HER2-positive Metastatic Breast Cancer Pts Research Articles

Abstract P4-01-37: Discontinuation of HER2+ targeted therapy among cancer survivors with metastatic HER2+ breast cancer: A case report

Abstract Background: Anti-HER2 directed therapy (aHER2tx) has significantly improved survival outcomes in patients with HER2-positive metastatic breast cancer (HMBC). Current United States (US) and European oncology practice guidelines recommend continuing aHER2tx until intolerable side effects or disease progression. It is estimated that 10-15% of treated patients (pts) may achieve prolonged complete remission (CR). Currently, the optimal duration of aHER2tx in patients achieving a CR is unknown. A PubMed literature search identified 7 case reports outside of the US that describe pts who remain in CR after discontinuation of aHER2tx. To our knowledge, this is the first analysis of similar cases in the US. Method: We identified pts with a diagnosis of HMBC who discontinued aHER2tx between January 1, 2010, to June 30, 2021, at a large integrated healthcare system in the US. Pts were included if they had discontinued aHER2tx for at least one year. Data collection included demographics, histology, confirmed sites of metastatic disease (mets), local and systemic treatment (tx) before and after aHER2tx discontinuation, documented radiographic response, and reason to discontinue aHER2tx. Data collection ended on June 30, 2022. Results: Our case report identified 15 pts (mean age at diagnosis 53.0 ± 13.2) based on inclusion criteria. Baseline demographics and characteristics are listed in Table 1. Common clinical characteristics of the cohort include mean age at mets diagnosis is 56 years, postmenopausal status (67%), invasive ductal carcinoma (87%), ER-negative (60%), HER2-positive 3+ by IHC (93%), de-novo mets (60%), multiple sites (93%) and multi-organ mets (87%). Among the cohort, 6 pts (40%) received prior adjuvant therapy, then later recurred, and of these only one had received HER2-based adjuvant tx. In all pts, first line therapy for mets included chemotherapy and aHER2tx, except one pt received endocrine therapy (ET) and aHER2tx. A CR was achieved in all but one pt (93%) with one line of aHER2tx consisting of trastuzumab (H) ± pertuzumab (P). One pt (7%) received local tx to all metastatic sites. In 13 pts, the median time to first radiologic complete response (RCR) after first line therapy for mets was 4 months (Interquartile (IQR) 3-15). Two cases were not included as we were unable to determine time to initial response after tx. All pts had confirmed RCR at the time of aHER2tx discontinuation. Median duration of aHER2tx was 8.3 years (IQR 4.8-9.5), including a median of 6.3 years (IQR 2.8-8.8) on maintenance aHER2tx. Twelve pts (80%) were off all therapy, and 3 pts (20%) continued ET for ER+ disease at the last follow-up (f/u). Patient preference (47%) was the most common reason for stopping aHER2tx. The median disease-free survival off aHER2tx was 4.8 years (IQR 3.1-6.2) and all pts were alive without evidence of disease at last f/u. Conclusion: A subset of HMBC pts successfully discontinued aHER2tx without experiencing recurrence with a median of 4.8 years off therapy in a US cohort. In this case report, common clinical features like strong HER2 overexpression, no prior aHER2tx, and achieving RCR while on first line aHER2tx with H ± P are potential indicators for prolonged CR after discontinuing aHER2tx. Future studies with a comparator group are needed to fully understand the pt population who may safely stop aHER2tx after a CR. Table 1: Baseline Demographics and Clinical Characteristics Citation Format: Lai Fong Hui, Nina N. Shah, Rita L. Hui. Discontinuation of HER2+ targeted therapy among cancer survivors with metastatic HER2+ breast cancer: A case report [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-37.

Abstract P3-01-05: Liquid biopsy methods and machine learning modeling to understand organ tropism and metastatization behavior of metastatic breast cancer

Abstract Background: Liquid biopsy provides a growing amount of real-time data about prognosis and the genomic landscape of metastatic breast cancer (MBC) and its comprehensive analysis is an emerging clinical need. Machine Learning (ML) data-driven models are able to “learn” information about a system and to adaptively improve their performance by directly observing its data. This enables the discovery of hidden patterns in complex heterogeneous and high dimensional data. The aim of this study was to explore the combination of clinical characteristics, circulating tumor DNA-detected aberrations (ctDNA) and CTC enumeration in estimating target organs more susceptible to MBC involvement using a ML modeling approach. Methods: The study retrospectively analyzed 88 MBC patients (pts) treated and characterized for CTCs and circulating tumor DNA (ctDNA) at Northwestern University (Chicago, IL) independently from treatment line. Blood samples were collected at baseline, concomitantly with imaging. CTCs were isolated through the CellSearch™ kit (Menarini Silicon Biosystems, PA), while ctDNA was analyzed using the Guardant360™ NGS-based assay (Guardant Health, CA). All features were normalized and included in a random forest algorithm implemented in Python (Scikit learn, BSD license), node splitting criterion for the decision tree classifiers was varied using Gini index and entropy. Hyperparameters of the random forest were then optimized including number of trees and the minimum leaf size by implementing hyperparameter grid search using 10-fold cross validation. Results: The median number of lines at baseline collection was 1 (interquartile range: 1-3), while the median number of metastatic sites was 3 (inter quartile range: 1-3) with the most observed sites being bone (37%), lymph nodes (29%), lung (27%) and liver (25%). The cohort consisted of 43% hormone receptor positive (HRpos), 32% TNBC, and 25% HER2-positive MBC. In the overall population, continuous CTC number (n_CTC), inflammatory breast cancer diagnosis (IBC), and aberrations in ESR1, KITand CDK4were the main features linked to liver metastases (AUC: 0.842), n_CTC, ESR1, PIK3CA, CCNE1and CDK6were the features linked to bone involvement (AUC: 0.770), while PIK3CA, METand MYC, were linked to lung organotropism (AUC: 0.701). Factors linked to the metastatization net combination pattern were then explored within each MBC subtype. Intriguingly, AR, n_CTC, TP53and ESR1were the main drivers in HRpos MBC (Mean per class error0.46), while EGFR, KITand NOTCH1were the main features in TNBC (Mean per class error 0.605). Consistently, n_CTC, ERBB2, PIK3CAwere the driving features among HER2 positive MBC pts (Mean per class error 0.87). Conclusions: This novel analysis demonstrates that liquid biopsy integrating both CTCs enumeration and genomic characterization by ctDNA could prove useful in a detailed description of the metastatic process, allowing a more tailored monitoring and therapeutic approach. Intriguingly, features linked to Epithelial to Mesenchymal transition were found to be a potential driver of the metastatization behavior, underlining the need to further elucidate the clinical impact of this process. Citation Format: Lorenzo Gerratana, Andrew A Davis, Maurizio Polano, Qiang Zhang, Ami N Shah, Chenyu Lin, Debora Basile, Giuseppe Toffoli, Firas Wehbe, Fabio Puglisi, Amir Behdad, Leonidas C Platanias, William J Gradishar, Massimo Cristofanilli. Liquid biopsy methods and machine learning modeling to understand organ tropism and metastatization behavior of metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-01-05.

Long-term toxicity profile of trastuzumab emtansine (T-DM1): A multicenter real-life study.

e12507 Background: T-DM1 is widely used in HER2 positive metastatic breast cancer (MBC) patients (pts), often for many cycles until progression. However, little is known about its long term toxicity. The aim of this study was to evaluate the safety profile of T-DM1 when delivered for ≥12 cycles. Methods: HER2 positive MBC pts who had received ≥12 cycles of T-DM1 across 18 Italian cancer centers were enrolled from January 2017 to September 2018. The 12 cycles cut-off was chosen based on the EMILIA trial median PFS (9.6 months), to identify a patient population treated with T-DM1 for longer time. Tumor and clinical characteristics were collected. Standard haematological tests, blood chemistries and side effects (nausea, vomiting, diarrhea, stomatitis, asthenia) were recorded cycle by cycle, according CTCAE criteria version 4. Haematological and laboratory toxicities were available for 86 patients, while other toxicities for all 115 patients. Results: Overall, 115 pts were enrolled. Median age was 54.5 (range 29.6–81.9); median time from diagnosis of metastatic disease to first T-DM1 cycle was 32.5 months. T-DM1 was administered as 2nd line and 3rd line of treatment in 45.2% and 27.8% of pts, respectively. Median number of cycles was 18 (range 12-59). Complete response, partial response and stable disease rates were 11.4%, 43% and 45.6%, respectively. Treatment related side effects are shown in table 1. Interestingly, no increased liver toxicity was observed in pts with liver metastases. Analysis of mean CTCAE grade by cycle showed that no relevant incremental toxicity was observed during long term T-DM1 therapy. Conclusions: T-DM1 is safe and well tolerated in these long responding pts. We found no relevant cumulative toxicity. Patients should be treated with T-DM1 as long as their tumor responds, as no safety issues are related to its long term use. [Table: see text]

Phase I study of alpelisib (BYL-719) and T-DM1 in HER2-positive metastatic breast cancer after trastuzumab and taxane therapy.

1026 Background: Constitutive activation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway is a mechanism of trastuzumab resistance in HER2-positive metastatic breast cancer (MBC). Alpelisib (BYL-719) is the first oral PI3K inhibitor that selectively inhibits the PI3Kα isoform. We aimed to determine the maximum tolerated dose (MTD), safety, and activity of alpelisib with ado-trastuzumab emtansine (T-DM1) in HER2-positive MBC that failed standard therapy. Methods: In this phase I study, pts received alpelisib daily (cohort 1: 300 mg, (-1): 250 mg) and T-DM1 3.6 mg/m2 on Day 1 every 21 days using a 3+3 design with dose expansion at MTD. Dose-limiting toxicity (DLT) was defined as CTCAE Grade 3/4 adverse events (AE) during cycle 1. Data cut-off is Jan. 1, 2017. Results: 17 pts were enrolled. Median age was 53 (40-66). Median prior lines of therapy in metastatic setting was 4.5 (0-13) including 9 pts who progressed on prior T-DM1 (after median 8 cycles). Median number of metastatic sites was 2 (1-5). Median number of cycles per pt who completed at least 1 cycle was 8 (1-19). Five pts were enrolled in cohort 1 with 2 DLTs (grade 3 rash), leading to cohort (-)1, in which there were no DLTs. The most common alpelisib-related AEs were hyperglycemia (n = 9, 53%), fatigue (n = 9, 53%), nausea (n = 7, 35%), and rash (n = 8, 47%). Grade 3 alpelisib-related AEs included rash (n = 7), hyperglycemia (n = 3), weight loss (n = 1), hypertension (n = 2), and pancreatitis (n = 1). Grade 3 rash occurred during cycle 1, which resolved with interruption and subsequent dose reduction of alpelisib and use of steroids. Grade 3 hyperglycemia was reversible with oral anti-diabetic treatment. One Grade 4 AE occurred (thrombocytopenia) likely due to T-DM1. MTD for alpelisib was established as 250 mg daily. Median follow-up was 11.6 months (0.3-19.5). Median PFS was 6 months (95% CI 2.9-10.6). In 11 pts without prior T-DM1 mPFS was 4.3 months (95% CI 2.0-8.8) and in 6 pts with prior T-DM1 it was 10.6 months (95% CI 1.6-12.6), p = 0.18. Conclusions: The combination of alpelisib 250 mg daily and T-DM1 appears to be safe in HER2-positive MBC pts with significant anti-tumor activity, even in pts previously treated with T-DM1. A phase II study is planned. Clinical trial information: NCT02038010.

Abstract PD5-04: NSABP FB-7: A phase II randomized trial evaluating neoadjuvant therapy with weekly paclitaxel (P) plus neratinib (N) or trastuzumab (T) or neratinib and trastuzumab (N+T) followed by doxorubicin and cyclophosphamide (AC) with postoperative T in women with locally advanced HER2-positive breast cancer

Abstract Background: Trastuzumab (T), the first anti-HER-2-directed therapy, dramatically changed the natural history of operable HER-2 positive breast cancer. A subsequent improvement occurred when pertuzumab was added to a T/docetaxel regimen in NeoSphere, a phase II randomized neoadjuvant trial, in which the pathologic complete response rate (pCR) in breast and nodes was increased from 21.5% to 39.3%, leading to accelerated approval of this combination by the FDA. Another dual anti-HER trial, NeoALTTO, which combined lapatinib with T, resulted in pCR (breast and nodes) increase from 27.6% to 46.8%. Neratinib (N) + paclitaxel (P) followed by AC was tested in the neoadjuvant I-SPY 2 trial resulting in pCR of 55% for hormone-negative, HER2-positive breast cancer. A 300-patient phase III trial of N or T with standard chemotherapy is planned. In the FB-7 phase II trial in HER2-positive patients (pts) with locally advanced disease, pts were randomly assigned to N or T or the combination (N+T) with weekly P followed by standard AC. Arm 3 of this trial, N+T+P, was based on the phase Ib results from NSABP FB-8, a study in heavily pretreated HER2-positive metastatic breast cancer pts, which demonstrated an overall response rate of 38% and clinical benefit rate of 52%. Methods: NSABP FB-7 opened in October 2010 as a two-arm trial (Arm 1, N+P→AC and Arm 2, T+P→AC). After accrual of 30 pts, accrual was suspended in December 2011 as NSABP FB-8, a phase Ib trial of neratinib, trastuzumab, and paclitaxel (N+T+P), was conducted and a recommended phase II dose for the combination of N+T+P was determined. NSABP FB-7 reopened in September 2012 adding Arm 3 (N+T+P→AC). 141 pts enrolled in this trial between October 2010 and November 2014. Three withdrew consent before treatment and were replaced. A total of 126 US, Canadian, and European pts were randomized to Arm 1 (N+P→AC), Arm 2 (T+P→AC) or Arm 3 (N+T+P→AC). 12 additional pts from the US were treated on Arm 3 as nonrandomized (NR) pts. These NR pts are included for toxicity but not for efficacy. Eligibility criteria included women >18 years of age, ECOG PS 0-1, stage IIB-IIIC invasive breast cancer, HER2-positivity by IHC 3+, FISH, or CISH as determined by local laboratories, hormone receptor positive or negative, LVEF >50%, and adequate laboratory parameters. The primary endpoint is pCR in breast and nodes. Conclusions: The last patient enrolled on this trial in November 2014. Datalock for the primary endpoint will occur on or before September 1, 2015. Pathologic complete response data and toxicity will be reported on the entire cohort of pts. Biomarkers will be analyzed on a subset of pts. Support: Puma Biotechnology, Inc. Citation Format: Jacobs SA, Robidoux A, Garcia JMP, Abraham J, La Verde N, Orcutt JM, Cazzaniga ME, Calvo L, Aguirre E, Buyse M, Pogue-Geile KL, Srinivasan A, Song N, Balousek AD, Wolmark N. NSABP FB-7: A phase II randomized trial evaluating neoadjuvant therapy with weekly paclitaxel (P) plus neratinib (N) or trastuzumab (T) or neratinib and trastuzumab (N+T) followed by doxorubicin and cyclophosphamide (AC) with postoperative T in women with locally advanced HER2-positive breast cancer. [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 PD5-04.

A24 - First line trastuzumab-based therapy in her2-positive metastatic breast cancer patients presenting with de novo or recurrent disease

Background: Approximately 5-10% of breast cancer (BC) patients (pts) have metastases at the time of diagnosis (de novostage IV), suggesting distinct biological and clinical implications as compared to those relapsing after prior treatment for early stage BC (recurrent disease). We evaluated the patterns of care and clinical outcomes of HER2-positive metastatic breast cancer (MBC) pts receiving first line trastuzumab-based therapy, according to the type of metastatic presentation. Materials and methods: This is an ancillary study of a retrospective cohort study conducted in 14 Italian centers within the GIM (Gruppo Italiano Mammella) group. Consecutive pts undergoing first-line trastuzumab-based therapy were eligible for the study. Analyses were performed according to the type of presentation of metastatic disease (de novoor recurrent). Dichotomous clinical outcomes were analyzed using logistic regression and time-to-event outcomes using Cox proportional hazards models controlling for relevant demographic, clinicopathologic and therapy characteristics. All data were analyzed using Stata 12.3 (StataCorp LP). Results: A total of 416 MBC pts (median age, range 42–63 years) were included, 113 (27.2%) with de novo stage IV and 303 (72.8%) with recurrent disease: 64 (56.6%) and 186 pts (61.4) had hormone-receptor positive disease, respectively. Among pts with recurrent disease 101 (33.3%) received prior trastuzumab-based therapy in the (neo)adjuvant setting. Overall survival (OS) and progression-free survival (PFS) median follow-up were 2.59 years (1.56–4.41) and 1.11 years (0.63–2.17), respectively. In pts with de novo stage IV disease and in those with recurrent disease the following outcomes were observed, respectively: objective response rate (complete response + partial response), 163 pts (67.1%) vs 72 pts (72.0%) (adjusted OR = 0.90; 95% CI 0.34–2.38; p = .833); clinical benefit rate (complete response + partial response + stable disease), 76 pts (76.0%) vs 187 pts (77.0%) (adjusted OR = 1.21; 95% CI 0.40–3.64; p = .731); median PFS, 14.4 months vs 14.7 months (adjusted HR = 1.21; 95% CI 0.79–1.86;p = .380);median OS, 55.9 months vs 49.0 months (adjusted HR = 1.26; 95% CI 0.71–2.23; p = .439). Conclusions: The study shows that clinical outcomes of HER2-positive MBC pts with de novo stage IV disease do not differ significantly from those of pts with recurrent disease.

A59 - T-DM1 for HER2 positive advanced breast cancer: a single institution, “real life” experience

Background: Ado-trastuzumab emtansine (T-DM1) is a novel antibody drug conjugate effective for HER2-positive metastatic breast cancer (MBC) patients (pts) previously treated with trastuzumab and taxanes. Patients and method: Consecutive HER2 positive MBC pts treated at our institution with T-DM1 3.6 mg/kg iv every 21 days were eligible for the study. Clinicopathologic and treatment characteristics were reported. Adverse events (AEs) and severe adverse events (SAEs) were graded according to National Cancer Institute Common Terminology Criteria. Results: Between July 2013 and May 2015, we identified 24 consecutive pts. Median age 57.5 years (range 36-80); <65 yrs 16 pts (67%), >65 yrs 8 pts (33%). Histology: ductal carcinoma 23 pts (95%), other 1 pt (5%). 17 pts (71%) had hormonal receptor (HR) positive disease and 7 (29%) HR-negative cancer; 6 pts (25%) showed an HER2 negative primary tumor, but HER2 positive on metastatic site. 6 pts (25%) showed bone metastases (mts), 8 pts (33%) visceral mts, and 10 pts (42%) both bone and visceral mts. 14 pts (58%) received a neadjuvant/adjuvant treatment. All pts were previously treated with trastuzumab and taxanes. T-DM1 was administred as first line in 1 pt (4%), as second line in 7 pts (30%), as third line in 8 pts (33%) and in 8 pts (33%) in subsequent lines. Pts received T-DM1 for a median time of 5.2 months. mPFS was 6.3 months (range 2.7-12.6). 7 pts (33%) showed a progressive disease (PD) as best response, 4 (19%) stable disease (SD), 8 (38%) partial response (PR) and 2 (10%) complete response (CR); among the 6 pts with an HER2 negative primary tumor 4 (67%) showed a PD and 2 (33%) a SD as best response. The most common toxicities reported were elevated serum concentrations of transaminases (G1-2), observed in 11 pts (46%); asthenia (G1-3) in 12 pts (50%) and nausea (G1-3) in 10 pts (42%). Thrombocytopenia (G1) was observed in 5 pts (21%). No SAEs neither cardiac events were observed. T-DM1 dose reduction due to AEs was necessary in 2 pts (8%) and no drug interruption due to toxicity was observed. No difference in AEs rate was noticed in elderly patients. Conclusions: Our single intitution “real life” experience confirmed the very favorable toxicity profile of T-DM1, even in elderly pts. However, with the limitations of the retrospective nature of the study and the small sample size, we observed an inferior mPFS than reported previously. Interestingly the higher rate of PD in pts who showed an HER2 negative primary tumor.

Abstract OT1-1-13: A phase II study with lead-in safety cohort of cabazitaxel plus lapatinib as therapy for patients with HER2-positive metastatic breast cancer (MBC) and intracranial metastases

Abstract Background: HER2-targeted therapy has improved the progress of patients (pts) with HER2-positive breast cancer; however, CNS metastases remain a significant source of morbidity and mortality. It is hypothesized that the inability of drugs like trastuzumab to cross the intact blood-brain barrier (BBB) may render the CNS as a sanctuary site for metastases. Lapatinib is an oral small molecule tyrosine kinase EGFR1/HER2 inhibitor that crosses the BBB and has activity against CNS metastases. Cabazitaxel is a new taxoid that is active in docetaxel- or paclitaxel-resistant breast cancer, and differs from other taxanes in its ability to cross the BBB. The promising systemic activity shown by cabazitaxel in taxane-resistant MBC coupled with the CNS penetrance of both cabazitaxel and lapatinib make this an attractive combination to evaluate in HER2-positive MBC pts with CNS metastases. Study Objectives: The primary objectives of the study are to determine the safety and CNS objective response rate (ORR = CR+PR) in HER2-positive MBC pts with CNS metastases when treated with cabazitaxel and lapatinib. The secondary objectives include evaluation of the clinical benefit rate (CBR), 3- and 6-month PFS rate for CNS metastases, and response rate and CBR for extra-cranial metastases. Key eligibility: Pts &amp;gt;18 yrs with HER2-positive (IHC 3+ or FISH/SISH-positive) MBC and unequivocal evidence of brain metastases are eligible. Additional eligibility criteria include: at least one measurable brain lesion &amp;gt;1.0cm in longest dimension on MRI; pts with brain lesions previously treated with WBRT and/or SRS must have at least one intra-cranial lesion &amp;gt;1.0cm not treated with SRS and must have evidence of intra-cranial progressive disease. Pts must have received at least 1 prior HER2-directed therapy in the adjuvant or metastatic setting; pts without prior chemotherapy for MBC are eligible if they progressed during or within 6 months of adjuvant therapy. Otherwise, there is no specific minimum or maximum number of previous chemotherapy regimens for MBC. ECOG performance status 0-2, adequate renal, bone marrow, and hepatic function are required; prior treatment with cabazitaxel or lapatinib (for MBC) not permitted. Trial design: This is an open-label, non-randomized, phase II study with a lead-in safety cohort. During the lead-in phase, 6-15 pts will be treated in cohorts of 3 with increasing doses of cabazitaxel and lapatinib to determine the tolerability and optimal dose. Once the safety and dose is confirmed, subsequent pts will be treated at the optimal dose of the 2 agents. Each treatment cycle is 3 weeks and restaging will occur systemically and intra-cranially every 2 cycles for the first 8 cycles and every 3 cycles thereafter until progressive disease or unacceptable toxicity. Statistical methods: We hypothesize that the addition of cabazitaxel will increase the CNS ORR from 6% (expected with single agent lapatinib) to ≥20% in this pt population. Treatment of 27 evaluable pts with the identified phase II doses will detect this difference with a power of 80% and alpha = 10% (one-sided test). Accounting for a 10% inevaluable rate and lead-in pts, a total of 45 pts will be enrolled on the study. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-1-13.

Choice of primary endpoints in first-line phase III trials of HER2-negative or HER2-unknown metastatic breast cancer (MBC).

607 Background: OS is considered the most clinically relevant endpoint in cancer therapy trials, but OS can be confounded by post-trial therapy, particularly in settings with long post-progression survival (PPS). Based on statistical modelling with 50,000 simulated trials, Broglio &amp; Berry [JCNI 2009] suggested the association between improved progression-based endpoints (eg, PFS) and OS is weak in settings with PPS &gt;12 months and can only be shown in very large trials. To test this hypothesis, we analysed efficacy outcomes and choice of primary endpoints in first-line MBC trials. Methods: Data wereanalysed from:randomised, controlled phase III trials comparing systemic chemotherapies and/or targeted agents; enrolling ≥150 pts; published in peer-reviewed journals from 2000–2011. Trials that enrolled only HER2-positive MBC pts or evaluated non-EU approved agents were excluded. Results: Of27 trials, 1 (3.7%) had OS as the primary endpoint, while 18 (66.7%) had progression-based parameters, commonly PFS (9 trials, 33.3%). A significant increase in progression-based parameters was seen in 14 trials (51.9%). All 5 trials (18.5%) showing a significant OS benefit had a PPS &lt;12 months. Mean PPS was considerably longer in trials published in 2006–2011 vs 2000–2005 (14.1 ± 4.0 vs 9.7 ± 2.3 months, respectively), as was mean PFS (8.3 ± 2.2 vs 6.6 ± 1.6 months) and mean OS (25.4 ± 5.6 vs 18.6 ± 3.0 months). A weak correlation was seen between OS and PFS (Pearson’s coefficient r=0.32), but a higher correlation was seen in treatment arms with an OS benefit (r=0.59), as well as in treatment arms with a PPS &lt;12 months (r=0.43) or older studies (r=0.51). Data were insufficient to allow a valid analysis of the effect of further-line therapies or cross-over on OS (16 trials reported further-line therapies; 9 cross-over therapy). Conclusions: In support of the hypothesis by Broglio &amp; Berry, a significant OS advantage was shown exclusively in trials with a PPS &lt;12 months. Due to the weak correlation between PFS and OS, it is difficult to determine the possible surrogacy of PFS for OS. Thus, as an OS benefit might be increasingly difficult to attain, progression-based parameters appear to be valid endpoints in MBC clinical trials.

243 - Impact OF PIK3CA Mutations and P95HER2 Expression on the Outcome of HER2-Positive Metastatic Breast Cancer Patients Treated With a Trastuzumab-Based Therapy

ABSTRACT Background Currently, no biomarkers of Trastuzumab (T) clinical resistance have been validated. The aim of this pilot study was to evaluate the impact of PIK3CA mutations and p95HER2 (pHER2 truncated form) expression on the efficacy of a T based-therapy in a HER2-positive metastatic breast cancer (MBC) patients (pts). Methods 107 HER2-positive MBC pts, treated in the last 10 years, were evaluated. Median age was 54 years (25-79); ECOG performance status was 0 in 56% of pts; all pts received several lines of treatment including T; biomarkers molecular analysis was performed in 70 tumor specimens. The IHC expression of p95HER2 was evaluated by a monoclonal antibody that specifically recognizes only the HER2 external domain; the HER2 integrity was defined by the presence of a homogeneous membrane staining (moderate or intense) in at least 30% of the cells, otherwise the HER2 was defined as p95HER2 positive. PIK3CA mutations in exons 9 and 20 were detected by automated sequencing. The molecular data were correlated to Time to progression (TTP) of the first line treatment including T and the Overall Survival (OS) by using the Kaplan-Meir method and the log-rank-test. Results p95HER2 positive pts and PIK3CA mutations in exon 9 or 20 were detected in 42% and 22% of tumor specimens, respectively. p95HER2 positive tumors showed a shorter TTP and OS that did not reach statistical significance; PIK3CA mutations correlated with a worse TTP (median 7,6 vs 11,3 months) and OS (median 20,1 vs 41,0 months, p= 0,046). Conclusions These preliminary results suggest a possible role of PIK3CA mutational status in predicting the outcome of MBC pts treated with T. Disclosure All authors have declared no conflicts of interest.

Impact of PIK3CA mutations and p95HER2 expression on the outcome of HER2-positive metastatic breast cancer patients treated with a trastuzumab-based therapy.

629 Background: Currently, no biomarkers of trastuzumab (T) clinical resistance have been validated. The aim of this pilot study was to evaluate the impact of PIK3CA mutations and p95HER2 (pHER2 truncated form) expression on the efficacy of a T based-therapy in a HER2-positive metastatic breast cancer (MBC) patients (pts). Methods: 107 HER2-positive MBC pts, treated in the last 10 years, were evaluated. Median age was 54 years (25-79); ECOG performance status was 0 in 56% of pts; all pts received several lines of treatment including T; biomarkers molecular analysis was performed in 70 tumor specimens. The IHC expression of p95HER2 was evaluated by a monoclonal antibody that specifically recognizes only the HER2 external domain; the HER2 integrity was defined by the presence of a homogeneous membrane staining (moderate or intense) in at least 30% of the cells, otherwise the HER2 was defined as p95HER2 positive. PIK3CA mutations in exons 9 and 20 were detected by automated sequencing. The molecular data were correlated to Time to progression (TTP) of the first line treatment including T and the Overall Survival (OS) by using the Kaplan-Meir method and the log-rank-test. Results: p95HER2 positive pts and PIK3CA mutations in exon 9 or 20 were detected in 42% and 22% of tumor specimens, respectively. p95HER2 positive tumors showed a shorter TTP and OS that did not reach statistical significance; PIK3CA mutations correlated with a worse TTP (median 7,6 vs 11,3 months) and OS (median 20,1 vs 41,0 months, p= 0,046). Conclusions: These preliminary results suggest a possible role of PIK3CA mutational status in predicting the outcome of MBC pts treated with T.

Abstract P3-02-03: Prognostic Value of Circulating Tumor Cells (CTC) in HER-2 Positive Metastatic Breast Cancer (MBC) Patients (pts) Treated with Anti-HER2-Based Therapy

Abstract Background. Detection of ≥5 CTC per 7.5 mL of blood before starting systemic treatment is a strong and independent predictor of worse progression-free survival (PFS) and overall survival (OS) in MBC. Trastuzumab (Herceptin®) was shown to be highly effective in reducing CTC number in all HER-2 amplified MBC cases after the first dose (De Giorgi et al., SABCS 2009). Furthermore, trastuzumab can target chemotherapy-resistant CTC in pts with breast cancer (Bozionellou et al. 2004). To date no significant analysis exploring the effect of another anti-HER2 therapy, lapatinib (Tykerb®) on CTC has been published.We hypothesized that anti-HER2-based therapy may modify the detection rate and prognostic value of CTC in pts with HER-2 amplified MBC. Patients and Methods. We retrospectively evaluated 91 HER-2 positive MBC pts, treated at the M. D. Anderson Cancer Center with trastuzumab-based (n=59), or lapatinib-based therapy (n=32). In all pts, CTC were enumerated before starting systemic treatments, using CellSearch™. Follow-up CTC counts were available for 41 (69%) pts treated with trastuzumab and 25 (78%) pts treated with lapatinib. PFS and OS were estimated by Kaplan-Meier product limit, and compared between groups according to baseline CTC count (&amp;lt;5 vs ≥5) by log-rank test. Results. Median follow-up was 27 months (range, 8-65) and 16 months (range, 3-33) for pts receiving trastuzumab and lapatinib, respectively. Treatments administered and CTC counts are reported in table 1. Two (5%) pts receiving trastuzumab and 4 (16%) pts treated with lapatinib had CTC ≥5 at the follow-up assessment. Estimated median PFS and OS according to baseline CTC value, for both treatments are shown in table 2. An elevated CTC count was associated with poor prognosis in pts treated with lapatinib (median OS: 25.8 vs 13.6 months in pts with CTC &amp;lt;5 and ≥5, respectively, P=.072). Surprisingly, in the trastuzumab group, PFS showed a non-statistically significant trend in favor of pts with CTC ≥5 compared to those with &amp;lt;5. Conclusions. According to previously published data, our study confirms that trastuzumab-based therapies can drastically reduce the number of CTC and neutralize their negative prognostic value. Furthermore, we found that lapatinib had a limited effect on the detection rate and prognostic value of CTC, although the low number of pts and the high percentage of pre-treated women do not allow us to draw definitive conclusions. Table 1 Table 2 Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-02-03.

Lapatinib plus capecitabine in highly pretreated HER2-positive metastatic breast cancer: A single-institution experience.

1145 Background: Therapies targeting HER2 are very effective in metastatic breast cancer (MBC) combined with chemotherapeutic agents (CAs). Lapatinib (L) demonstrated activity and improved time to disease progression in pts who had progressed on trastuzumab (T) (Cameronet al 2008). Since April 2007, L in combination with capecitabine (X) was available in Italy within an expanded access program and thereafter as commercial drug. Methods: From April 2007 to March 2009, 58 HER2-positive MBC pts who had developed progression after antracycline-, taxane-, and T-based regimens, were treated with L plus X in our Institution. Results: Fifty-seven pts were evaluable for response. The median number of previous treatment lines, including the adjuvant setting, was 3 (ranging from 1 to 7). The median duration of previous T treatment (given alone or with chemotherapy) was 19 months (range 2.5-57 months). The median time to progression (MTTP) after first line T plus a cytotoxic agent (CA) was 11 months. At progression, 40 pts (69%) had visceral disease and in particular 8 pts (14%) had brain metastasis. The median number of cycles of L-X was 7 (range 2-29+ cycles). MTTP after L-X was 5,3 months. Clinical benefit (CB) (defined as complete remission plus partial remission plus stable disease lasting for at least 6 months) was noted in 33 pts (57%) with 4 pts having long lasting CR in visceral sites. The most frequent nonhematological toxicity was diarrhea and hand-foot syndrome. No G4 toxicity was noted. Conclusions: The combination of L and X is confirmed to be an active regimen even in highly pretreated HER2-positive MBC pts and in pts with visceral and brain metastases. Unfortunately the toxicity of both agents appears to be partly overlapping, even if only few pts experienced severe toxicities. Comparative studies with other CAs appear to be warranted. No significant financial relationships to disclose.

Everolimus in combination with weekly paclitaxel and trastuzumab in patients (pts) with HER2-overexpressing metastatic breast cancer (MBC) with prior resistance to trastuzumab and taxanes: A multicenter phase II clinical trial.

1013^ Background: Resistance to trastuzumab (H) may be associated with deregulation of PTEN or mutations in PI3K/AKT pathway. Preclinically, everolimus (E), an oral inhibitor of mTOR, enhances activity, reverses resistance to H and demonstrates synergistic activity with paclitaxel (T). The objective of this phase II study was to evaluate the efficacy of E combined with T and H in heavily pretreated HER2-positive MBC pts. Methods: A multicenter, Novartis sponsored, phase II trial was conducted using: T 80mg/m2, IV on days 1, 8 and 15 q4w; H 4mg/kg IV loading dose, then weekly 2mg/kg; E daily 10mg in patients whose disease is resistant to both H (progression on or within 3 months of the end of H therapy for metastatic cancer or within 12 months after the end of neoadjuvant or adjuvant H) and taxanes (progression on or within 4 months of the end of taxane therapy for metastatic cancer or within 12 months after the end of neoadjuvant or adjuvant therapy.) Treatment continued until progression or unacceptable toxicity. Results: The study completed enrollment (n=55). Analyses were performed on 37 evaluable pts. Median treatment duration is 12 weeks (2-43) with19 pts still on treatment and 6 beyond 6 cycles. Pt characteristics were median age 56 y; visceral disease in 33 pts (89%) with lung and liver involvement in 18 pts (49%) and 21 pts (57%), respectively; median no. of prior chemo lines for metastatic disease 3 (range 0-8); prior anthracyclines in 25 pts (68%); prior lapatinib in 23 pts (62%). Twenty-five pts were evaluable for efficacy. We observed 5 (20%) confirmed PRs, 14 (56%) SDs and 6 (24%) PDs. Treatment was well tolerated. G3-4 neutropenia occurred in 12 pts (32%) with 1 case of febrile neutropenia, G3 stomatitis in 5 pts (13%) and G3 asthenia/fatigue in 2 pts (5%). Conclusions: These preliminary results confirm a previous phase I study showing that E in combination with T and H has an acceptable safety profile and promising anticancer activity in HER2-positive MBC pts pretreated with trastuzumab and taxanes. Updated safety, efficacy, and PFS results will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis, Pfizer Novartis Novartis, Pfizer Genentech, Novartis In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519-521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2010 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest.

Randomized phase III study of trastuzumab monotherapy followed by docetaxel and trastuzumab versus the combination of trastuzumab and docetaxel as first-line treatment in patients with HER2 positive metastatic breast cancer.

Abstract Abstract #3132 Introduction: Treatment with trastuzumab (H) is a standard therapy for the patients with HER2 positive metastatic breast cancer (MBC) and both the combination with H and chemotherapy (CT) and H alone are very popular. However, it is unknown which is better; sequential H alone followed by combination of CT and H at disease progression or the combination with H and CT as first-line therapy. Therefore, we conducted phase III randomized trial compared them in HER2 positive MBC.&amp;#x2028; Methods: Eligible patients were HER2 positive MBC patients (pts) with measurable tumour based on RECIST, ECOG Performance status 0 or 1 and left ventricular ejection fraction (LVEF) &amp;gt;50%. Patients with prior CT for MBC, adjuvant H, and Docetaxel (DTX) were excluded. They were randomly assigned to sequential weekly H 2 mg/kg (loading 4 mg/kg) alone followed by combination of DTX (60 mg/m2, q3wks) and H at disease progression (arm A) or concurrent combination of H and DTX (arm B). Primary endpoints were time to progression (TTP) of H alone (arm A) and combination of H and DTX (arm B) and overall survival (OS). Secondary endpoints were overall response rate (ORR), TTP and safety in arm A and B.&amp;#x2028; Results:Of the 108 pts registered, 105 pts were eligible. Baseline characteristics of all pts in two groups were well-balanced. Median age was 57/55 years, prior adjuvant CT 38/45% and single metastatic site 30/31% in arm A and B, respectively. Median TTP in arm A was 137 days compared to 445 days in arm B (hazard ratio=4.15; P&amp;lt;0.0001). ORRs were 15% and 71% in arm A and B, respectively. Median OS has not been reached yet, however, the number of deaths were 11 pts in arm A and 4 pts in arm B (hazard ratio=3.36; P=0.028). Adverse event incidence of grade 3 or 4 was 51/85% in each arm. An Efficacy and Safety Evaluation Committee recommended stopping this trial based on the results of TTP and OS.&amp;#x2028; Discussion: These results suggested that the combination of H and CT is superior to sequential H alone followed by DTX and H as first-line therapy in HER2 positive MBC pts despite the number of pts did not reach to the planned sample size. We will continue further investigation based on extended follow-up period. The updated data will be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3132.

EGFR, MAPK, and Akt status by immunohistochemistry (IHC) are not correlated with clinical outcome in HER2-positive (HER2+) metastatic breast cancer (MBC) patients (pts) treated with trastuzumab (T) with or without chemotherapy (CT)

1090 Background: T alone or in combination with CT has been shown to be an active therapy in HER2-positive MBC pts. However, not all pts will benefit and mechanisms of resistance to T are still poorly understood. The aim of this study was to evaluate the IHC expression of EGFR and two downstream effectors of the EGFR family signaling pathway, MAPK and Akt and their correlation with clinical outcome in HER2-positive MBC pts treated with T ± CT. Methods: 133 consecutive HER2+ MBC pts were treated between 04/99 and 03/06 but tumor tissue was available for this analysis only from 45 pts. HER2 evaluated by CB11 was scored according to Herceptest. Tumors were considered EGFR positive if =1% positive tumor cells and MAPK positive and Akt positive if the percentage of positive tumor cells was =10%. Results: At median follow up of 57 months (range 5–229) from the start of T, 45 pts were evaluable for TTP and OS and 42 for response to T. Median age of pts was 53 years (23–77). Twenty seven objective responses (CR+PR) to T ± CT (64.28%) were observed; median TTP was 24 months (3.3–179.8). In 11 of the 27 responsive pts (40.7%), progression was observed in CNS ± other sites. Median OS from the start of T was 74 months. EGFR positive tumors were 10 (22.2%), MAPK positive tumors were 16 (35.5%) and Akt positive tumors were 23 (51.1%). We analyzed the correlation of HER2, EGFR, MAPK and Akt status with response to T, TTP and OS. HER2 was significantly correlated with response to T (p = 0.013): in HER2 3+ tumors we observed 22 (9 CR and 13 PR) out of 27 objective responses but, no significant correlation was found between HER2 status and TTP and OS. EGFR, MAPK and Akt status of tumor were not significantly associated with response to T, TTP and OS in this series of HER2+ MBC pts. Conclusions: We did not found any significant correlation between EGFR, MAPK, Akt status evaluated by IHC and clinical outcome in HER2+ MBC pts treated with T ± CT. Only HER2 status evaluated by IHC significantly correlated with response to T ± CT. No significant financial relationships to disclose.

Predictors of brain relapse in HER-2 positive metastatic breast cancer (MBC) patients (pts)

10508 Background: Brain relapse is a common occurrence in HER2-positive breast cancer pts. We assessed factors determining the risk of this event in a large unselected series of HER2-positive MBC pts. Methods: Study group included 233 consecutive HER2-positive (IH 3+ or FISH+) MBC pts (median age 53 years); 49% premenopausal, 49% postmenopausal and 2% with unknown menopausal status. Dominant site of disease included viscera (78%), soft tissue (11%) and bones (10%). Of the 206 pts (88%) with known steroid receptor status, ER+/PgR+, ER+/PgR-, ER-/PgR+, ER-/PgR- phenotypes included 58%, 15%, 5% and 21% of pts, respectively. Prior (neo)adjuvant chemotherapy, endocrine therapy or a combination thereof was administered in 40%, 6% and 35% of pts, respectively. Disease-free interval to the development of MBC ranged between 0 and 142 months (median 16 months). 184 pts (79%) received trastuzumab for MBC, usually in combination with chemotherapy. Statistical analysis included contingency tables, chi-square test, Kaplan-Meier survival analysis and Cox proportional hazard model. Results: Median follow-up from the development of MBC was 25 months (range 0.5–130 months). 54 pts (23%) developed brain metastases after a median of 13 months (range, 0 to 81 months). Cumulative risk of brain relapse was 11% (95% CI: 7–16%) and 24% (95% CI: 17–32%) at one and two years, respectively. Trastuzumab treatment was associated with insignificantly reduced risk of brain metastases (HR 0.63, 95% CI 0.29–1.39, p = 0.25). In the univariate analysis, premenopausal status was the only significant factor associated with increased risk of brain relapse (HR 2.56, 95% CI 1.28–5.00, p = 0.008). Conclusion: HER-2 positive MBC pts carry high risk of brain relapse, in particular prior to menopause. Protective role of trastuzumab warrants further research. [Table: see text]

Optimal tolerance of an all-oral combination chemotherapy (CT) of oral vinorelbine (NVBo), capecitabine (C) with/without trastuzumab (T) in metastatic breast cancer (MBC) patients (pts): Safety Results of two international multicenter studies

10607 Background: Combination therapy of T and Vinorelbine has recently been reported to be an active and safe regimen for HER2 positive MBC pts. The current safety analysis investigated NBVo and C, which offers the convenience of an all-oral regimen given alone or in combination with T, if pts were HER2 positive, as first-line therapy for MBC patients, KPS ≥ 70%. Methods: In the HER2 negative study ([A]) (IHC 0- 2+/FISH−) 38 pts received: NVBo 60 mg/m2 (Cycle 1) or 80 mg/m2 (from Cycle 2) D1 &amp; D8 and C 2000 (1500 if ≥ 65 y) mg/m2/d D1-D14 every 3 weeks. In the HER2 positive study ([B]) (IHC 2+ or 3+ confirmed by FISH+) 25 pts received : NVBo, and C at the same doses as [A] + T, 4 mg/kg on D 1 as loading dose and then 2 mg/kg i.v. weekly starting on D8. Treatment was continued in both studies till progression. Results: Median age: [A] 61.5y (17 pts ≥ 65 y), [B] 53.0 y (5 pts ≥ 65 y); Prior (neo)adjuvant CT: [A] 21 pts (55.3%), [B] 16 pts (64%); Visceral involvement: [A] 28 pts (73.7%), [B] 22 pts (88%); &gt; 2 metastases: [A] 15 pts (39.5%), [B] 10 pts (40%); Median dose intensity (%): NVBo [A] 45.1 mg/m2/w (90.5%), [B] 39.5 mg/m2/w (75.7%); C [A] 7733 mg/m2/w (87%), [B] 7140 mg/m2/w (83.7%); T [B] 2.1 mg/kg/w (98.1%). NVBo dose escalation to 80 mg/ m2: [A] 33 pts (94.3%), [B] 23 pts (92%). Tolerance: ([A] n = 38 pts, [B] n = 25 pts) (% of pts with G3/4 NCI CTC v2): Neutropenia [A] 29/16, [B] 52/16; Infection with G3/4 neutropenia [A] 3/3, [B] 8/0; Stomatitis [A] 5/3, [B] 0/4; Bilirubin [A] 3/0, [B] 0/0; HF Syndrome [A] 3/0, [B] 8/0; Nausea [A] 3/0, [B] 0/4; Vomiting [A] 10/0, [B] 4/4; Diarrhoea [A] 5/0, [B] 12/4; Ileus [A] 0/0, [B] 4/0; Febrile Neutropenia: [A] 5%, [B] 8%. Efficacy: the preliminary results on the evaluable pts confirm an optimal disease control (CR + PR + SD): [A] 25/27 pts (92.6%), [B] 22/24 pts (91.7%). Conclusion: The combination of NVBo and C can be safely administered in the palliative setting of MBC and calls for further comparative studies vs i.v. combinations. The addition of T in HER2 positive patients does not alter the favourable safety profile. [Table: see text]

Paclitaxel (P), pegylated liposomal doxorubicin (PLD) and trastuzumab as 1st-line chemotherapy (chemo) in HER2/neu-positive (+) metastatic breast cancer (MBC)

10663 Background: Addition of trastuzumab (Herceptin, H) to successive neoadjuvant taxane+anthracycline-based chemo in patients (pts) with HER-2 (+) breast cancer significantly increases the pathological complete response (CR) rates. PLD has considerably less cardiotoxicity compared to parent drug. The aim of the study was to evaluate the activity and safety of combining H with PLD and P as 1st-line chemo in HER-2 (+) MBC pts. Methods: Inclusion criteria were: histologically confirmed MBC or relapsed after adjuvant chemo, ≥1 measurable lesion, adequate organ function, ECOG-PS 0–1, left ventricular ejection fraction (LVEF) by MUGA ≥55% (reevaluated after cycles 3 and 6). HER-2 positivity was determined by IHC and confirmed with CISH. Chemo was administered as follows: H 6mg/kg (8mg/kg-1st cycle) infused over 90min, PLD 35mg/m2 over 1hr, and P 175mg/m2 over 3hrs on day 1, with prophylactic G-CSF, recycled every 3 weeks. In responders, H was administered as consolidation (6mg/kg/3wks) until disease progression. Results: From 10/2003–10/2005, 19 female HER-2 positive MBC pts were enrolled. Median age: 68 (range, 42–78). Metastatic sites were: lung 6, liver 1, bone 3, lymph nodes 11, soft tissue 5 [median: 2 (range, 1–4)]. Pts received a median of 6 (range, 1–8) for a total of 102 cycles. PLD was started at 35 mg/m2, but in pts with grade 3 hand-foot syndrome (HFS) dose was reduced by 25% (6 pts), or the drug was omitted for 1 cycle (1 pt). 17 pts completed 3–6 cycles and were evaluable for response, all treated patients were evaluable for toxicity. Response rates (RR) were 71%; CR 41%, PR 30%, SD 29%, with no PD. Two pts rendered operable had pCR. Toxicities were: HFS; grade 4: 1, grade 3: 6 (overall 37%), grade 3–4 neutropenia: 4, grade 3 anemia: 1, grade 3–4 mucositis: 2, and grade 2 alopecia: 19. Neither significant LVEF decline, nor symptomatic cardiac event was observed. It is too early to provide data on response duration, TTP, and OS, and these will be available at the meeting. Conclusions: H+P+PLD as 1st-line chemo in HER-2(+) MBC pts is a very active and well tolerated regimen with no significant morbidity/mortality. HFS was the most relevant toxicity. The study is ongoing. No significant financial relationships to disclose.