1348 The new engl and journal o f medicine correspondence Pertuzumab plus Trastuzumab in Metastatic Breast Cancer To the Editor: Baselga and colleagues (Jan. 12 issue) 1 report that in the Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA; ClinicalTrials.gov number, NCT00567190) trial involving patients with human epidermal growth factor receptor 2 (HER2)positive metastatic breast cancer receiving first-line therapy, the addition of pertuzumab to docetaxel plus trastuzu mab was associated with a 6-month increase in progression- free survival. Pertuzumab, a recombinant human- ized monoclonal antibody binding to the HER2 dimerization domain, prevents dimerization of HER2 with other HER receptors (HER3, HER1, and HER4), especially with HER3. 2 Chiu et al. re- ported that HER3 overexpression was identified in 10.0% of tumors in patients with breast cancer in one randomized study and can be a clinically significant marker of reduced survival in such patients. 3 In another randomized, phase 2 study, Makhija et al. found that low HER3 levels corre- sponded with the positive response to pertuzu- mab in patients with platinum-resistant ovarian cancer. 4 On these grounds, it would be interesting to know the distribution of HER3 overexpression among the groups in the CLEOPATRA trial, since this variable might have influenced the outcomes of this study. HER3 overexpression may be a use- ful marker for predicting which patients are most likely to benefit from pertuzumab. Mehmet A.N. endur, M.D. Sercan Aksoy, M.D. Nurullah Zengin, M.D. Ankara Numune Education and Research Hospital Ankara, Turkey masendur@yahoo.com.tr No potential conflict of interest relevant to this letter was re- ported. 1. Baselga J, Corts J, Kim S-B, et al. Pertuzumab plus trastuz- umab plus docetaxel for metastatic breast cancer. N Engl J Med 2012;366:109-19. 2. Adams CW, Allison DE, Flagella K, et al. Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab. Cancer Immunol Immuno- ther 2006;55:717-27. 3. Chiu CG, Masoudi H, Leung S, et al. HER-3 overexpression is prognostic of reduced breast cancer survival: a study of 4046 patients. Ann Surg 2010;251:1107-16. 4. Makhija S, Amler LC, Glenn D, et al. Clinical activity of gem- citabine plus pertuzumab in platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. J Clin Oncol 2010;28:1215-23. To the Editor: In the study by Baselga et al., the incidence of severe febrile neutropenia in patients from Asia was 26% in the pertuzumab group and 12% in the control group. In patients from other areas, the incidence was approximately 10% in both groups. This suggests ethnic factors asso- ciated with the risk of neutropenia. To untangle this discordance, we would again plead 1 for bet- ter definitions of Asian and ethnicity. The interpretation of the results for Asian subgroups is unclear, since genomic predictors of efficacy and adverse effects may not cosegregate. The HLA-B*1502 allele, a predictor of carbamazepine hypersensitivity, is common (>5.0%) in Han Chi- nese persons from Taiwan and Thais but relatively rare in Japanese persons, with a prevalence that this weeks letters 1348 Pertuzumab plus Trastuzumab in Metastatic Breast Cancer 1350 Subclinical Atrial Fibrillation and the Risk of Stroke 1353 Low-Dose Interleukin-2 and HCV-Induced Vasculitis 1354 Defense Costs of Medical Malpractice Claims The New England Journal of Medicine Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on September 15, 2014. For personal use only. No other uses without permission. Copyright 2012 Massachusetts Medical Society. All rights reserved. correspondence n engl j med 366;14 nejm.org april 5, 2012 1349 is 50 times as low as the rate among these other Asian groups and closer to that of whites (<0.1%). 2 The CLEOPATRA study included phar- macogenetically diverse Hispanics 3 who were classified as white. We are beginning to better dissect the elements of ethnicity that are predic- tive of drug response, including each persons ethnicity-associated intestinal microbiome. 4 In- fection was the most common cause of death in the CLEOPATRA trial. Can the authors of this study help by detailing the frequency of severe neutropenia in each Asian ethnic subgroup? Alain Li-Wan-Po, Ph.D. National Genetics Education and Development Centre Birmingham, United Kingdom a.liwanpo@talk21.com No potential conflict of interest relevant to this letter was re- ported. 1. Li-Wan-Po A. Personalised medicine: who is an Asian? Lancet 2007;369:1770-1. 2. Ozeki T, Mushiroda T, Yowang A, et al. Genome-wide asso- ciation study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population. Hum Mol Genet 2011;20:1034-41. 3. Choudhry S, Ung N, Avila PC, et al. Pharmacogenetic differ- ences in response to albuterol between Puerto Ricans and Mexi- cans with asthma. Am J Respir Crit Care Med 2005;171:563-70. 4. Li-Wan-Po A, Farndon P. Barking up the wrong genome we are not alone. J Clin Pharm Ther 2011;36:125-7. To the Editor: The heart is an ever acting, never resting tissue that needs a constant background mechanism of repair. Myocardial maintenance is the responsibility of the ill-defined neuregulin- ErbB signaling pathways, comprising neuregulin interactions with the epidermal growth factor re- ceptor 1 (EGFR1) and ErbB2, ErbB3, and ErbB4. 1 A rational theoretical hypothesis would hint toward greater cardiac toxicity with dual blockade of ErbB2 and ErbB3 than with the use of ErbB2 blockade alone. However, in the CLEOPATRA trial, it was surprising that lower rates of systolic dysfunction were noted among patients receiv- ing pertuzumab in addition to trastuzumab than among those receiving trastuzumab alone, in spite of the fact that the doses of trastuzumab were the same in the two groups. Though the CLEOPATRA trial stratified pa- tients according to the use or nonuse of prior chemotherapy, no attempt was made to stratify the patients according to the prior use or nonuse of radiotherapy. This could be an overlooked source of bias, since radiotherapy is known to affect cardiac function more so in patients who have received radiotherapy for cancer in the left breast. 2 Swaroop Revannasiddaiah, M.D. Rajeev Seam, M.D. Manoj Gupta, M.D. Regional Cancer Centre Shimla, India swarooptheone@gmail.com No potential conflict of interest relevant to this letter was re- ported. 1. Britsch S. The neuregulin-I/ErbB signaling system in devel- opment and disease. Adv Anat Embryol Cell Biol 2007;190:1-65. 2. Correa CR, Litt HI, Hwang WT, Ferrari VA, Solin LJ, Harris EE. Coronary artery findings after left-sided compared with right- sided radiation treatment for early-stage breast cancer. J Clin Oncol 2007;25:3031-7. The Authors Reply: We agree with endur et al. that HER3 is one of several molecules that are important to explore as potential markers for treatment benefit with pertuzumab plus trastuz- umab plus docetaxel in HER2-positive metastatic breast cancer. Gianni et al. recently presented re- sults of analyses of exploratory biomarkers (which included HER3 protein and messenger RNA [mRNA]) in the Neoadjuvant Study of Pertuz- umab and Herceptin in an Early Regimen Evalu- ation (NEOSPHERE; NCT00545688), a study of pertuzumab plus trastuzumab-based neoadjuvant therapy in HER2-positive early breast cancer. 1 In their study, the level of HER3 protein and mRNA did not correlate with treatment outcome. Re- sults from the predefined HER3 biomarker analy- ses in the CLEOPATRA trial are consistent with the findings in NEOSPHERE indicating that pa- tients derive benefit from the combination of pertuzumab plus trastuzumab plus docetaxel, re- gardless of the level of HER3 protein or mRNA expression. However, we and others have recently reported that HER3 expression and activation is modulated in response to HER2, HER3, or phos- phatidylinositol 3 kinase pathway inhibition, 2-4 which may not be reflected by the analysis of primary tumors. HER signaling pathways are involved in myo- cardial homeostasis, and trastuzumab has been associated with cardiac dysfunction, especially in patients with exposure to anthracyclines. 5 Be- cause two anti-HER2 antibodies were combined in the CLEOPATRA trial, cardiac adverse events were closely monitored, but no difference in their The New England Journal of Medicine Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on September 15, 2014. For personal use only. No other uses without permission. Copyright 2012 Massachusetts Medical Society. All rights reserved. The new engl and journal o f medicine n engl j med 366;14 nejm.org april 5, 2012 1350 incidence was observed between the groups. Revannasiddaiah et al. highlight the potential for an imbalance between the groups with re- gard to the use or nonuse of prior radiotherapy, which could have an effect on the cardiac events observed in our trial. A total of 43% of the pa- tients in each group had received radiotherapy before study entry. Therefore, although prior radiotherapy was not a stratification factor in our trial, this variable did not result in an imbalance between the groups. Li-Wan-Pos point regarding ethnic differences and patient responses to treatment is an impor- tant and complex issue. Although detailed eth- nicity data were not collected in the CLEOPATRA trial, we agree that obtaining more comprehen- sive data on ethnicity is an important consider- ation for future global studies. As Li-Wan-Po also points out, the incidence of febrile neutropenia of grade 3 or more was higher in patients from Asia, and in the overall study population, infec- tion was the most common cause of death due to an adverse event. In our trial, the incidence of grade 3 or higher infections and infestations was similar between the control and the pertu- zumab groups (10.1% vs. 11.1%); the incidence of deaths due to infections, sepsis, or febrile neutropenia was low (1.0% overall) and similar between the two groups within the overall study population and in patients from Asia. Jos Baselga, M.D., Ph.D. Massachusetts General Hospital Cancer Center Boston, MA jbaselga@partners.org Mark C. Benyunes, M.D. Genentech South San Francisco, CA Sandra M. Swain, M.D. MedStar Washington Hospital Center Washington, DC Since publication of their article, the authors report no fur- ther potential conflict of interest. 1. Gianni L, Bianchini G, Kiermaier A, et al. Neoadjuvant per- tuzumab (P) and trastuzumab (H): biomarker analyses of a 4-arm randomized Phase II study (NeoSphere) in patients (pts) with HER2-positive breast cancer (BC). Presented at the 34th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, Decem- ber 610, 2011. abstract. 2. Makhija S, Amler LC, Glenn D, et al. Clinical activity of gem- citabine plus pertuzumab in platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. J Clin Oncol 2010;28:1215-23. 3. Serra V, Scaltriti M, Prudkin L, et al. PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer. Oncogene 2011;30:2547-57. 4. Chandarlapaty S, Sawai A, Scaltriti M, et al. AKT inhibition relieves feedback suppression of receptor tyrosine kinase ex- pression and activity. Cancer Cell 2011;19:58-71. 5. Seidman A, Hudis C, Pierri MK, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 2002;20: 1215-21. Subclinical Atrial Fibrillation and the Risk of Stroke To the Editor: In their article on the results of the Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT; ClinicalTrials.gov number, NCT00256152), Healey et al. (Jan. 12 issue) 1 note that subclinical atrial fibrillation is believed to be a major cause of stroke of unknown cause, and their article supports this idea. We recently performed 7-day Holter monitor- ing in an unselected population of patients with stroke and found paroxysmal atrial fibrillation in 12.5% of all patients, but only 18% of strokes in patients with paroxysmal atrial fibrillation had been classified as stroke of unknown cause. 2 In many cases, patients with paroxysmal atrial fi- brillation have competing risks such as athero- sclerotic disease, but paroxysmal atrial fibrilla- tion may not be detected in these patients because of selection bias (i.e., deferred further diagnostic testing after findings that provide support for the competing cause). Other studies on diagnostic approaches for paroxysmal atrial fibrillation have been limited to strokes of unknown cause. 3 We therefore ask the authors to provide some infor- mation on the classification of ischemic stroke (e.g., with the use of the Trial of Org 10172 in Acute Stroke Treatment [TOAST] criteria) 4 in the patients in the ASSERT study who had strokes. Rolf Wachter, M.D. Raoul Stahrenberg, M.D. University of Gttingen Gttingen, Germany wachter@med.uni-goettingen.de Klaus Grschel, M.D. University of Mainz Mainz, Germany The New England Journal of Medicine Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on September 15, 2014. For personal use only. No other uses without permission. Copyright 2012 Massachusetts Medical Society. All rights reserved.