Concurrent Use Of Trastuzumab Research Articles

Radiation Oncologists’ Views on Breast Radiation Therapy Guidelines: Utilizing an Online Q&A Platform to Assess Current Views on Whole-Breast Irradiation Therapy

IntroductionPoor adherence to the 2011 American Society for Radiation Oncology (ASTRO) evidence-based guideline on whole-breast irradiation (WBI) has been reported. We utilized theMednet to assess the views of the updated 2018 guideline among radiation oncologists (ROs). MethodsWe identified 11 questions asked by community ROs on theMednet, a web-based platform, between October 27, 2014 and May 2, 2017 that were updated in the 2018 guideline. New answers provided by senior authors of the 2018 guideline, cited guidelines, and polls to survey ROs were disseminated in 3 theMednet's newsletters between March 16, 2018 and May 1, 2018. Any question with less than 60% consensus was resubmitted on October 9, 2019 and assessed on February 13, 2020. ResultsA total of 792 ROs responded to the initial surveys. In each survey, the answer choice(s) that received the majority of the votes aligned with the 2018 guideline. The strongest consensus was for the use of hypofractionated (HF)-WBI regardless of histology (97%), followed by HF-WBI boost dose (92%), molecular subtype (90%), grade (88%), and concurrent use of trastuzumab (87%). The least consensus was for age at which HF-WBI should be offered with 53% of respondents, specifically 73% of academic ROs versus 47% of community ROs (P = .001), agreeing with the guideline. The re-submitted survey 19 months later showed 77% of 287 new respondents now agreed with the guideline regarding age. ConclusionThe majority of ROs concur with the 2018 WBI guideline in theMednet surveys, with better agreement among academic ROs than community ROs for certain components of the guideline. Further research into the different practice patterns may optimize patient care.

Abstract P6-16-05: Radiation oncologists' views on breast radiation therapy guidelines: Utilizing an online Q&A platform to assess current views on whole breast radiation therapy

Abstract Introduction: Adherence to clinical practice guidelines (CPGs) has long been a challenge due to a lack of knowledge about CPGs and the fact that CPGs may not be practical in the context of a particular patient's situation. Poor adherence to the 2011 American Society for Radiation Oncology (ASTRO) evidence-based guideline on whole breast irradiation has been reported, especially for hypofractionated whole breast radiotherapy (HBRT). In 2018, updated ASTRO guidelines were published. We utilized theMednet, an online Q&A platform of over 3,600 US community and academic radiation oncologists (ROs), to assess current views regarding whole breast RT and evaluate relationships between the the strength of guideline recommendation statements and ROs views on treatment choices. Methods: We identified 11 questions previously asked by community ROs on theMednet that were not addressed in the 2011 ASTRO whole breast irradiation guideline. Questions were originally asked between 10/27/2014 and 5/2/2017. These questions were sent to a senior author of the 2018 guidelines to post an updated response on theMednet, citing the guidelines and degree of consensus. A link to view the full guidelines was provided. New answers citing the guidelines were disseminated in 3 biweekly newsletters between 3/16/2018 and 5/1/2018, along with polls to survey radiation oncologists participating in theMednet. Results: A total of 792 ROs responded to polls, of whom 523 were community ROs, 129 were academic ROs, and 93 were residents. Of the 11 questions, 10 pertained to WBRT and 1 pertained to conventional dose fractionation. For each question, the answer choice receiving the majority of the votes aligned with the 2018 guideline. Of the 5 questions which referenced a conditional recommendation in the 2018 guideline, the majority vote ranged from 54% to 87%; whereas, of the 6 questions which referenced a strong recommendation in the 2018 guideline, the majority vote from 62% to 97%. The strongest consensus was for HBRT to be used regardless of histology (97%), followed by molecular subtype (90%), grade (89%), and concurrent use of trastuzumab (87%). The least consensus was for age at which HBRT should be offered, with only 54% of respondents agreeing with the guideline consensus that HBRT should be offered regardless of age. When comparing academic and community ROs, 73% of academic ROs do not specify an age threshold for offering HBRT, compared to 47% of community ROs (P=0.0240). Regarding boost dose-fractionation, 83% of academic ROs prefer a 10Gy in 4 fractions while 54% of community ROs prefer 10 Gy in 5 fractions and 41% prefer 10Gy in 4 fractions (P=0.1495). Responses were similar between academic and community ROs for all other questions. Conclusion: Utilizing an online platform, theMednet, we were able to assess current views of management of whole breast radiation therapy among participating ROs. The majority of ROs agree with the major recommendations from this guideline, with practice variation greater in areas with weaker underlying evidence. Citation Format: Burt L, Haffty BG, Smith B, Housri N. Radiation oncologists' views on breast radiation therapy guidelines: Utilizing an online Q&A platform to assess current views on whole breast radiation therapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-16-05.

Biomarkers for Predicting Clinical Outcomes of Chemoradiation-Based Bladder Preservation Therapy for Muscle-Invasive Bladder Cancer.

Chemoradiation-based bladder preservation therapy (BPT) is currently a curative option for non-metastatic muscle-invasive bladder cancer (MIBC) patients at favorable risk or an alternative to radical cystectomy (RC) for those who are unfit for RC. In BPT, only patients who achieve complete response (CR) after chemoradiation have a favorable prognosis and quality of life with a preserved functional bladder. Thus, predicting CR and favorable prognosis is important for optimal patient selection for BPT. We reviewed biomarkers for predicting the clinical outcomes of chemoradiation-based BPT. The biomarkers studied were categorized into those related to apoptosis, cell proliferation, receptor tyrosine kinases, DNA damage response genes, hypoxia, molecular subtype, and others. Among these biomarkers, the Ki-67 labeling index (Ki-67 LI) and meiotic recombination 11 may be used for selecting BPT or RC. Ki-67 LI and erythroblastic leukemia viral oncogene homolog 2 (erbB2) may be used for predicting both the chemoradiation response and the prognosis of patients on BPT. Concurrent use of trastuzumab and a combination of carbogen and nicotinamide can overcome chemoradiation resistance conferred by erbB2 overexpression and tumor hypoxia. Further studies are needed to confirm the practical utility of these biomarkers for progress on biomarker-directed personalized management of MIBC patients.

Efficacy and cardiac safety of the concurrent use of trastuzumab and anthracycline-based neoadjuvant chemotherapy for HER2-positive breast cancer: a systematic review and meta-analysis.

The concurrent use of trastuzumab and anthracycline-based neoadjuvant chemotherapy (NAC) has been proposed to improve the pathologic complete response (pCR) rate, although there are conflicting views about its efficacy and safety. The purpose of this study was to evaluate the efficacy and cardiac safety of the concurrent use of trastuzumab and anthracycline-based NAC for human epidermal growth factor receptor 2 (HER2)-positive locally advanced breast cancer. We systematically searched PubMed, Embase, and Cochrane databases from inception until July 1, 2017, for relevant articles. A total of 13 studies were included in the meta-analysis. The results showed that the pCR rate was significantly higher in the concurrent use of trastuzumab and anthracycline group (45%) than that in the nonconcurrent use group (32%) (OR: 2.36, 95% CI: 1.69–3.30, P<0.0001). Besides, the pooled absolute rate of breast conservation surgery (BCS) was 48% (95% CI: 0.35–0.61) and 38% (95% CI: 0.14–0.62) in the experimental and control groups, respectively (OR: 1.10, 95% CI: 0.64–1.90, P=0.73). No significant differences were found in the left ventricular ejection fraction (LVEF), which decreased by >10% (OR: 1.26, 95% CI: 0.55–2.88, P=0.59), and in terms of cardiac failure (OR: 2.17, 95% CI: 0.24–19.84, P=0.49), when comparing the concurrent use of trastuzumab and anthracyclines with their nonconcurrent use. In conclusion, the concurrent use of trastuzumab and anthracycline-based NAC for certain HER2-positive locally advanced breast cancers significantly improves the pCR rates without obvious increases in the cardiotoxicity.

Significantly higher pathologic complete response (pCR) after the concurrent use of trastuzumab and anthracycline-based neoadjuvant chemotherapy for HER2-positive breast cancer: Evidence from a meta-analysis of randomized controlled trials.

Objectives: To investigate the effect of the concurrent use of trastuzumab and anthracycline-based neoadjuvant chemotherapy (NAC) for HER2-positive breast cancer in terms of pCR and cardiotoxicity.Methods: We systematically searched Pubmed, Embase, Cochrane and SinoMed databases from inception until 1 July 2017 for relevant articles of randomized controlled studies. After identified all relevant studies that reported the concurrent use of trastuzumab and anthracycline-based NAC for HER2-positive locally advanced breast cancer, five eligible randomized studies were extracted relevant data and assessed for design and quality, and the meta-analysis was conducted to evaluate the risk ratio (RR) of pCR and other interesting outcomes, such as left ventricular ejection fraction (LVEF) decrease more than 10%, responses, recurrence free survival (RFS) and overall survival (OS).Results: A total of five randomized controlled studies were included in the meta-analysis, including 232 HER2-positive locally advanced breast cancer patients received the concurrent use of trastuzumab and anthracycline-based NAC. The results showed that the pCR rate was significantly higher in the group received the concurrent use of trastuzumab and anthracycline-based NAC (48%) than that in the non-concurrent use of trastuzumab and anthracycline-based NAC group (26%) (RR: 1.76, 95%CI: 1.37-2.26, p<0.0001). Besides, higher rate of RFS (RR: 1.14, 95%CI: 1.03-1.26, p=0.009) was observed in the concurrent use of trastuzumab and anthracycline-based NAC group. No significant differences in LVEF decreased more than 10% (p=0.50) between both groups.Conclusions: Our meta-analysis of randomized controlled studies showed that pCR rates are significantly higher in the concurrent use of trastuzumab and anthracycline-based NAC compared with the non-concurrent use of trastuzumab and anthracycline-based NAC for certain HER2-positive breast cancer, meanwhile without significant increase of the cardiotoxicity.

Trastuzumab, non-pegylated liposomal-encapsulated doxorubicin and paclitaxel in the neoadjuvant setting of HER-2 positive breast cancer.

Neoadjuvant treatment based on the combination of trastuzumab plus chemotherapy is the standard of care in patients with HER2-positive early or locally advanced breast cancer. The concurrent use of trastuzumab, anthracyclines and taxanes is frequently used in this setting despite the potential cardiotoxicity of both anthracyclines and trastuzumab. However, not much information is available about this chemotherapy scheme. We wanted to evaluate the efficacy and safety profile of the combination of trastuzumab, liposome-encapsulated doxorubicin and paclitaxel as neoadjuvant scheme. We also tried to establish predictive factors of pathologic complete response. The study was carried out in a tertiary University Hospital of Spain. This is a descriptive study of the clinical practice performed in our hospital. Efficacy was measured in terms of pathologic complete response, which was defined as the absence of invasive cancer cells in the breast and the axilla after neoadjuvant treatment. Thirty patients were included, the median age was 48. Seventeen (56.7 %) were hormonal receptor (HR) positive, 14 (46.6 %) had IIIa-b clinical stage and one of them had inflammatory breast cancer. 12 patients (40 %) achieved pCR. Patients with HR-negative BC achieved a higher pCR rate than those ones with HR-positive BC (61.5 % and 23.5 %, respectively; p value = 0.035). 21 patients (70 %) underwent breast conservative surgery. The treatment was in general well tolerated, most frequent grade 3-4 adverse events were neutropenia (20 %), asthenia and liver enzyme alteration (10 %) and febrile neutropenia (6.7 %). No patient developed heart failure, but one (3.3 %) presented a 10 % asymptomatic absolute reduction in left ventricular fraction ejection. The studied treatment for the neoadjuvant setting of HER2 positive breast cancer seems to be an effective therapeutic option. Despite the expected high rate of cardiotoxicity of this regimen, the study results shows that this treatment regimen appears to be safe. The combination of trastuzumab, non-pegylated liposomal-encapsulated doxorubicin and paclitaxel should be considered for the treatment of HER2-overexpressing breast cancer.

Predictors of pathological complete response to neoadjuvant chemotherapy in stage II and III breast cancer: The impact of chemotherapeutic regimen.

In this study, we sought to determine the predictors of pathological complete response (pCR) and compare the chemotherapeutic regimens administered to breast cancer patients with and those without pCR. We retrospectively reviewed the data of 879 patients treated at the Alvin J. Siteman Cancer Center between 2006 and 2010, to identify patients who were diagnosed with primary stage II or III breast cancer and received neoadjuvant chemotherapy. Patients who received only neoadjuvant endocrine therapy were considered to be ineligible. Patient, tumor, and treatment characteristics, including type of chemotherapy, were compared between patients who did and those who did not achieve pCR using Chi-square or Fishers exact tests and multivariate logistic regression analysis. Two-sided P-values of <0.05 were considered significant. Of the 333 patients who met the inclusion criteria, 61 (18.3%) had documented pCR. Compared with patients not achieving pCR, a greater proportion of patients with pCR had stage II disease (80.3 vs. 68%, P=0.057), had poorly differentiated (grade 3) tumors (82 vs. 59.2%, P<0.001), had negative lymph node involvement (41 vs. 34%, P=0.0004) and had tumors that were HER2-amplified (41 vs. 23.5%, P=0.0054). A greater proportion of patients with pCR received taxane-based chemotherapy (23 vs. 12.5%, P=0.016) or trastuzumab in conjunction with chemotherapy (41.0 vs. 16.9%, P<0.001). No patients receiving solely anthracycline-based therapy achieved pCR in our study. Our study demonstrated that, for stage II and III breast cancer, lower stage, negative lymph node involvement and HER2 receptor amplification were each associated with pCR. Taxane therapy and the concurrent use of trastuzumab were also associated with a higher likelihood of pCR.

Abstract P3-14-08: A randomized phase II trial comparing docetaxel plus cyclophosphamide with epirubicin plus cyclophosphamide followed by docetaxel as neoadjuvant chemotherapy for hormone receptor-negative breast cancer. Kanagawa breast oncology group (KBOG) 1101 study

Abstract Background: Taxane-based regimens have been developed and used widely to treat breast cancer. It has therefore become important to identify subgroups of patients in which anthracyclines are indispensable. Pathological response to neoadjuvant chemotherapy (NAC) predicts prognosis in hormone-negative subtypes. We therefore initiated a randomized phase II NAC study to compare a taxane with and without an anthracycline in these breast-cancer subtypes. Aim: To determine the safety and activity of six cycles of docetaxel and cyclophosphamide (TC6) compared with 5-fluorouracil, epirubicin, and cyclophosphamide followed by docetaxel (FEC-D), and to examine the predictive factors for each regimen. Methods: Eligibility criteria were operable hormone-receptor-negative breast cancer, age younger than 75 years and ECOG PS0-1. According to HER2 status, patients were randomly assigned to TC (75/600 mg/m2) every 3 weeks X 6 or FEC (500/100/500 mg/m2) every 3 weeks X 3 followed by D (100 mg/m2) every 3 weeks X 3. The primary endpoint was the rate of pathological complete response (pCR; grade 3). Triple-negative (TN) breast cancer was subdivided by cytokeratin 5/6 and epidermal growth factor receptor into basal- and non-basal subtypes. Secondary endpoints were safety, breast-conserving surgery, disease-free survival, overall survival, and predictive factors: Ki-67, p53, aldehyde dehydrogenase (ALDH) 1 and topoisomerase 2A by both immunohistochemistry and fluorescence in situ hybridization for each regimen. Results: Ninety-seven of 103 patients were analyzed successfully (50 for FEC-D and 47 for TC6). Significantly more severe adverse events (grade 2) were observed in FEC-D-treated patients (poor appetite, nausea and vomiting: p = 0.001; febrile neutropenia: p = 0.016). The pCR rate tended to be higher in FEC-D-treated patients compared with TC6-treated patients (pCR: 36.0 vs. 25.5%, n.s.). FEC-D treatment was significantly more effective than TC6 in basal-type (p = 0.033) but not in non-basal and HER2 subtypes. ALDH1 was associated with resistance to both regimens (FEC-D: p = 0.047, TC6: p = 0.085) Conclusions: TC6 was safer, but not more effective than FEC-D. TC6 was significantly less active than FEC-D in basal subtype, and equivalent to FEC-D in HER2 and non-basal subtypes. Concurrent use of trastuzumab with TC could thus represent a reasonable option for NAC in HER2-subtype patients. ALDH1 could provide a marker for novel strategies such as stem cell-based therapies for breast cancer. Analyses on pathological factors in surgical specimens after NAC will be presented at the meeting. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-14-08.

A randomized phase II trial comparing docetaxel plus cyclophosphamide with epirubicin plus cyclophosphamide followed by docetaxel as neoadjuvant chemotherapy for hormone receptor-negative breast cancer: Kanagawa Breast Oncology Croup (KBOG) 1101 study.

1047 Background: Taxane-based regimens have been widely used to treat breast cancer. Accordingly, it has become important to identify subgroups in which anthracyclines are indispensable. Thus, we initiated a randomized phase II neoadjuvant chemotherapy (NAC) study to compare taxane with and without anthracycline in hormone-negative subtypes. Methods: Eligibility criteria were hormone-negative, an age younger than 80 years and ECOG PS0-1. According to HER2 status, patients were randomly assigned to TC (75/600 mg/m2) q3wks ×6 or FEC (500/100/500 mg/m2) q3wks ×3 followed by D (100 mg/m2) q3wks ×3. The primary endpoint was the rate of pathological complete response (pCR; Grade 3 and Quasi-pCR; Grade 3+2b). Secondary endpoints were safety, breast-conserving surgery ratio, disease-free survival, overall survival, and predictive factors (HER2, Ki-67, P-53, CK5/6, EGFR, and TOP2A by IHC and TOP2A by FISH) for each regimen. Results: 97 out of 103 patients were successfully analyzed (47 for TC6 and 50 for FEC-D). Severe adverse events (Grade ≥2) were frequently observed in FEC-D-treated patients with statistical significance (poor appetite, nausea/vomiting: p&lt;0.001; febrile neutropenia: p=0.016). The pCR rate tended to be higher in FEC-D-treated patients compared with that of TC6-treated patients (pCR: 36.0 vs. 25.5%, n.s.; Quasi-pCR: 46.0 vs. 40.4%, n.s.). There was no significant difference of pCR rates in the HER2 and triple negative (TN) subtypes between each regimen. Among predictors, only positive markers CK5/6 and EGFR predicted the superiority of the FEC-D treatment (p=0.05). Conclusions: TC6 was safe and relatively active even in HER2 subtype patients. Therefore, the concurrent use of trastuzumab with TC could be a reasonable option for NAC in HER2 subtype patients. However, anthracyclines are required to treat basal-type TN cancer. Clinical trial information: UMIN000002215.

Alterations of the genes involved in the PI3K and estrogen-receptor pathways influence outcome in human epidermal growth factor receptor 2-positive and hormone receptor-positive breast cancer patients treated with trastuzumab-containing neoadjuvant chemotherapy

BackgroundChemotherapy with trastuzumab is widely used for patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer, but a significant number of patients with the tumor fail to respond, or relapse. The mechanisms of recurrence and biomarkers that indicate the response to the chemotherapy and outcome are not fully investigated.MethodsGenomic alterations were analyzed using single-nucleotide polymorphism arrays in 46 HER2 immunohistochemistry (IHC) 3+ or 2+/fluorescent in situ hybridization (FISH)+ breast cancers that were treated with neoadjuvant chemotherapy with paclitaxel, cyclophosphamid, epirubicin, fluorouracil, and trastuzumab. Patients were classified into two groups based on presence or absence of alterations of 65 cancer-associated genes, and the two groups were further classified into four groups based on genomic HER2 copy numbers or hormone receptor status (HR+/−). Pathological complete response (pCR) and relapse-free survival (RFS) rates were compared between any two of the groups.Results and discussionThe pCR rate was 54% in 37 patients, and the RFS rate at 3 years was 72% (95% CI, 0.55-0.89) in 42 patients. The analysis disclosed 8 tumors with nonamplified HER2 and 38 tumors with HER2 amplification, indicating the presence of discordance in tumors diagnosed using current HER2 testing. The 8 patients showed more difficulty in achieving pCR (P=0.019), more frequent relapse (P=0.018), and more frequent alterations of genes in the PI3K pathway (P=0.009) than the patients with HER2 amplification. The alterations of the PI3K and estrogen receptor (ER) pathway genes generally indicated worse RFS rates. The prognostic significance of the alterations was shown in patients with a HR+ tumor, but not in patients with a HR- tumor when divided. Alterations of the PI3K and ER pathway genes found in patients with a HR+ tumor with poor outcome suggested that crosstalk between the two pathways may be involved in resistance to the current chemotherapy with trastuzumab.ConclusionsWe recommend FISH analysis as a primary HER2 testing because patients with IHC 2+/3+ and nonamplified HER2 had poor outcome. We also support concurrent use of trastuzumab, lapatinib, and cytotoxic and anti-hormonal agents for patients having HR+ tumors with alterations of the PI3K and ER pathway genes.

The Dual-Targeted HER1/HER2 Tyrosine Kinase Inhibitor Lapatinib Strongly Potentiates the Cardiac Myocyte-Damaging Effects of Doxorubicin

The anticancer drug lapatinib (Tykerb) is a dual tyrosine kinase inhibitor targeting the HER2 (ERBB2) and EGFR (ERBB1, HER1) pathways that have been shown in clinical trials to display some cardiotoxicity. Because trastuzumab also targets HER2 receptors, the lapatinib/doxorubicin combination provides a good model to probe the mechanism of the increased cardiotoxicity caused by the concurrent use of trastuzumab and doxorubicin. Using a neonatal rat cardiac myocyte model, we have investigated the ability of lapatinib alone and in combination with doxorubicin to damage myocytes. Lapatinib treatment alone only slightly induced myocyte damage. However, doxorubicin-induced myocyte damage was greatly potentiated by the addition of nanomolar lapatinib concentrations. Lapatinib alone treatment decreased phosphorylated ERK (MAPK), which may have, in part, contributed to the increased myocyte damage. As measured by flow cytometry, lapatinib-treated myocytes displayed an increased accumulation of doxorubicin. As lapatinib is a strong inhibitor of several ATP-dependent ABC-type efflux transporters, this likely occurred because lapatinib blocked doxorubicin efflux, thereby increasing intracellular doxorubicin concentrations and, thus, increasing myocyte damage. These results suggest that the clinical use of concurrent doxorubicin and lapatinib should be approached with care due to the possibility of lapatinib increasing doxorubicin cardiotoxicity.

A multicenter, phase II study of epirubicin/cyclophosphamide followed by docetaxel and concurrent trastuzumab as primary systemic therapy for HER-2 positive advanced breast cancer (the HER2NAT study)

The outcome in patients with human epidermal growth factor receptor-2 (HER-2)-positive locally advanced breast cancer may be improved by integrating trastuzumab with primary systemic therapy (PST). The efficacy and safety of PST comprising EC (epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2), four cycles every 3 weeks) followed by docetaxel (75 mg/m(2), four cycles every 3 weeks) and concurrent trastuzumab (loading dose 4 mg/kg followed by 2 mg/kg, 12 cycles every week) was investigated in a multicenter, prospective, phase II study in patients with HER-2-positive stage IIIB/IIIC/IV breast cancer. The primary endpoint was pathologic complete response (pCR) including the tumor intraductal component confirmed by central pathologic review. In total, 38 patients were enrolled (stage IIIB, 63.2 %; IIIC, 23.7 %; IV, 13.2 %; estrogen receptor- and/or progesterone receptor-positive, 47.4 %). The pCR rate was 16.2 % in the primary tumor (six of 37 patients in the Full Analysis Set) and 56.8 % (21/37) in the ipsilateral axillary lymph nodes. Treatment was given according to protocol in 28 of 37 patients; six of 28 in the Per-Protocol Set achieved pCR (21.4 %). The clinical response rate was 67.6 % (25/37 patients; complete response, 13.5 %; partial response, 54.1 %). No patients developed congestive heart failure; however, three patients had a non-symptomatic decrease of >10 % of left ventricular ejection fraction. PST including concurrent use of trastuzumab combined with docetaxel is effective and well-tolerated in HER-2-positive advanced breast cancer patients, including those patients requiring mastectomy for local control.

Abstract 935: Lapatinib and other tyrosine kinase inhibitors greatly potentiate doxorubicin-induced damage to cardiac myocytes

Abstract Lapatinib (Tykerb) is dual tyrosine kinase inhibitor targeting the HER2 (ERBB2) and EGFR (ERBB1, HER1) pathways. Lapatinib has been shown in a clinical trial to produce low levels of cardiotoxicity that is reversible. Using a neonatal rat cardiac myocyte model we have investigated the ability of lapatinib alone, and in combination with doxorubicin, to damage myocytes. Lapatinib alone at pharmacological concentrations only slightly induced myocyte damage. However, doxorubicin-induced myocyte damage was greatly potentiated by the addition of low nanomolar lapatinib concentrations. Because trastuzumab also targets ERBB2 receptors, the lapatinib/doxorubicin combination also provides a good model to probe the mechanism of the increased cardiotoxicity caused by the concurrent use of trastuzumab and doxorubicin. Lapatinib treatment alone had little or no effect on myocyte mitochondrial membrane potential, on oxidation of intracellular DCF (dichlorofluorescein), on intracellular ATP levels, or on caspase 3/7 induction. While the doxorubicin cardioprotective agent dexrazoxane was able to greatly reduce doxorubicin-induced myocyte damage, it could only partially reduce the increase in myocyte damage produced by the lapatinib/doxorubicin treatment. Lapatinib alone had little effect on the phosphorylation status of ACC (acetyl-coenzyme A carboxylase) and AKT. Lapatinib alone decreased phosphorylated ERK (MAPK), which may have, in part, contributed to the increased doxorubicin-mediated myocyte damage. As measured by flow cytometry lapatinib-treated myocytes demonstrated an increased accumulation of doxorubicin. As lapatinib is a strong inhibitor of several ATP-dependent ABC-type efflux transporters, this likely occurred because lapatinib blocked doxorubicin efflux, thereby increasing intracellular doxorubicin concentrations. These results suggest that the clinical use of concurrent doxorubicin and lapatinib should be approached with care due to the possibility of lapatinib increasing doxorubicin cardiotoxicity. Several other kinase inhibitors (imatinib, dasatinib, sorafenib, sunitinib, gefitinib, pazopanib, nilotinib, erlotinib, vandetanib and canertinib) were also examined for their ability to potentiate doxorubicin-induced myocyte damage and induce an increase in intracellular doxorubicin levels. Support: CIHR and a Canada Research Chair in Drug Development to BBH. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 935. doi:1538-7445.AM2012-935

Impact on Cardiac Toxicity With Trastuzumab and Radiotherapy: The Question Is Still Ongoing

TO THE EDITOR: In a recent issue of Journal of Clinical Oncology, Halyard et al retrospectively examined adverse events data from the North Central Cancer Treatment Group phase III trial N9831 and directly evaluated the effect of trastuzumab on radiation-induced cardiac toxicity. At a median follow-up of 3.7 years, radiotherapy concurrently with trastuzumab did not increase relative frequency of cardiac events, regardless of treatment side, suggesting that concurrent adjuvant radiation therapy and trastuzumab was not associated with increased acute adverse events. To our knowledge, the cardiac effects of the interaction of trastuzumab and radiation therapy had not been reported before, and this content-rich article is one of the best pieces of literature that elaborates on the cardiac toxicity of concurrent use of trastuzumab and radiation therapy. However, several shortcomings are present and should be highlighted. Firstly, there is a need to focus not only on severe symptomatic cardiac disease. Subtle functional declines and minor cardiovascular changes may also increase mortality with longer follow-up. Unchanged value in left ventricular ejection fraction is not equated to a lack of cardiotoxicity and additional strategies for the monitoring of radiation-induced cardiotoxicity are being explored. Secondly, strategies involving concurrent targeted therapies and radiotherapy should be considered in randomized trials in which every effort should be made to minimize the dose to the heart. A substantial amount of relevant information should be required in further clinical trials, including doses delivered to cardiac structures, especially the coronary arteries. This information would be of first importance. Finally, preliminary experiences with trastuzumab suggest a need for continued cardiac follow-up. Close attention to the long-term cardiovascular adverse effect profile of targeted agents is imperative during their clinical development, particularly when evaluating combinations of new agents with radiotherapy and/or chemotherapy.