstract P2-16-11: Impact of adjuvant trastuzumab (T) with chemotherapy on breast cancer specific and cardiac outcomes in older women with small, node-negative HER2-positive breast cancer

Abstract Introduction: For women with high risk early breast cancer that overexpresses HER2, the role of adjuvant T with chemotherapy is well established. Although the benefits of this approach in women with small, node negative tumors are less well defined, we previously published a retrospective sequential cohort study that suggested that T with chemotherapy is active in this setting. However there are few data about the safety and efficacy of adjuvant T in older women with small, node negative HER2+ breast cancer. Thus, this we conducted a retrospective study of breast cancer specific and cardiac outcomes for this subset. Methods: From our previously reported dataset, we identified women > 60y with <2 cm, node-negative HER2+ breast cancer. We identified a “no-T” cohort of 32 women diagnosed Jan ‘02 - May ‘05 and a “T” cohort of 39 patients diagnosed May ‘05 - Dec ‘08. Electronic medical records were reviewed to examine risk factors and incidence of cardiotoxicity as well as patient outcomes including distant disease-free survival (DDFS) and overall survival (OS). Results: Women in the two cohorts had similar baseline characteristics including cardiac risk factors (Table 1). There were no cardiac events in the no-T group. In the T group, 3 patients discontinued T due to a cardiac event: 1 with asymptomatic decline in ejection fraction (EF), 1 with atrial fibrillation and dyspnea, and 1 with symptomatic EF decline associated with myocardial infarct and valvular disease. Patients in both cohorts had excellent disease control at a median follow up of 9y and 6y for the no-T and T cohorts respectively. The 3y DDFS numerically favors the T cohort, the confidence intervals are broad and overlapping (Table 1). There were no detectable differences in OS between groups. In our previous report (not selected for age), DDFS at 3yrs was 95% (90-99) and 100% in the no-T (N = 106) and T (N = 155) cohorts respectively. Conclusion: In this small retrospective study, older women with small, node negative HER2+ breast cancers had excellent disease control and a low risk of cardiotoxicity. The possible benefits of T in this setting are consistent with prior reports uncontrolled for age. Table 1 No Trastuzumab N = 32 N (%)Trastuzumab N = 39 N (%)Tumor Size (cm), median (range)1.4 (0.1-2.0)1.3 (0.5-2.0)Multifocal Disease6 (19)4 (10)Grade 324 (75)33 (85)ER Positive20 (63)20 (51)Age, median (range)66 (60-85)65 (60-82)BMI, median (range)24.7 (18.2-34.2)27.3 (18.2-47.1)Chemotherapy16 (50)39 (100)Radiotherapy23 (72)25 (64)Hypercholesterolemia11 (34)18 (46)Hypertension12 (38)13 (33)3yr DDFS (95% CI)91% (74-97)97% (83-100)3yr OS (95% CI)97% (80-100)97% (83-100) Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-11.

Abstract P3-08-05: Chemotherapy-related amenorrhea on adjuvant paclitaxel-trastuzumab (APT trial)

Abstract Background: Chemotherapy-related amenorrhea (CRA) is associated with infertility and menopausal symptoms. The majority of premenopausal women experience prolonged CRA (persisting for at least a year after chemotherapy has finished) with standard adjuvant breast cancer chemotherapy regimens. Trastuzumab is not believed to cause CRA. No studies to date have evaluated the risk of CRA from a taxane in the absence of other gonadotoxic therapy. If the paclitaxel-trastuzumab regimen is adopted for treatment of women with low to moderate risk Her2+ breast cancer, understanding its impact on this important survivorship issue will be of great interest. Methods: 410 patients enrolled on a single-arm phase 2 adjuvant chemotherapy study of 12 weeks of paclitaxel-trastuzumab followed by nine months of trastuzumab monotherapy for patients with <3cm of node-negative Her2+ breast cancer (APT Trial). Participants who reported they were premenopausal at enrollment were asked to complete menstrual surveys at baseline and every 6-12 months throughout a 60 month follow-up period. Women who had follow-up menstrual survey data at least 15 months after their first dose of chemotherapy and were premenopausal at study entry (last menstrual period, LMP, <6 months before enrollment) were included in this analysis. For each participant, the last available survey was reviewed. Women were defined as amenorrheic if the LMP on the most recent follow-up survey was more than 12 months prior. Results: Seventy-seven participants in the APT trial were premenopausal at enrollment, of whom 12 (16%) did not have follow-up menstrual data at least 15 months after their first dose of chemotherapy. In the remaining 65, median age was 44 years (range 27-52), and 59 (91%) were white. Forty-two (65%) had ER+ disease. Thirty-three (51%) were taking tamoxifen and 3 (7%) were taking an aromatase inhibitor when they completed their most recent menstrual surveys. The median time between first dose of chemotherapy and the last available menstrual survey was 40 months (range 17-63 months). At the time of their last available menstrual survey, 19 (29%) were amenorrheic and 46 (71%) were not amenorrheic. Conclusions: Amenorrhea rates among premenopausal women treated with adjuvant paclitaxel-trastuzumab for early stage breast cancer appear lower than would have been expected with standard adjuvant cytotoxic breast cancer regimens (most studies of various standard regimens have found CRA rates of at least 50%). Additional follow-up and analyses are planned to clarify how menstrual functioning changes over time after paclitaxel-trastuzumab. Future studies are also needed to understand the impact of this regimen on related issues of fertility and menopausal symptoms in young women. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-08-05.

Adverse prognostic impact of intratumor heterogeneous HER2 gene amplification in patients with breast cancer.

617 Background: There is increasing recognition of the existence of intratumoral heterogeneity of the human epidermal growth factor receptor (HER2), which affects interpretation of HER2 positivity in clinical practice and may have implications for patient prognosis and treatment. Only patients (pts) with HER2 positivity - defined as 3+ by IHC or FISH amplified defined as a HER2 gene to chromosome 17 (HER2/CEP17) ratio ≥ 2.0 - are eligible to receive trastuzumab treatment. Limited information is available on the prognosis of pts with HER2 2+ or FISH test with a HER2/CEP17 ratio < 2.0. Methods: We retrospectively analyzed data from 455 consecutive early BC pts with HER 2+ and HER2/CEP17 ratio < 2.0 who underwent surgery after 2007. The association between HER2/CEP17 ratio and other known prognostic factors was evaluated with multivariable linear regression models. The role of HER2/CEP17 ratio on recurrence free survival was assessed with multivariable Cox regression models. Results: Fifty-one percent of the evaluated pts were node negative, 51% were postmenopausal, 93% had ER positive BC and 85% had Ki-67 ≥14%. The mean HER2/CEP17 ratio was 1.27 (SD=0.3). A significant positive relationship between HER2/CEP17 ratio and Ki-67 was observed (p<0.01). During a median follow-up time of 2.7 years, 40 recurrences were observed (15 locoregional events and 25 distant metastases). Overall, the association between HER2/CEP17 and the risk of recurrence was not significant. From subgroup analysis, a significant interaction between HER2/CEP17 ratio and nodal involvement emerged (p=0.02). Among pts with node-negative disease, pts with HER2/CEP17 ratio ≥1.27 were at higher risk of recurrence with respect to pts with HER2/CEP17 ratio < 1.27 (adjusted HR 4.0, 95% CI 1.01-15.9). Conclusions: Among pts with BC and HER2 intratumoral heterogeneity, HER2/CEP17 ratio ≥1.27 could have a strong prognostic role in node negative HER2 2+ BC, thus suggesting potential future therapeutic approaches in this setting of pts.

Effects of adjuvant chemotherapy in HER2-positive or triple-negative pT1ab breast cancers: a multi-institutional retrospective study

Previous studies have reported higher recurrence rates in T1a/b N0 breast cancers characterized by high-risk biology (HER2+ or triple-negative), but the benefits of adjuvant chemotherapy in these patients have not been established. This study was designed to determine whether recurrence risk is reduced with chemotherapy and to define a group of patients most appropriate for treatment based on retrospective data. We pooled cases from two multi-institutional databases spanning the period of 1996-2010. A propensity score model adjusted unbalanced confounders between the groups treated or untreated with adjuvant chemotherapy and, in case of HER2-positive disease, with trastuzumab. Competing risk analysis was utilized to study effects of chemotherapy on cancer recurrences in the matched populations. Among the 318 patients identified, 41 % received adjuvant chemotherapy and 54 % of HER2+ patients received it with trastuzumab. The cumulative risk of recurrence at 5 years was 7.3 %. Age less than 35 years and triple-negative status were the only significant prognostic factors. Overall, administration of chemotherapy was not associated with a significant decrease in the risk of recurrence (HR 0.93, p = 0.91). The rate of recurrence in HER2+ patients who received trastuzumab was lower but not statistically significant (HR 0.50, p = 0.63). Clinical characteristics are of limited prognostic value for stratifying risk of recurrence in very small, node-negative HER2+, or triple-negative cancers. While limited by the small number of events, our analysis does not support the increasingly prevalent practice of administering adjuvant chemotherapy in this population without more accurate prognostic and predictive factors.

Cardiac safety of adjuvant pegylated liposomal doxorubicin with concurrent trastuzumab: a randomized phase II trial

The cardiac safety of trastuzumab concurrent with pegylated liposomal doxorubicin (PLD) in an adjuvant breast cancer treatment regimen is unknown. Women with resected node-positive or intermediate-risk node-negative HER2 overexpressing breast cancer and baseline left ventricular ejection fraction (LVEF)≥55% were randomized (1:2) to doxorubicin 60 mg/m2 (A)+cyclophosphamide 600 mg/m2 (C) every 21 days (q21d) for four cycles or PLD 35 mg/m2+C q21d+trastuzumab 2 mg/kg weekly (H) for 12 weeks. Both groups then received paclitaxel (Taxol, T) 80 mg/m2 with H for 12 weeks followed by H to complete 1 year. The primary end point was cardiac event rate or inability to administer 1 year of trastuzumab. Of 181 randomized patients, 179 underwent cardiac analysis. The incidence of cardiac toxicity or inability to administer trastuzumab due to cardiotoxicity was 18.6% [n=11; 95% confidence interval (CI) 9.7% to 30.9%] with A+C→T+H and 4.2% (n=5; 95% CI 1.4% to 9.5%) with PLD+C+H→T+H (P=0.0036). All events, except one, were asymptomatic systolic dysfunction or mildly symptomatic heart failure. Mean absolute LVEF reduction at cycle 8 was greater with doxorubicin (5.6% versus 2.1%; P=0.0014). PLD+C+H→T+H is feasible and results in lower early cardiotoxicity rates compared with A+C→T+H.

Role of clinical and histologic factors in decision making on adjuvant therapy of small HER2-positive breast cancer.

e11053 Background: With increased use of screening mammography for breast cancer (BC), the incidence of small (T1a, b), node negative BC has increased. These cancers are considered low-risk and hence not offered adjuvant (adj) chemotherapy (CT). However, increasing retrospective studies suggest that outcomes in small node negative HER-2 positive BC might be worse than the HER-2 negative tumours of similar size. Current guidelines generally do not recommend adj CT and Trastuzumab (T) for small (T1 a, b) HER-2 positive tumours. As a part of our ongoing audit on the outcome of small HER -2 positive BC, we wished to determine the factors that oncologists consider in decision making on adj treatment of these tumours in the absence of clear guidelines. Methods: Patients (pts) with a diagnosis of node negative T1a, b, HER-2 positive BC treated across our cancer network, between Jan 2008 and Dec 2011, were identified from our electronic database. Results: A total 230 pts had stage T1, HER 2 +ve BC. Out of those 41(17%) pts had tumour size of < 1cm (13, 31%pts were T1a and 28, 74%pts wereT1b) and node negative disease. Median age was 55 years (29-84yrs). 33 Pts had BCS and 8 pts had mastectomy. All pts with BCS received adj radiotherapy and all pts who were ER positive received adj endocrine therapy. 21(51%) out of 41pts received adjuvant CT and T. All pts had anthracycline based CT. The clinical and pathological characteristics of pts who received adj CT and T were as follows; Median age- 50 (33-64years), grade 1- 1(4%), grade 2 – 9(43%), grade 3- 11(53%), LVI present- 2(9%), LVI absent- 7(34%), LVI unknown – 12(57%), ER positive- 16(76%), ER negative – 5(24%). None of the pts had recurred or died at the time of analysis of the data and longer follow up is needed for survival analysis. Conclusions: In the absence of clear guidelines on adj CT and T in node negative small HER-2 positive BC, the oncologists relied on the traditional factors such as grade, ER status in risk stratification and decision on adj therapy. Tumour grade was the most important factor but age and ER status were not discriminating factors in this study. Prospective randomised trials needed to clearly define the role of adj systemic therapy in this group of pts.

Impact of adjuvant trastuzumab-based chemotherapy in T1ab node-negative HER2 overexpressing breast carcinomas.

601 Background: HER2 overexpression has been recognized as a pejorative prognostic factor in node negative T1ab (T1abN0) breast tumors. Randomized clinical trials have shown benefit of adjuvant trastuzumab-based chemotherapy (ATBC) for node-positive and/or greater than 1 cm (T1c or more) HER2+ breast carcinomas. There are no prospective efficacy data of ATBC in T1abN0 HER2+ tumors. Methods: We retrospectively evaluated 276 cases of T1ab node-negative HER2+ breast tumors in 8 French Comprehensive Cancer Centers. We assessed clinical, therapeutic features and outcome. We estimated the probability of disease-free survival (DFS), analyzed associations of ATBC, patient and tumor characteristics with DFS and prognosis factors using the log-rank test, multivariate analysis with logistic regression and Cox’s proportional hazards model. Results: Out of the 276 T1abN0 cases, 129 (47%) received ATBC (ATBC+) and 123 (45%) were not treated by either trastuzumab or chemotherapy (ATBC-). Of these 252 ATBC+ or ATBC- patients, decision of ATBC was associated with date of diagnosis (before or after ASCO 2005 Annual Meeting when interim results from three trastuzumab adjuvant trials were reported) and with poor prognosis features: negative hormone receptors (HR-) status, Elston-Ellis high grade, tumor size > 5 mm and age. With a median follow-up of 44 months 16 recurrences were observed (13 in the ATBC- group, 2 in the ATBC+ and 1 with adjuvant chemotherapy alone). Nine recurrences were distant metastases. A survival benefit in ATBC+ was observed with a 99% 40-months DFS versus 93% for ATBC- (logrank p-test = 0.018). In an exploratory analysis, two factors were significantly associated with worst prognosis for ATBC- that were not observed for ATBC+ : HR- status (98% 40-months DFS for ATBC+ patients versus 84% for ATBC- patients; logrank p-test = 0.0003) and presence of lymphovascular invasion (100% 40-months DFS for ATBC+ versus 73% in ATBC- cases; logrank p-test = 0.003). Conclusions: In our seriesATBC is associated with a significant reduction of risk of recurrence of T1abN0 HER2+ tumors. A clear DFS benefit of ATBC was observed in HR- tumors and/or in presence of lymphovascular invasion.

P2-18-02: Cardiac Outcomes of Patients on Adjuvant Weekly Paclitaxel (T) and Trastuzumab (H) for Node Negative, HER2 Positive Breast Cancer (BCA).

Abstract Background Patients (pts) with (w/) node-negative HER2−positive BCA have a higher risk of recurrence than those with node-negative HER2−negative disease. Several randomized trials have shown the benefit of chemotherapy (most with an anthracycline) and trastuzumab (H) for pts with node-positive and high-risk node-negative BCA. However, the benefit of chemotherapy and H needs to be further explored in the node-negative group. Due to the 2–4% risk of symptomatic congestive heart failure (CHF) with an anthracycline-based treatment (Rx) followed by H, we set out to conduct a study of a taxane-based Rx with H in a node-negative population. Design: This is a single arm, multicenter, phase II study of paclitaxel (T) (80 mg/m2) and trastuzumab (H) x 12 weekly (w) (4 mg/kg load →2 mg/kg) → H x 52 w (2 mg/kg weekly or 6 mg/kg q 3 w). Pts with HER2−positive BCA (IHC 3 + or FISH amplified at ≥ 2.0) with negative nodes (micrometastasis later allowed) and with a tumor size ≤ 3 cm were enrolled. The primary endpoint is disease-free survival. Secondary endpoints include the incidence of G 3/4 left ventricular systolic dysfunction or congestive heart failure (CHF). Pts had serial left ventricular ejection fraction (LVEF) monitored at baseline (BSLN), and at month (mo) 3, mo 6, and mo 12 w/a multigated acquisition scan or echocardiogram. H was held for significant asymptomatic (Asx) LVEF ↓ (10-15% ↓ from BSLN and < lower limit of normal or ≥ 16% ↓ from BSLN), and H was stopped for CHF. Results: From 10-9-2007 to 9-3-2010, 406 pts were enrolled. The median (med) age was 55 years (range 23–84 years); 118/406 (29%) had hypertension and 30/406 (7%) had diabetes. As of 6-1-2011, 307 are reported as off Rx of which 261 have completed protocol therapy; 99 remain on therapy. To date, 100%, 94%, 84%, and 83% of pts had LVEF monitoring at BSLN, mo 3, mo 6, and mo 12. The med LVEF at BSLN was 65% (range 50%-81%), at mo 3 was 64% (range 45%-81%), at mo 6 was 64% (range 45%-81%), and at mo 12 was 65% (range 37%-90%). Two pts had CHF; 1 pt had CHF at mo 11 (LVEF was 55% at BSLN and 37% w/CHF event) and 1 pt had CHF at mo 6 (LVEF was 66% at BSLN and 49% w/CHF event). To date, 13 pts had H held for significant Asx LVEF ↓; details on those who had appropriate LVEF recovery and had H restarted will be provided. All patients will have completed 12 mo of Rx by October 2011, and an accurate report of the incidence of CHF will be available. Conclusion: This represents the cardiac report of pts receiving TH as adjuvant Rx for node-negative (micrometastasis allowed) HER2 positive BCA. Both the CHF events and number of pts w/H hold due to significant Asx ↓ LVEF appear low. Overall, the serial med LVEFs remain stable throughout the 12 mo of Rx. Final data on all 406 pts will be available in December 2011. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-18-02.

MS4-1: The Neoadjuvant Setting, HER2−Driven and Triple Negative Breast Cancer.

Abstract The benefits of neoadjuvant therapy include: tumor cytoreduction, minimizing surgical resection volume, conversion to breast conservation, and the opportunity to test new drugs and regimens because response in the breast is a surrogate for long-term survival. Off-trial, neoadjuvant regimens should mimic adjuvant regimens in drug, dose, and schedule; “tailored” approaches or treatment to best response have not been adequately studied. In HER2+ and triple negative (ER−, PR-, and HER2−negative, TNBC) BrCa, the backbone of neoadjuvant treatment is chemotherapy, with HER2−targeting added to the former. In hormone receptor-positive, HER2−negative BrCa, randomized clinical trials suggest similar efficacy of endocrine therapy and chemotherapy in response, however pathologic complete response (pCR) is rare. HER2−targeting with the anti-HER2 antibody trastuzumab (H) added to chemotherapy for HER2+ BrCa augments pCR, with 1 year of H completed adjuvantly. Off-trial options include AC-docetaxel (D) + H, AC-paclitaxel (T) + H, and D + carboplatin + H (DCH). It is likely that small, node-negative HER2+ BrCa are overtreated by these regimens; a challenge is to develop less chemotherapy-intensive regimens for the lower-risk setting. Several studies have examined other HER2−targeted drugs. In NeoALTTO, HER2+ patients received either TH, T + HER1/HER2 inhibitor lapatinib (TL), or the combination THL. pCR was lower (and toxicity higher) in TL; THL had the highest pCR rate (47%). GeparQuinto compared EC-DH to EC-DL and also found lower pCR rate and higher toxicity in the L-containing arm. NeoSPHERE examined the anti-HER2 heterodimerization domain antibody pertuzumab (P), pCR rates were higher with combination DHP (46%) vs. DH (29%) and DP (24%). The all-biologic HP arm had a 17% pCR rate. In TBCRC006, HL alone resulted in a 28% pCR rate. These studies support combination HER2−targeting-based regimens in adjuvant trials. TNBC lacks the known targetable molecules, ER, PR, or HER2, leaving chemotherapy the mainstay of treatment. Early TNBC is sensitive to conventional agents, and possesses one of the highest pCR rates to neoadjuvant anthracycline/taxane-based chemotherapy. The use of DNA-damaging drugs in TNBC is based on the association of Basal-like BrCa with BRCA1 germline mutations. Neoadjuvant studies are small and heterogeneous but supportive of a high pCR rate (>70%) to platinums in known carriers, however studies of sporadic TNBC are less clear. CALGB 40603, an ongoing randomized phase II study of taxane with or without carboplatin and with and without the antiVEGF antibody bevacizumab (B), will provide direct evidence. Although lacking known targeted therapy, subset analysis of the HER2−negative component of GeparQuinto suggested that TNBC had higher pCR rates with EC-D + B (45%) compared with chemotherapy alone (36%). The biology and identification of novel targets in TNBC as well as optimization of the chemotherapy remain subjects of intense study. Neoadjuvant therapy is an excellent approach for patients with clinical stage II-III in whom the nature of systemic therapy is clear. It also provides a rich laboratory for drugs, regimens, and the identification of predictive markers and subtype biology in a timely and efficient manner. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr MS4-1.

Efficacy results of node-negative HER2-amplified breast cancer subset from BCIRG 006 study: A phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC-T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC-TH) with docetaxel, carboplatin, and trastuzumab (TCH).

553 Background: Trastuzumab-chemotherapy-based adjuvant therapy (AC-TH or TCH) provide significant improvement in disease-free survival (DFS) and overall survival (OS) compared to chemotherapy-based adjuvant therapy (AC-T) in HER2 amplified breast cancer [Rommond E et al NEJM 2005 and Slamon D et al SABC 2009 and NEJM 2011 (in press)]. BCIRG 006 included 928 patients (pts) with stage I or II node-negative high risk HER-2 amplified breast cancer. We reported patient and tumor characteristics and efficacy outcome [disease-free survival (DFS) and overall survival (OS)] of this subset of pts. Methods: Pts were randomized to either AC (60/600 mg/m2 q3wk ×4) followed by T (100 mg/m2 q3wk × 4) or AC followed by TH × 4 (H q1wk during chemotherapy then q3wk × 9 months) or TCH (75 mg/m2 / AUC6 q3wk × 6, and H q1wk during chemotherapy then q3wk × 7.5 months). High risk axillary node negative HER-2 amplified breast cancer was prospectively defined as any of these patient/tumor characteristics: age ≤35 years, or tumor...

BACH: A randomized phase II trial of doxorubicin-cyclophosphamide (AC) versus pegylated liposomal doxorubicin (PLD)-cyclophosphamide-trastuzumab (CCH) followed by paclitaxel-trastuzumab (TH) as adjuvant therapy for HER2-positive breast cancer (BC)—Cardiac safety analysis.

559 Background: For patients (pts) with HER2+ BC, concurrent AC-H results in unacceptable cardiotoxicity rates. Substituting PLD for A in an adjuvant regimen may minimize cardiotoxic risk and permit earlier integration of adjuvant H. Methods: Inthis randomized phase II trial, pts with resected lymph node+ or high-risk, node-negative HER2+ BC were stratified by age and randomized (1:2) to: Arm A: AC (60/600 mg/m2 q21d × 4) followed by T 80 mg/m2 + H 2 mg/kg qwk × 12 or Arm B: PLD 35 mg/m2 + C 600 mg/m2 q21d × 4 + H 2 mg/kg/wk × 12, followed by T 80 mg/m2 + H 2 mg/kg qwk × 12. Subsequent H for a total of 1y was given as per institutional standards. Primary objective was incidence of level 1 (cardiac death or severe heart failure with left ventricular ejection fraction [LVEF] drop > 10% to < 50%) and level 2 (asymptomatic/mild heart failure with LVEF drop > 10% to < 50%) cardiac event rates during the 8 cycles of chemotherapy (CT). This analysis reports cardiotoxicity for the entire patient population completing 8 cycles of CT. Results: 181 pts were randomized between 8/2007 and 4/2009; 59 in Arm A and 118 in Arm B were eligible for cardiac toxicity assessment (modified ITT). Median age was 52.5 y (Arm A; range 30-71) and 50.1 y (Arm B; range 20-83); 98.3% in Arm A and 100% in Arm B had ECOG PS 0-1. No level 1 cardiotoxic events were observed in either arm. Three level 2 cardiotoxic events occurred in Arm A (5.1%; 95% CI: 1.1-14.1) and 1 event in Arm B (0.8%; 95% CI: 0.0-4.6). The mean LVEF reduction from baseline to completion of CT in Arm A was 5.3% (SD 6.38), vs. 2.2% (SD 6.25) in Arm B (p = 0.0015). 16.7% of pts in Arm B vs. 11.9% in Arm A experienced a serious adverse event (AE). Grade 3-4 AEs included (Arm A vs. B) alopecia (8.5 vs. 1.7%), PPE (0 vs. 15%), fatigue (0 vs. 1.7%), rash (0 vs. 4.2%), mucositis (0 vs. 2.5%), nausea (3.4 vs. 0%), and febrile neutropenia (6.8 vs. 4.1%). Conclusions: Concurrent CCH followed by TH as adjuvant therapy for HER2+ BC appears to be safe from a cardiac standpoint and did not increase cardiac event rates compared to AC-TH. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline, Roche Roche, sanofi-aventis, Schering-Plough Roche, University Hospital Leuven

Treatment of node-negative infra-centimetric HER2+ invasive breast carcinomas: A joint AERIO/REMAGUS study

517 Background: Trials have shown benefit of adjuvant trastuzumab (TZM) for node-positive (N+) or supra-centrimetric HER-2+ breast carcinomas. There are limited data concerning infra-centimetric HER-2+ invasive breast carcinomas (InfraHER-2). These tumors are being recognized as a high-risk group among all T1a/b tumors. Methods: Retrospective multicenter series from 2000 to 2008 of infra-centimetric HER-2+ invasive breast carcinomas (InfraHER-2). Tumors with ≥80% of ductal carcinoma in situ, multifocal and metastatic tumors were excluded. Results: 96 cases have been evaluated, 75 were node negative (N- InfraHER-2). All patients had surgery. 57% (n = 43) had a sentinel lymph node procedure. 73% (n = 55) had a local irradiation and 36 a tumor bed boost. Nodal irradiation of internal mammar and infra/supraclavicular regions was done in 20% and 17% respectively. 44% (n = 33) had chemotherapy (CT), almost all (31) were associated to TZM. Anthracycline-based (A), taxane-based (T) and A/T combinations were chosen for 54%, 4% and 42% respectively. One patient developed myocardial infarction after A resulting in heart failure; 2 had a transient left ventricular ejection fraction decrease below 50% after TZM. Decision of adjuvant CT was associated (all p &lt; 0.05) with hormonal receptors (HR) negative status, Elston-Ellis grade (EE) 2/3 and high mitotic index (MI) while patients with HR+/low MI tumors were rarely treated (p &lt; 0.001). 32/39 HR+ patients received hormonotherapy (80%); 21 received aromatase inhibitors, 6 tamoxifen and 5 LHRH agonists. With a 25 months median follow-up, there was no invasive recurrence in TZM treated patients. 3 of the 44 patients treated without TZM nor CT (7%) had local or metastatic recurrence including one fatal; they had initially HR- EE 2/3 T1b tumors. Conclusions: In our practice, decision of TZM-based therapy for InfraHER-2 N- tumors is associated with high-risk profile. Indeed, N- InfraHER-2 tumors may have a significant risk of recurrence which could be avoided by adjuvant TZM. Patients with N- InfraHER-2 tumors should be included in HER-2-targeted adjuvant trials. [Table: see text]

Treatment of infra-centimetric HER2-positive(+) invasive breast tumors. The Institut Curie experience.

Abstract Abstract #3152 Background: According to the adjuvant trastuzumab (T) trials, node-positive infracentimetric tumors stand for around 7% of all HER2+ breast carcinomas. The benefit of adjuvant T for women with node positive or supracentrimetric HER2+ breast tumors is established. There are no firm data establishing efficacy of T for infracentrimetric node-negative HER2+ tumors. We report our experience on infracentimetric tumors describing the received treatment, its efficacy and tolerance and the criteria that lead to therapeutic decision. Methods: We retrospectively reviewed electronic records of patients (pts) with invasive infra-centimetric HER2+ breast tumors treated in our institution from 2000 to 2008. Clinical, pathological, biological and therapeutic data were assessed. Tumors with a majority (≥80%) of ductal carcinoma in situ (DCIS) were excluded from this analysis. Results: 43 case records have been evaluated. Median age at diagnosis was 56 years (31-84). All tumors were treated by local surgery. 11 pts (26%) had node-positive tumors when including pN0i+ and pNmi+ tumors. 9 pts (82%) had local irradiation. A majority (n=8, 73%) were treated by chemotherapy and T except 1 with a pN0i+ tumor and 2 pts treated before T approval (2000-2001).32 pts (74%) had pN0 tumors. Ductal carcinomas accounted for 91% of tumors (n=29), and 14 (44%) were hormonal receptors-negative. Radiotherapy was given in 28 (88%) of them. 8 (29%) had nodal irradiation covering internal mammar chains, infra and supraclavicular regions. 21 of these pts (75%), had a 16 Gy breast tumor bed boost. Half the pts had chemotherapy (n=16). A sequential anthracycline/taxan (ATx)regimen was chosen for 10 pts (63%). Other regimen were A-based for 5 pts (31%) and Tx-based for 1 pt (6%). 1 pt developped myocardial infarction after her third anthracycline cycle. 22 pts (69%) have been treated with T. 13 of them have been treated by a chemotherapy/T (59%) combination. No significant correlation was found between decision of systemic treatment and age, hormone receptor status, grade, mitotic index or lymphovascu lar emboles. T treatment was complicated for 2 pts (13%) by left ventricular ejection fraction diminution under 50% after 5 and 6 months.With a median follow-up of 18 months, none of the 43 pts have developed recurrent invasive disease. In one pure micropapillary case, in situ local recurrence with micro-infiltration was seen at 5 years.Conclusion: In our experience, almost all pts were treated by local surgery and radiotherapy and around half pts received T since its approval with no significative clinical nor pathological factor leading to this decision. Usefulness of adjuvant chemotherapy and T for this tumors should be analyzed with data from prospective ongoing or closed trials. Systemic adjuvant treatment should be proposed for stage II tumors and discussed for smaller tumors taking into account age, grade, mitotic index, hormonal receptors status and presence of vascular invasion. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3152.

High Expression of Lymphocyte-Associated Genes in Node-Negative HER2+ Breast Cancers Correlates with Lower Recurrence Rates

Gene expression analysis has identified biologically relevant subclasses of breast cancer. However, most classification schemes do not robustly cluster all HER2+ breast cancers, in part due to limitations and bias of clustering techniques used. In this article, we propose an alternative approach that first separates the HER2+ tumors using a gene amplification signal for Her2/neu amplicon genes and then applies consensus ensemble clustering separately to the HER2+ and HER2- clusters to look for further substructure. We applied this procedure to a microarray data set of 286 early-stage breast cancers treated only with surgery and radiation and identified two basal and four luminal subtypes in the HER2- tumors, as well as two novel and robust HER2+ subtypes. HER2+ subtypes had median distant metastasis-free survival of 99 months [95% confidence interval (95% CI), 83-118 months] and 33 months (95% CI, 11-54 months), respectively, and recurrence rates of 11% and 58%, respectively. The low recurrence subtype had a strong relative overexpression of lymphocyte-associated genes and was also associated with a prominent lymphocytic infiltration on histologic analysis. These data suggest that early-stage HER2+ cancers associated with lymphocytic infiltration are a biologically distinct subtype with an improved natural history.

BCIRG 006: Docetaxel and trastuzumab-based regimens improve DFS and OS over AC-T in node positive and high risk node negative HER2 positive early breast cancer patients: Quality of life (QOL) at 36 months follow-up

19647 Background: The primary objective of the BCIRG 006 trial was to determine if the use of trastuzumab in early high-risk HER2-positive breast cancer significantly improved clinical outcomes. A secondary objective was to evaluate the QOL of patients receiving the 2 treatments. Methods: The BCIRG 006 trial compared adjuvant standard AC (doxorubicin/cyclophosphamide x 4 cycles) followed by docetaxel x 4 [AC-T] or 2 trastuzumab-containing regimens, AC followed by T with trastuzumab x 1 year [AC-TH] or TCarbo x 6 with trastuzumab x 1 year [TCH] in patients with node positive or high-risk node negative HER2-positive early breast cancer (n=3222). Results: The 2nd planned interim analysis, median follow-up at 36 months, showed that both AC-TH and TCH significantly improved the DFS and OS over the control (relative reduction risk of relapse 39% (P&lt;0.0001) and 33% (P=0.0003) respectively, for AC-TH and TCH vs control). Relative reduction in the risk of death was 41% (P=0.0041) and 34% (P =0.017) respectively, for AC-TH and TCH vs control. Congestive heart failure occurred in 0.4% of patients in AC-T and TCH vs 1.9% of patients in AC-TH. Global safety profile was acceptable in all 3 arms and more favourable in TCH than AC-TH. QOL, a secondary endpoint of this trial, was assessed using the EORTC QLQC-30, BR-23, and EQ5D. We will present the primary QOL endpoints comparing Physical Function, Global Health Status, Future Perspectives, and Systemic Treatment Effects change scores from baseline to mid-chemotherapy, end of chemotherapy, and 12 months follow-up (with a 10% change considered clinically important). The proportion of patients with improved/stable/worsened QOL scores will be compared with chi-square tests. Other QOL exploratory analyses will be presented. [Table: see text]

C-myc, not HER-2/neu, can predict recurrence and mortality of patients with node-negative breast cancer.

At present, node-negative, high-risk breast cancer patients cannot be identified with sufficient accuracy. Consequently, further strong prognostic factors are needed. Among 181 node-negative breast cancer (NNBC) patients, c-myc and HER-2/neu oncogenes were identified prospectively using double differential PCR. The possible impact of amplification of those oncogenes on disease-free survival (DFS) and overall survival was examined. Furthermore, the possible effects of adjuvant therapies on rate of recurrence and mortality in oncogene-amplified NNBC patients were investigated. The prevalence rates for amplification of c-myc and HER-2/neu were 21.5% and 30.4%, respectively. On univariate analysis, c-myc-amplified NNBCs were associated with significantly shorter DFS at 36 months after the initial diagnosis (85.3% versus 97.3%). As compared with nonamplified cancers, HER-2/neu-amplified NNBCs did not exhibit any significant differences after 36 months and 95 months. Multivariate analysis indicated that c-myc amplification and tumour size, in contrast to HER-2/neu amplification, oestrogen receptor status, grading and age, were the only independent parameters for DFS. During the period of observation, we found no evidence for an impact of amplification of the oncogenes on overall survival in all cases. With respect to various adjuvant systemic therapies such as chemotherapy (cyclophosphamide, methotrexate, 5-fluorouracil; fluorouracil, epirubicin, cyclophosphamide) and endocrine therapy (tamoxifen), no significant differences were identified in oncogene-amplified NNBC patients in terms of DFS and overall survival. However, those c-myc-amplified NNBC patients who did not receive adjuvant systemic therapy exhibited significantly shorter DFS and overall survival as compared with c-myc-nonamplified patients. C-myc amplification appears to be a strong prognostic marker with which to predict early recurrence in NNBC patients. C-myc-amplified NNBC patients without adjuvant systemic therapy experienced shorter DFS and overall survival.