José Baselga

Memorial Sloan-Kettering Cancer Center, New York City, New York, United States

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Publications (242)3350.18 Total impact

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    ABSTRACT: Human epidermal growth factor receptor 2 (HER2)-positive breast cancers are currently treated with trastuzumab, an anti-HER2 antibody. About 30% of these tumors express a group of HER2 fragments collectively known as p95HER2. Our previous work indicated that p95HER2-positive tumors are resistant to trastuzumab monotherapy. However, recent results showed that tumors expressing the most active of these fragments, p95HER2/611CTF, respond to trastuzumab plus chemotherapy. To clarify this discrepancy, we analyzed the response to chemotherapy of cell lines transfected with p95HER2/611CTF and patient-derived xenografts (n = 7 mice per group) with different levels of the fragment. All statistical tests were two-sided. p95HER2/611CTF-negative and positive tumors showed different responses to various chemotherapeutic agents, which are particularly effective on p95HER2/611CTF-positive cells. Furthermore, chemotherapy sensitizes p95HER2/611CTF-positive patient-derived xenograft tumors to trastuzumab (mean tumor volume, trastuzumab alone: 906mm(3), 95% confidence interval = 1274 to 538 mm(3); trastuzumab+doxorubicin: 259mm(3), 95% confidence interval = 387 to 131 mm(3); P < .001). This sensitization may be related to HER2 stabilization induced by chemotherapy in p95HER2/611CTF-positive cells.
    JNCI Journal of the National Cancer Institute 11/2014; 106(11). · 14.34 Impact Factor
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    ABSTRACT: To explore the prognostic and/or predictive value of human epidermal growth factor receptor 2 (HER2) pathway-related biomarkers in the phase III CLEOPATRA study of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel as first-line treatment for patients with HER2-positive metastatic breast cancer.
    Cancer Research 10/2014; · 8.65 Impact Factor
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    ABSTRACT: Patients with Langerhans Cell Histiocytosis (LCH) and Erdheim-Chester Disease (ECD) have a high frequency of BRAFV600E mutations and respond to RAF inhibitors. However, detection of mutations in tissue biopsies is particularly challenging in histiocytoses due to low tumor content and stromal contamination. We applied a droplet-digitial PCR assay for quantitative detection of the BRAFV600E mutation in plasma and urine cell-free (cf)DNA and performed a prospective, blinded study in 30 ECD/LCH patients. There was 100% concordance between tissue and urinary cfDNA genotype in treatment naïve samples. cfDNA analysis facilitated identification of previously undescribed KRASG12S mutant ECD and dynamically tracked disease burden in patients treated with a variety of therapies. These results indicate that cfDNA BRAFV600E mutational analysis in plasma and urine provides a convenient and reliable method of detecting mutational status and can serve as a non-invasive biomarker to monitor response to therapy in LCH and ECD.
    Cancer Discovery 10/2014; · 15.93 Impact Factor
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    ABSTRACT: Purpose: mTOR inhibition activates compensatory IGFR signaling. We evaluated the ridaforolimus (mTOR inhibitor) and dalotuzumab (anti-IGF1R antibody) combination. Experimental design: In vitro and in vivo models, and a phase I study where advanced cancer patients received ridaforolimus (10-40 mg/day QD×5/week) and dalotuzumab (10 mg/kg/week or 7.5 mg/kg QOW) were explored. Results: Preclinical studies demonstrated enhanced pathway inhibition with ridaforolimus and dalotuzumab. With 87 patients treated in the phase I study, main DLTs of the combination were primarily mTOR-related stomatitis and asthenia at doses of ridaforolimus lower than expected, suggesting blockade of compensatory pathways in normal tissues. Six confirmed partial responses were reported (3 breast cancer patients); 10/23 breast cancer patients and 6/11 ER+/high proliferative breast cancer patients showed antitumor activity. Conclusions: Our study provides proof-of-concept that inhibiting the IGF1R compensatory response to mTOR inhibition is feasible with promising clinical activity in heavily pretreated advanced cancer, particularly in ER+/high proliferative breast cancer.
    Clinical cancer research : an official journal of the American Association for Cancer Research. 10/2014;
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    ABSTRACT: Neratinib is a potent irreversible pan-tyrosine kinase inhibitor with antitumor activity and acceptable tolerability in patients with human epidermal growth factor receptor 2 (HER2) -positive breast cancer. A multinational, open-label, phase I/II trial was conducted to determine the maximum-tolerated dose (MTD) of neratinib plus capecitabine in patients with solid tumors (part one) and to evaluate the safety and efficacy of neratinib plus capecitabine in patients with HER2-positive metastatic breast cancer (part two).
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 10/2014;
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    ABSTRACT: To document the rate and outcome of trastuzumab-associated cardiac dysfunction in patients following 1 or 2 years of adjuvant therapy.
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 06/2014;
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    ABSTRACT: Inhibition of the activated epidermal growth factor receptor (EGFR) with either enzymatic kinase inhibitors or anti-EGFR antibodies such as cetuximab, is an effective modality of treatment for multiple human cancers. Enzymatic EGFR inhibitors are effective for lung adenocarcinomas with somatic kinase domain EGFR mutations while, paradoxically, anti-EGFR antibodies are more effective in colon and head and neck cancers where EGFR mutations occur less frequently. In colorectal cancer, anti-EGFR antibodies are routinely used as second-line therapy of KRAS wild-type tumors. However, detailed mechanisms and genomic predictors for pharmacological response to these antibodies in colon cancer remain unclear.
    Molecular cancer. 06/2014; 13(1):141.
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    ABSTRACT: We report detailed safety analyses by geographic region from the phase III study CLEOPATRA with pertuzumab, trastuzumab, and docetaxel in patients with human epidermal growth factor receptor 2 (HER2)-positive first-line metastatic breast cancer.PATIENTS AND METHODS: Patients received pertuzumab/placebo at 840 mg in cycle 1 and 420 mg in subsequent cycles, and trastuzumab at 8 mg/kg in cycle 1 and 6 mg/kg in subsequent cycles; docetaxel was initiated at 75 mg/m(2). All study drugs were given intravenously, 3 times weekly.RESULTS: Docetaxel dose reductions below 75 mg/m(2) were more common in patients from Asia (47.0%) than other regions (13.4%); docetaxel dose escalations to 100 mg/m(2) were less frequent in Asia (2.4%) than other regions (18.7%). Rates of edema (26.1% and 5.4% for Asia and other regions, respectively), myalgia (42.3%, 14.7%), nail disorder (39.9%, 15.1%), febrile neutropenia (18.6%, 7.1%), upper respiratory tract infection (25.7%, 10.2%), decreased appetite (47.0%, 19.1%), and rash (44.3%, 22.0%) were at least twice as high in Asia as in other regions. Adverse events did not result in a reduction in the median number of study treatment cycles administered in patients from Asia. Efficacy analyses per region showed hazard ratios similar to those of the whole intention-to-treat (ITT) population for progression-free survival (ITT: 0.63; Asia: 0.68; other regions: 0.61) and overall survival (ITT: 0.66; Asia: 0.64; other regions: 0.66).CONCLUSION: Despite a higher proportion of docetaxel dose reductions in patients from Asia, survival benefits were comparable between regions. The benefit-risk profile of pertuzumab, trastuzumab, and docetaxel supports this regimen as the first-line therapy for patients with HER2-positive metastatic breast cancer from all geographic regions.
    The Oncologist 05/2014; · 4.10 Impact Factor
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    ABSTRACT: Agents targeting the insulin-like growth factor receptor type 1 (IGF1R) have shown antitumor activity. Based on the evidence for interaction between the IGF-1 and TRAIL pathways, we hypothesized that the combination of ganitumab (monoclonal antibody to IGF1R) with the pro-apoptotic death receptor 5 agonist, conatumumab, might increase antitumor response. Ganitumab and conatumumab were tested in combination in a Colo-205 xenograft model. Part 1 of the clinical study was a phase Ib program of three doses of conatumumab (1, 3, 15 mg/kg) in combination with 18 mg/kg ganitumab to determine the maximum tolerated dose (MTD) in patients with advanced solid tumors. Part 2 was conducted in six cohorts with advanced non-small cell lung cancer (squamous or non-squamous histology), colorectal cancer, sarcoma, pancreatic cancer, or ovarian cancer, treated at the recommended doses of the combination. The combination was significantly more active in the Colo-205 xenograft model than either single agent alone (p < 0.0015). In part 1 of the clinical study, no dose-limiting toxicities were observed and the MTD of conatumumab was 15 mg/kg in combination with 18 mg/kg ganitumab. In part 2, 78 patients were treated and there were no objective responses but 28 patients (36 %) had stable disease (median 46 days, range 0-261). The combination was well-tolerated with no new toxicities. In conclusion, the combination of ganitumab and conatumumab was well-tolerated but had no objective responses in the population tested. The successful future application of this combination of antitumor mechanisms may rely on the identification of predictive biomarkers.
    Targeted Oncology 05/2014; · 3.46 Impact Factor
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    ABSTRACT: In our randomised, controlled, phase 3 trial NeOAdjuvant Herceptin (NOAH) trial in women with HER2-positive locally advanced or inflammatory breast cancer, neoadjuvant trastuzumab significantly improved pathological complete response rate and event-free survival. We report updated results from our primary analysis to establish the long-term benefit of trastuzumab-containing neoadjuvant therapy. We did this multicentre, open-label, randomised trial in women with HER2-positive locally advanced or inflammatory breast cancer. Participants were randomly assigned (1:1), by computer program with a minimisation technique, to receive neoadjuvant chemotherapy alone or with 1 year of trastuzumab (concurrently with neoadjuvant chemotherapy and continued after surgery). A parallel group with HER2-negative disease was included and received neoadjuvant chemotherapy alone. Our primary endpoint was event-free survival. Analysis was by intention to treat. This study is registered at www.controlled-trials.com, ISRCTN86043495. Between June 20, 2002, and Dec 12, 2005, we enrolled 235 patients with HER2-positive disease, of whom 118 received chemotherapy alone and 117 received chemotherapy plus trastuzumab. 99 additional patients with HER2-negative disease were included in the parallel cohort. After a median follow-up of 5·4 years (IQR 3·1-6·8) the event-free-survival benefit from the addition of trastuzumab to chemotherapy was maintained in patients with HER2-positive disease. 5 year event-free survival was 58% (95% CI 48-66) in patients in the trastuzumab group and 43% (34-52) in those in the chemotherapy group; the unadjusted hazard ratio (HR) for event-free survival between the two randomised HER2-positive treatment groups was 0·64 (95% CI 0·44-0·93; two-sided log-rank p=0·016). Event-free survival was strongly associated with pathological complete remission in patients given trastuzumab. Of the 68 patients with a pathological complete response (45 with trastuzumab and 23 with chemotherapy alone), the HR for event-free survival between those with and without trastuzumab was 0·29 (95% CI 0·11-0·78). During follow-up only four cardiovascular adverse events were regarded by the investigator to be drug-related (grade 2 lymphostasis and grade 2 lymphoedema, each in one patient in the trastuzumab group, and grade 2 thrombosis and grade 2 deep vein thrombosis, each in one patient in the chemotherapy-alone group). These results show a sustained benefit in event-free survival from trastuzumab-containing neoadjuvant therapy followed by adjuvant trastuzumab in patients with locally advanced or inflammatory breast cancer, and provide new insight into the association between pathological complete remission and long-term outcomes in HER2-positive disease. F Hoffmann-La Roche.
    The Lancet Oncology 03/2014; · 25.12 Impact Factor
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    ABSTRACT: This study evaluated the safety, tolerability, pharmacodynamics, pharmacokinetics, and antitumor activity of ficlatuzumab, a humanized hepatocyte growth factor (HGF) inhibitory monoclonal antibody, as monotherapy in patients with advanced solid tumors and liver metastases. Patients and Methods: Patients with p-Met-positive tumors enrolled in 3 dose-escalation cohorts, receiving ficlatuzumab 2, 10, or 20 mg/kg once per 14-day cycle. Pharmacodynamic changes in liver tumor biopsies and serum, pharmacokinetics, safety, and clinical activity were assessed. No dose-limiting toxicities occurred in the 19 patients enrolled (n=6, 2 mg/kg; n=7, 10 mg/kg; n=6, 20 mg/kg). The most frequent diagnosis was colorectal cancer (n=15; 79%). The most common treatment-emergent adverse events were asthenia, peripheral edema, hepatic pain (32% each), and cough (26%). Laboratory abnormalities of decreased serum albumin were present in all patients. Ficlatuzumab at 20 mg/kg lowered median levels of tumor p-Met (-53%), p-ERK (-43%), p-Akt (-2%), and increased median HGF levels (+33%), at the last on-study time point relative to baseline. Mean serum HGF levels increased with ficlatuzumab dose and number of treatment cycles. Ficlatuzumab exhibited linear pharmacokinetics and long terminal half-life (7.4 to 10 days). Best overall response was stable disease (SD) in 28% of patients, including 1 pancreatic cancer patient with SD >1 year. Ficlatuzumab exhibited good safety/tolerability and demonstrated ability to modulate the HGF/c-Met pathway and downstream signaling in the tumor in patients with advanced solid tumors. Safety, pharmacodynamic, and pharmacokinetic data for ficlatuzumab confirmed the recommended phase 2 dose of 20 mg/kg once per 14-day cycle.
    Clinical Cancer Research 03/2014; · 7.84 Impact Factor
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    ABSTRACT: This phase I, first-in-human study evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics and preliminary efficacy of SAR245409, an inhibitor of pan-Class I PI3K and mTOR, administered orally once or twice daily in patients with advanced solid tumors. Eighty-three patients received SAR245409. Doses ranged from 15-120 mg twice daily, and 70-100 mg once daily. A 3+3 dose-escalation design was used to determine the MTD. Patients were evaluated for adverse events (AEs) and response. Assessments included PK, pharmacodynamic impact of SAR245409 on PI3K pathway signaling in hair sheath cells, skin and tumor, and characterization of tumor molecular alterations. The MTDs were 50 mg twice daily and 90 mg once daily. The most frequent treatment-related AEs were nausea (36.1%), diarrhea (21.7%), vomiting (19.3%) and decreased appetite (16.9%). The most frequent treatment-related grade 3/4 AEs were increases in alanine aminotransferase (6.0%) and aspartate aminotransferase (4.8%). SAR245409 had a relatively short plasma half-life (2.96-7.52 hours). At MTDs, once- and twice-daily regimens yielded similar mean steady-state plasma exposure. A reduction in PI3K and mTORC1/mTORC2 pathway signaling was observed in serial hair sheath cells, skin and tumor samples. Best response was stable disease (SD) in 48% of evaluable patients; seven patients had minor tumor regression. Twelve patients with SD were treated for ≥16 weeks. No trend was observed correlating tumor molecular alteration with antitumor activity. SAR245409 had a manageable safety profile, demonstrated reduced PI3K and mTORC1/mTORC2 pathway signaling and was associated with clinically relevant SD.
    Clinical Cancer Research 02/2014; · 7.84 Impact Factor
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    ABSTRACT: Pathological complete response has been proposed as a surrogate endpoint for prediction of long-term clinical benefit, such as disease-free survival, event-free survival (EFS), and overall survival (OS). We had four key objectives: to establish the association between pathological complete response and EFS and OS, to establish the definition of pathological complete response that correlates best with long-term outcome, to identify the breast cancer subtypes in which pathological complete response is best correlated with long-term outcome, and to assess whether an increase in frequency of pathological complete response between treatment groups predicts improved EFS and OS. We searched PubMed, Embase, and Medline for clinical trials of neoadjuvant treatment of breast cancer. To be eligible, studies had to meet three inclusion criteria: include at least 200 patients with primary breast cancer treated with preoperative chemotherapy followed by surgery; have available data for pathological complete response, EFS, and OS; and have a median follow-up of at least 3 years. We compared the three most commonly used definitions of pathological complete response-ypT0 ypN0, ypT0/is ypN0, and ypT0/is-for their association with EFS and OS in a responder analysis. We assessed the association between pathological complete response and EFS and OS in various subgroups. Finally, we did a trial-level analysis to assess whether pathological complete response could be used as a surrogate endpoint for EFS or OS. We obtained data from 12 identified international trials and 11 955 patients were included in our responder analysis. Eradication of tumour from both breast and lymph nodes (ypT0 ypN0 or ypT0/is ypN0) was better associated with improved EFS (ypT0 ypN0: hazard ratio [HR] 0·44, 95% CI 0·39-0·51; ypT0/is ypN0: 0·48, 0·43-0·54) and OS (0·36, 0·30-0·44; 0·36, 0·31-0·42) than was tumour eradication from the breast alone (ypT0/is; EFS: HR 0·60, 95% CI 0·55-0·66; OS 0·51, 0·45-0·58). We used the ypT0/is ypN0 definition for all subsequent analyses. The association between pathological complete response and long-term outcomes was strongest in patients with triple-negative breast cancer (EFS: HR 0·24, 95% CI 0·18-0·33; OS: 0·16, 0·11-0·25) and in those with HER2-positive, hormone-receptor-negative tumours who received trastuzumab (EFS: 0·15, 0·09-0·27; OS: 0·08, 0·03, 0·22). In the trial-level analysis, we recorded little association between increases in frequency of pathological complete response and EFS (R(2)=0·03, 95% CI 0·00-0·25) and OS (R(2)=0·24, 0·00-0·70). Patients who attain pathological complete response defined as ypT0 ypN0 or ypT0/is ypN0 have improved survival. The prognostic value is greatest in aggressive tumour subtypes. Our pooled analysis could not validate pathological complete response as a surrogate endpoint for improved EFS and OS. US Food and Drug Administration.
    The Lancet 02/2014; · 39.21 Impact Factor
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    ABSTRACT: This phase 1 trial was undertaken to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of the novel smoothened inhibitor sonidegib (LDE225), a potent inhibitor of hedgehog (Hh) signaling, in patients with advanced solid tumors. Oral sonidegib was administered to 103 patients with advanced solid tumors, including medulloblastoma (MB) and basal cell carcinoma (BCC), at doses ranging from 100 to 3000 mg daily and 250 to 750 mg twice daily, continuously, with a single-dose PK run-in period. Dose-escalations were guided by a Bayesian logistic regression model. Safety, tolerability, efficacy, PK, and biomarkers in skin and tumor biopsies were assessed. The MTDs of sonidegib were 800 mg daily and 250 mg twice daily. The main DLT of reversible grade 3/4 elevated serum creatine kinase (18% of patients) was observed at doses ≥ the MTD in an exposure-dependent manner. Common grade 1/2 adverse events included muscle spasm, myalgia, gastrointestinal toxicities, increased liver enzymes, fatigue, dysgeusia, and alopecia. Sonidegib exposure increased dose proportionally up to 400 mg daily, and displayed nonlinear PK at higher doses. Sonidegib exhibited exposure-dependent reduction in GLI1 mRNA expression. Tumor responses observed in patients with MB and BCC were associated with evidence of Hh pathway activation. Sonidegib has an acceptable safety profile in patients with advanced solid tumors and exhibits antitumor activity in advanced BCC and relapsed MB, which is strongly associated with activated Hh pathway, as determined by gene expression.
    Clinical Cancer Research 02/2014; · 7.84 Impact Factor
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    ABSTRACT: Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway activation in patients with HER2-positive (HER2+) breast cancer has been implicated in de novo and acquired trastuzumab resistance. The purpose of this study was to determine the clinical activity of the PI3K inhibitor buparlisib (BKM120) in patients with HER2+ advanced/metastatic breast cancer resistant to trastuzumab-based therapy. In the dose-escalation portion of this Phase I/II study, patients with trastuzumab-resistant locally advanced or metastatic HER2+ breast cancer were treated with daily oral doses of buparlisib and weekly intravenous trastuzumab (2 mg/kg). Dose escalation was guided by a Bayesian logistic regression model with overdose control. Of 18 enrolled patients, 17 received buparlisib. One dose-limiting toxicity of Grade 3 general weakness was reported at the 100-mg/day dose level (the single-agent maximum tolerated dose) and this dose level was declared the recommended Phase II dose (RP2D) of buparlisib in combination with trastuzumab. Common (>25%) adverse events included rash (39%), hyperglycemia (33%), and diarrhea (28%). The pharmacokinetic profile of buparlisib was not affected by its combination with trastuzumab. At the RP2D, there were two (17%) partial responses, seven (58%) patients had stable disease (≥6 weeks), and the disease control rate was 75%. Pharmacodynamic studies showed inhibition of the PI3K/AKT/mTOR and RAS/MEK/ERK pathways. In this patient population, the combination of buparlisib and trastuzumab was well tolerated and preliminary signs of clinical activity were observed. The Phase II portion of this study will further explore the safety and efficacy of this combination at the RP2D.
    Clinical Cancer Research 01/2014; · 7.84 Impact Factor
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    ABSTRACT: The effects of selective PI3K and AKT inhibitors were compared in human tumor cell lines in which the pathway is dysregulated. Both caused inhibition of AKT, relief of feedback inhibition of RTKs, and growth arrest. However, only the PI3K inhibitors caused rapid induction of cell death. In seeking a mechanism for this phenomenon, we found that PI3K inhibition, but not AKT inhibition, causes rapid inhibition of wild type RAS and of RAF/MEK/ERK signaling. Inhibition of RAS-ERK signaling is transient, rebounding a few hours after drug addition, and is required for rapid induction of apoptosis. Combined MEK and AKT inhibition also promotes cell death and in murine models of HER2+ cancer, either pulsatile PI3K inhibition or combined MEK and AKT inhibition causes tumor regressions. We conclude that PI3K is upstream of RAS and AKT and that pulsatile inhibition of both pathways is sufficient for effective antitumor activity.
    Cancer Discovery 01/2014; · 15.93 Impact Factor
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    ABSTRACT: We report a retrospective exploratory analysis of the association of the research-based prediction analysis of microarray 50 (PAM50) subtype predictor with pathologic complete response (pCR) and event-free survival (EFS) in women enrolled in the NeOAdjuvant Herceptin (NOAH) trial. Gene expression profiling was performed using RNA from formalin-fixed paraffin-embedded core biopsies from 114 pretreated patients with HER2-positive (HER2(+)) tumors randomized to receive neoadjuvant doxorubicin/paclitaxel (AT) followed by cyclophosphamide/methotrexate/fluorouracil (CMF), or the same regimen in combination with trastuzumab for one year. A control cohort of 42 patients with HER2-negative tumors treated with AT-CMF was also included. The PAM50 subtypes, the PAM50 proliferation score, and the PAM50 risk of relapse score based on subtype (RORS) and subtype and proliferation (RORP) were evaluated. HER2-enriched (HER2-E) tumors predominated within HER2(+) disease, although all PAM50 intrinsic subtypes were identified across the three cohorts. The OR for achieving pCR with trastuzumab-based chemotherapy for HER2(+)/HER2-E and HER2(+)/RORP-high were 5.117 (P = 0.009) and 8.469 (P = 0.025), respectively, compared with chemotherapy only. The pCR rates of HER2(+)/HER2-E and HER2(+)/RORP-high after trastuzumab-based chemotherapy were 52.9% and 75.0%, respectively. A statistically nonsignificant trend was observed for more pronounced survival benefit with trastuzumab in patients with HER2(+)/HER2-E and HER2(+)/RORP-high tumors compared with patients with HER2(+)/non-HER2-E and HER2(+)/non-RORP-high tumors, respectively. As determined by EFS and pCR, patients with HER2(+)/HER2-E tumors, or HER2(+)/RORP-high tumors, benefit substantially from trastuzumab-based chemotherapy. The clinical value of this genomic test within HER2(+) disease warrants further investigation. Clin Cancer Res; 20(2); 511-21. ©2014 AACR.
    Clinical Cancer Research 01/2014; 20(2):511-21. · 7.84 Impact Factor
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    ABSTRACT: Both abundant epidermal growth factor receptor (EGFR or ErbB1) and high activity of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway are common and therapeutically targeted in triple-negative breast cancer (TNBC). However, activation of another EGFR family member [human epidermal growth factor receptor 3 (HER3) (or ErbB3)] may limit the antitumor effects of these drugs. We found that TNBC cell lines cultured with the EGFR or HER3 ligand EGF or heregulin, respectively, and treated with either an Akt inhibitor (GDC-0068) or a PI3K inhibitor (GDC-0941) had increased abundance and phosphorylation of HER3. The phosphorylation of HER3 and EGFR in response to these treatments was reduced by the addition of a dual EGFR and HER3 inhibitor (MEHD7945A). MEHD7945A also decreased the phosphorylation (and activation) of EGFR and HER3 and the phosphorylation of downstream targets that occurred in response to the combination of EGFR ligands and PI3K-Akt pathway inhibitors. In culture, inhibition of the PI3K-Akt pathway combined with either MEHD7945A or knockdown of HER3 decreased cell proliferation compared with inhibition of the PI3K-Akt pathway alone. Combining either GDC-0068 or GDC-0941 with MEHD7945A inhibited the growth of xenografts derived from TNBC cell lines or from TNBC patient tumors, and this combination treatment was also more effective than combining either GDC-0068 or GDC-0941 with cetuximab, an EGFR-targeted antibody. After therapy with EGFR-targeted antibodies, some patients had residual tumors with increased HER3 abundance and EGFR/HER3 dimerization (an activating interaction). Thus, we propose that concomitant blockade of EGFR, HER3, and the PI3K-Akt pathway in TNBC should be investigated in the clinical setting.
    Science Signaling 01/2014; 7(318):ra29. · 7.65 Impact Factor
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    ABSTRACT: Background Findings from the randomised phase 3 NeoALTTO trial in women with HER2-positive early breast cancer showed that the combination of lapatinib and trastuzumab significantly improved rates of pathological complete response compared with either drug alone. Here, we report data for the prespecified secondary endpoints of event-free and overall survival, and assess the association between these outcomes and pathological complete response. Methods We enrolled women with HER2-positive early breast cancer and randomly assigned them to receive oral lapatinib (1500 mg), intravenous trastuzumab (4 mg/kg loading dose followed by 2 mg/kg), or lapatinib (1000 mg) plus trastuzumab (same dose as for single agent) in combination for 6 weeks, followed by an additional 12 weeks of the assigned anti-HER2 therapy in combination with weekly paclitaxel (80 mg/m2). Definitive surgery was done 4 weeks after the last dose of paclitaxel. After surgery, women received three cycles of FEC (fluorouracil 500 mg/m2 plus epirubicin 100 mg/m2 plus cyclophosphamide 500 mg/m2) given intravenously every 3 weeks, followed by 34 weeks of the same assigned neoadjuvant anti-HER2 therapy. The primary endpoint was pathological complete response. Secondary endpoints included event-free and overall survival (intention-to-treat analysis), and the association between pathological complete response and event-free or overall survival (analysed by landmark analysis at 30 weeks after randomisation). Follow-up is ongoing, and the trial is registered with ClinicalTrials.gov, number NCT00553358. Findings 455 patients were enrolled: 154 (34%) were assigned to the lapatinib group, 149 (33%) to the trastuzumab group, and 152 (33%) to the lapatinib plus trastuzumab group. At an event follow-up of 3·77 years (IQR 3·50–4·22), 3-year event-free survival was 78% (95% CI 70–84) in the lapatinib group, 76% (68–82) in the trastuzumab group, and 84% (77–89) in the combination group. Event-free survival did not differ between the lapatinib and trastuzumab groups (HR 1·06, 95% CI 0·66–1·69, p=0·81), nor between the combination and trastuzumab groups (0·78, 0·47–1·28, p=0·33). Median survival follow-up was 3·84 years (IQR 3·60–4·24), and 3-year overall survival was 93% (95% CI 87–96) for lapatinib, 90% (84–94) for trastuzumab, and 95% (90–98) for combination therapy. Overall survival did not significantly differ between the lapatinib and trastuzumab groups (HR 0·86, 95% CI 0·45–1·63, p=0·65), nor between the combination and trastuzumab groups (0·62, 0·30–1·25, p=0·19). Landmark analyses showed that 3-year event-free survival was significantly improved for women who achieved pathological complete response compared with those who did not (HR 0·38, 95% CI 0·22–0·63, p=0·0003), as was 3-year overall survival (0·35, 0·15–0·70, p=0·005). Adverse events occurred in 149 (99%) patients receiving lapatinib, 142 (96%) patients receiving trastuzumab, and 147 (99%) patients receiving combination therapy. The most common adverse events were diarrhoea, rash or erythema, hepatic adverse events, and neutropenia (not related to FEC administration), and were consistent with known safety profiles of lapatinib and trastuzumab. Three primary and eight secondary cardiac events occurred, with no significant difference in incidence between treatment groups for primary or any cardiac events. Interpretation Although event-free survival or overall survival did not differ between treatment groups, findings from our study confirm that patients who achieve pathological complete response after neoadjuvant anti-HER2 therapy have longer event-free and overall survival than do patients without pathological complete response. Funding GlaxoSmithKline.
    The Lancet. Oncology. 01/2014;
  • Aditya Bardia, José Baselga
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    ABSTRACT: The traditional drug development process in breast cancer based on large phase III studies has serious limitations and needs a major overhaul. Searching for new approaches, the testing of novel agents in the preoperative (neoadjuvant) setting approach offers a potentially rapid and efficient strategy for drug development utilizing pathologic complete response (path CR), a surrogate marker for survival, as the primary endpoint. In addition, neoadjuvant studies allow the assessment of drug effects on the target (pharmacodynamic response) and the development of predictive biomarkers of response. Molecular profiling of the residual tumor in the surgical specimen may also provide insights into actionable mechanisms of resistance. Recognizing the potential of neoadjuvant trials for drug development, the U.S. Food and Drug Administration (FDA) recently announced consideration of neoadjuvant trials for accelerated drug approval in early breast cancer, particularly for tumors with high risk of recurrence and unfavorable prognosis, and provided accelerated approval to neoadjuvant pertuzumab in September 2013. The FDA has emphasized that while improvement in path CR could be utilized for "accelerated" approval, improvement in survival will still need to be demonstrated for "regular" approval. Key considerations in conduct of such neoadjuvant drug development trials include (i) study design such as utilization of biomarker stratified design to evaluate a biomarker that could enrich response, (ii) definition of path CR, (iii) distribution of factors that influence path CR between the treatment arms, (iv) prespecified plan for follow-up to obtain data on survival, and (v) safety as it involves a patient population with curable disease. In the years to come, we anticipate an increase in the number of neoadjuvant trials testing novel therapies that hopefully will open a new path in bringing efficacious new therapies to patients with breast cancer. Clin Cancer Res; 19(23); 6360-70. ©2013 AACR.
    Clinical Cancer Research 12/2013; 19(23):6360-70. · 7.84 Impact Factor

Publication Stats

23k Citations
3,350.18 Total Impact Points

Institutions

  • 1994–2014
    • Memorial Sloan-Kettering Cancer Center
      • • Department of Medicine
      • • Division of Molecular Pharmacology & Chemistry
      New York City, New York, United States
  • 2013
    • Weill Cornell Medical College
      New York City, New York, United States
    • The Washington Institute
      Washington, Washington, D.C., United States
    • Duke University Medical Center
      Durham, North Carolina, United States
    • Unicancer
      Lutetia Parisorum, Île-de-France, France
    • IEO - Istituto Europeo di Oncologia
      Milano, Lombardy, Italy
  • 2012–2013
    • Université Libre de Bruxelles
      • Bordet Institute
      Brussels, BRU, Belgium
    • University of Valencia
      Valenza, Valencia, Spain
    • Institut Marqués, Spain, Barcelona
      Barcino, Catalonia, Spain
  • 2011–2013
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
    • Dana-Farber Cancer Institute
      • Department of Medical Oncology
      Boston, Massachusetts, United States
    • Sarah Cannon Research Institute
      Nashville, Tennessee, United States
    • Hospital Universitario Virgen del Rocío
      Hispalis, Andalusia, Spain
  • 2010–2013
    • University of Barcelona
      • Department of Statistics
      Barcelona, Catalonia, Spain
    • Novartis Institutes for BioMedical Research
      Cambridge, Massachusetts, United States
    • Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
      Milano, Lombardy, Italy
  • 2005–2013
    • Autonomous University of Barcelona
      • Department of Biochemistry and Molecular Biology
      Cerdanyola del Vallès, Catalonia, Spain
    • Indiana University-Purdue University Indianapolis
      Indianapolis, Indiana, United States
  • 2002–2013
    • Vall d’Hebron Institute of Oncology
      Barcino, Catalonia, Spain
    • The Portland Hospital
      Londinium, England, United Kingdom
  • 2011–2012
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2010–2012
    • Broad Institute of MIT and Harvard
      • Cancer Program
      Cambridge, Massachusetts, United States
  • 2002–2012
    • Vanderbilt University
      • • Vanderbilt-Ingram Cancer Center (VICC)
      • • Department of Medicine
      Nashville, MI, United States
  • 1997–2012
    • University Hospital Vall d'Hebron
      • Department of Medical Oncology
      Barcelona, Catalonia, Spain
  • 2009
    • University of Washington Seattle
      • Department of Medicine
      Seattle, WA, United States
  • 2008
    • Carl Gustav Carus-Institut
      Pforzheim, Baden-Württemberg, Germany
    • University of Leeds
      Leeds, England, United Kingdom
    • University of Antwerp
      Antwerpen, Flanders, Belgium
  • 2007
    • Universitair Ziekenhuis Antwerpen
      Antwerpen, Flanders, Belgium
  • 2006
    • VHIR Vall d’Hebron Research Institute
      Barcino, Catalonia, Spain
  • 2003–2006
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States
    • Karmanos Cancer Institute
      Detroit, Michigan, United States
    • Istituto Nazionale Tumori "Fondazione Pascale"
      Napoli, Campania, Italy
    • Kinki University
      • Department of Internal Medicine
      Ōsaka, Ōsaka, Japan
  • 2004
    • University Hospital Essen
      Essen, North Rhine-Westphalia, Germany