J Clin Oncol 26: by American Society of Clinical Oncology INTRODUCTION

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1 VOLUME 26 NUMBER 8 MARCH 1 28 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Response to Neoadjuvant Therapy and Long-Term Survival in Patients With Triple-Negative Breast Cancer Cornelia Liedtke, Chafika Mazouni, Kenneth R. Hess, Fabrice André, Attila Tordai, Jaime A. Mejia, W. Fraser Symmans, Ana M. Gonzalez-Angulo, Bryan Hennessy, Marjorie Green, Massimo Cristofanilli, Gabriel N. Hortobagyi, and Lajos Pusztai From the Departments of Breast Medical Oncology, Biostatistics and Applied Mathematics, and Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Department of Gynecology and Obstetrics, University of Münster, Münster, Germany; Department of Obstetrics and Gynecology, Marseille Public Hospital System, Marseille; and Breast Cancer Unit and Translational Research Unit UPRES3535, Institut Gustave Roussy, Villejuif, France. Submitted September 13, 27; accepted November 19, 27; published online ahead of print at on February 4, 28. Supported by grants to C.L. from the Deutsche Forschungsgemeinschaft; to L.P. from the National Cancer Institute (NCI; Grant No. RO1-CA1629), the Breast Cancer Research Foundation, and the Goodwin Foundation; and to G.N.H. from the NCI [Grant No. 2P3 CA (PP-4)] and the Nellie B. Connally Breast Cancer Research Fund. T.A. is a visiting professor supported by the Hungarian American Enterprise Scholarship Fund. Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 27, Chicago, IL. A B S T R A C T Purpose Triple-negative breast cancer () is defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression. In this study, we compared response to neoadjuvant chemotherapy and survival between patients with and non-. Patients and Methods Analysis of a prospectively collected clinical database was performed. We included 1,118 patients who received neoadjuvant chemotherapy at M.D. Anderson Cancer Center for stage I-III breast cancer from 1985 to 24 and for whom complete receptor information were available. Clinical and pathologic parameters, pathologic complete response rates (pcr), survival measurements, and organ-specific relapse rates were compared between patients with and non-. Results Two hundred fifty-five patients (23%) had. Patients with compared with non- had significantly higher pcr rates (22% v 11%; P.34), but decreased 3-year progression-free survival rates (P.1) and 3-year overall survival (OS) rates (P.1). was associated with increased risk for visceral metastases (P.5), lower risk for bone recurrence (P.27), and shorter postrecurrence survival (P.1). Recurrence and death rates were higher for only in the first 3 years. If pcr was achieved, patients with and non- had similar survival (P.24). In contrast, patients with residual disease (RD) had worse OS if they had compared with non- (P.1). Conclusion Patients with have increased pcr rates compared with non-, and those with pcr have excellent survival. However, patients with RD after neoadjuvant chemotherapy have significantly worse survival if they have compared with non-, particularly in the first 3 years. J Clin Oncol 26: by American Society of Clinical Oncology Authors disclosures of potential conflicts of interest and author contributions are found at the end of this article. Corresponding author: Lajos Pusztai, MD, PhD, Department of Breast Medical Oncology, Unit 1354, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX , USA; lpusztai@ mdanderson.org. 28 by American Society of Clinical Oncology X/8/ /$2. DOI: 1.12/JCO INTRODUCTION Triple-negative breast cancers (s) are characterized by the lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2). 1,2 These cancers occur in approximately 2% to 25% of all patients with breast cancer, and are associated with an unfavorable prognosis. 2-4 Patients with derive no benefit from molecularly targeted treatments such as endocrine therapy or trastuzumab, because they lack the appropriate targets for these drugs. The primary goal of this study was to describe the relation between triple-negative receptor status and major determinants of clinical outcome, such as response to neoadjuvant chemotherapy (rate of pathologic complete response [pcr]), progressionfree survival (PFS), site-specific distribution of recurrence, postrecurrence survival (PRS), and overall survival (OS). The secondary goal was to explain the relationship between the increased response rate to chemotherapy associated with this breast cancer subtype in contrast to the unfavorable prognosis. PATIENTS AND METHODS Study Design Of the 1,782 patients diagnosed with nonmetastatic breast cancer between 1985 and 24 who received neoadjuvant chemotherapy at M.D. Anderson Cancer Center (Houston, TX), 1,118 were included. Patient characteristics of the excluded patients are provided in the Appendix (online only). Patient cases were selected from the Breast 1275

2 Liedtke et al Medical Oncology Database based on the following criteria: (1) receipt of at least one cycle of chemotherapy; (2) availability of complete information on clinical (ctnm at diagnosis) and pathologic stage (ptnm after neoadjuvant chemotherapy); (3) response to treatment; and (4) known ER, PR, and HER-2 status. Patients were excluded from the analysis if they had an additional (metachronous or synchronous) breast cancer or if they had received trastuzumab or bevacizumab. Staging was performed according to American Joint Committee on Cancer guidelines. 5 Clinical and histologic characteristics of all patients were obtained from medical records and entered prospectively into an institutional clinical database. All primary tumors were reviewed by a dedicated breast pathologist on first referral to our institution. No central pathology rereview was performed for this analysis. Clinical tumor size was determined on the basis of physical examination and imaging tests, including mammograms. This data analysis was approved by our institutional review board. Pathology Assessment ER and PR status were assessed by immunohistochemistry (IHC; 6F11; Novocastra Laboratories Ltd.; Newcastle, UK); HER-2 status was assessed by either fluorescent in situ hybridization or IHC (Dako North America Inc, Carpinteria, CA). The cutoff for ER positivity and PR positivity was 1% positive tumor cells with nuclear staining. HER-2 positivity was defined as either HER2 gene amplification (fluorescent in situ hybridization) or were scored as 3 (IHC). Nuclear grade was assessed using the modified Black s nuclear grading system. 6 pcr was determined by microscopic examination of the excised tumor and lymph nodes after completion of chemotherapy, and was defined as no residual invasive cancer in either one. Patients with in situ carcinoma in the absence of an invasive component were considered pcr. 7 Statistical Analyses Tumors negative for ER, PR, and HER-2 were classified as s and compared with tumors with any receptor positivity (non-). Logistic regression was used to determine factors predictive of pcr. Parameters assessed comprised race, age at the time of diagnosis, tumor histology, menopausal status, nuclear grade, clinical (ie, before chemotherapy) and pathologic (ie, postchemotherapy) tumor (T) and nodal (N) score, type of neoadjuvant chemotherapy regimen, number of chemotherapy cycles, and type of surgery (breast-conserving therapy v mastectomy). Patient age at diagnosis was considered as both a continuous variable and as cohorts of age groups at 1- year intervals. OS was measured from the date of definitive surgery to the date of last follow-up or death. PFS was measured from the date of definitive surgery to the date of last follow-up or disease relapse. PRS was measured from the date of disease relapse to the date of last follow-up or death. Breast cancer relapse was defined as locoregional or distant recurrence/metastasis. Statistical analyses were performed using S-PLUS 7. for Windows (Insightful Corp, Seattle, WA) and more details on the statistical methods are given in the Appendix. RESULTS Patient Characteristics Two hundred fifty-five patients (23%) were designated as having and 863 patients (77%) were designated as non-. Expression of ER, PR, or HER-2 was observed in 645 (58%), 524 (47%), and 272 (24%) patients, respectively. The mean age of patients with (48 years) was slightly younger compared with non- (5 years; P.2). When age group cohorts were compared, there was no association between patient age group and incidence of relative to non-. This may not represent the true incidence pattern of in the general population but rather reflects a selection bias because the database included only patients who received neoadjuvant chemotherapy. African American (31.8%) and Hispanic women (33.6%) showed an increased incidence of compared with white patients: 32%, 34%, and 19%, respectively (P.3 and P.18, respectively). This observation is concordant with previous reports. 2,8 A small subset of patients had inflammatory breast cancer (n 59); the incidence of in this subset was similar (27%) to those with noninflammatory histology (23%; P.253). Table 1 lists patient characteristics and results of multivariate analysis for patients with compared with non-. Table 2 lists the chemotherapy regimens that were administered. Adjuvant therapy after surgery consisted of additional cytotoxic therapy in 379 patients. Greater than 99% of patients with ER-positive disease (n 641) received adjuvant endocrine therapy, including either tamoxifen (n 465), anastrozole (n 168), letrozole (n 6), or exemestane (n 1). One patient underwent bilateral salpingo-oophorectomy. Effect of Triple-Negative Status on Response to Neoadjuvant Chemotherapy Overall, 163 patients (15%) experienced pcr compared with 945 patients (85%) with residual disease (RD). In multivariate analysis, increased pcr rates were observed for patients with compared with non- (22% v 11%; odds ratio [OR] 1.53; 95% CI, 1.3 to 2.26; P.34) for ductal histology compared with nonductal histology (OR 2.14; 95% CI, 1.8 to 4.25; P.3) and high nuclear grade (one grade unit increase, OR 6.63; 95% CI, 3.49 to 12.6; P.1). Decreased pcr rates were observed for larger ct (OR.78; 95% CI,.64 to.95; P.13). Individually, all ER-positive/PR-negative/HER-2 negative, ER-positive/PR-positive/ HER-2 negative, and ER-positive/PR-positive/HER-2 positive breast cancers exhibited significantly lower rates of pathologic complete response compared with (P.1, P.1, and P.67, respectively). Table 2 lists pcr rates as a function of triple-negative status and chemotherapy regimens. Increased pcr rates in association with were observed for patients treated with fluorouracil, doxorubicin, and cyclophosphamide/fluorouracil, epirubicin, and cyclophosphamide, or weekly/once every 3 weeks paclitaxel/docetaxel followed by fluorouracil, doxorubicin, and cyclophosphamide plus weekly/once every 3 weeks paclitaxel/docetaxel followed by fluorouracil, epirubicin, cyclophosphamide chemotherapy (P.1 and P.72, respectively). There was a trend for higher pcr rate for single-agent taxane or other regimens that did not reach statistical significance (P.82 and P.33, respectively), probably because of the small sample size in these categories and scarcity of pcr with single-agent therapy. Effect of Triple-Negative Status on Survival Parameters During the study period, 284 progression events were recorded; 171 patients died and 133 patients are alive after disease recurrence. Mean follow-up was 2.9 and 3.8 years for and non-, respectively. In multivariate analysis, a significantly decreased PFS was observed for patients with compared with non-. The 3-year freedom from progression was 63% v 76%, respectively (HR 1.86; 95% CI, 1.39 to 2.5; P.1). Other predictors of poor PFS were young age at diagnosis (1-year increase, HR.98; 95% CI,.96 to 1.; P.15), ductal compared with nonductal histology (HR 1.79; 95% CI, 1.23 to 2.61; P.22), high nuclear grade (HR 1.6; 95% CI, 1.2 to 2.15; P.16), and higher tumor stage (HR 1.22; 95% CI, 1.6 to 1.41; P.56). In contrast, an increased number of neoadjuvant chemotherapy cycles (HR.93; 95% CI,.89 to.98; P.28) and white compared with African American ethnicity (HR.63; 95% CI,.41 to.95; P.29) were associated with better PFS JOURNAL OF CLINICAL ONCOLOGY

3 Clinical Features of Triple-Negative Breast Cancer Characteristic Table 1. Patient Characteristics by Triple-Negative Status No. of Patients % Non- No. of Patients % OR * 95% CI P * Age range, years to Mean SE Prechemotherapy T stage to Tis. 1.1 T T T T T Unknown Prechemotherapy N stage to N N N N Unknown Histology to Ductal Nonductal Nuclear grade to Unknown Ethnicity Non-Hispanic white African American to Hispanic to Other Surgical therapy to Breast-conserving therapy Mastectomy Adjuvant radiation to No Yes NOTE. Bold text indicates significant variables. Abbreviations:, triple-negative breast cancer; OR, odds ratio. * Determined by multivariate logistic regression analysis. Compared with classification of non-hispanics. Unequal variance t test. Decreased OS was also observed for patients with compared with non- (3-year OS rates: 74% v 89%; HR 2.53; 95% CI, 1.77 to 3.57; P.1), ductal compared with nonductal histology (HR 1.8; 95% CI, 1.11 to 2.92; P.17), high nuclear grade (HR 2.2; 95% CI, 1.48 to 3.25; P.1), and higher tumor stage (HR 1.22; 95% CI, 1.3 to 1.45; P.2). Figures 1A and 1D show the Kaplan-Meier estimates of PFS and OS for patients with and non-, respectively. The 1-, 3-, and 5-year estimates for PFS were 81%, 63%, and 61% for ; and 9%, 76%, and 7% for non-, respectively. The 1-, 3-, and 5-year estimates for OS were 9%, 74%, and 64% for ; and 97%, 89%, and 81% for non-, respectively. Figures 1B and 1E show kernel estimates of the hazard functions of progression and death, respectively. The 1-, 3-, and 5-year progression HR estimates were.22,.4, and.2 for ; and.1,.5, and.3 for non-, respectively. The 1-, 3-, and 5-year death HR estimates were.14,.7, and.3 for ; and.4,.5, and.5 for non-, respectively. The estimated hazard curves cross at about 2.5 and 4.5 years for

4 Liedtke et al Regimens Table 2. pcr Rates as Function of Triple-Negative Status and Chemotherapy Regimens pcr Rates All Patients Non- No. % No. % No. % Differences 95% CI P * FAC /FEC /AC (n 38) to.25.1 TFAC /TFEC (n 588) to.2.72 Single-agent taxane# (n 58) to Other ** (n 164) to Total (n 1,118) to Abbreviations: pcr, pathologic complete response;, triple-negative breast cancer; FAC, fluorouracil, doxorubicin, and cyclophosphamide; FEC, fluorouracil, epirubicin, and cyclophosphamide; AC, doxorubicin and cyclophosphamide; TFAC, weekly/once every 3 weeks paclitaxel/docetaxel followed by fluorouracil, doxorubicin, and cyclophosphamide; TFEC, weekly/once every 3 weeks paclitaxel/docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide. * Cox regression model. n 241; mean cycles 4.3 (range, 2-8). n 15, mean cycles 5.3 (range, 4.-6.). n 52, mean cycles 4.1 (range ). n 471, mean cycles 11.7 (range, ). n 117, mean cycles 13.9 (range, ). #Single-agent paclitaxel, weekly/three-weekly paclitaxel (n 4), 6.6 (2.-2.); single-agent docetaxel, weekly/three-weekly docetaxel (n 18), 4.6 (3.-12.). ** Other, other regimes, n 164, mean cycles 6.1 (range, ). disease progression or death. Figures 1C and 1F give the estimates of the ratio of the OS and PFS hazard functions including point-wise 95% CIs for compared with non-, respectively. The 1-, 3-, and 5-year HRs for disease progression were 1.4, 1., and.9, respectively. The 1-, 3-, and 5-year HRs for death were 1.8, 1.4, and 1., respectively. Hence, recurrence and death rates were higher for compared with non- only in the first 3 years. Patients with /RD had significantly decreased OS compared withthosewithnon-/rd(hr 1.5;95%CI,1.3to1.8;P.1). Importantly, no such significant difference was observed among patients who achieved pcr (HR 1.7; 95% CI,.7 to 4.2; P.24). Individually, ER and PR expression was associated with increased PFS (HR.66; 95% CI,.51 to.86; P.2 and HR.66; 95% CI,.5 to.86; P.23, respectively) and OS (HR.48; 95% CI,.35 to.65; P.1 and HR.68; 95% CI,.5 to.94; P.2, respectively). HER-2 expression showed a trend toward decreased PFS (HR 1.27; 95% CI,.98 to 1.64; P.71), while not exhibiting any significant effect on OS (HR.98; 95% CI, 72 to 133; P.89). We stratified patients into eight groups according to ER, PR, and HER-2 expression. PFS was increased for ER-positive/PR-negative/HER-2 negative (P.98), ER-negative/PR-positive/HER-2 negative (P.37), ER-positive/PR-positive/HER-2 negative (P.1), and ER-positive/PR-positive/HER-2 positive (P.29) tumors compared with. OS was increased for ER-positive/PR-negative/HER-2 negative (P.2), ER-positive/PR-positive/HER-2 negative (P.1), and ER-positive/PR-positive/HER-2 positive (P.7) tumors compared with (Appendix Figs A1 and A2; Table A1, online only). Tests for interactions between individual receptor expression and outcome (pcr, PFS, or OS) did not yield significant results. In other words, the effect, which might be seen as a consequence of expression of two receptors in the absence of the third, might be significantly different from the effect observed when the latter is present. Effect of Receptor Expression on Site of Recurrence and Postrecurrence Survival Patients with disease recurrence were grouped into three mutually exclusive categories according to the initial site of recurrence: (1) viscera, (2) bone, and (3) soft tissue, following a hierarchical approach with regard to survival as described previously. Information on site of recurrence was missing in 17 patients. Patients with had higher rates of recurrence in visceral organs and soft tissue, and lower rates of bone disease (P.27). Individually, both ER positivity and PR positivity predicted for increased risk of recurrence in bone and decreased risk of soft tissue and visceral recurrence (P.1 and P.25, respectively). Inversely, HER-2 positivity predicted for decreased risk of recurrence in bone and increased risk of visceral recurrence (P.2; Table 3). was a significant predictor of decreased postrecurrence survival (PRS, P.1) in all patients with recurrence compared with non-. This was observed among each subgroup of patients including visceral (P.5) and bone (P.81) recurrence (Table 4). DISCUSSION We present the results of the largest study to date, to our knowledge, that comprehensively examines the clinical phenotype of with regard to response to neoadjuvant chemotherapy and survival parameters. Our data indicate that pcr rate is higher in compared with non-. More importantly, we also showed that patients who achieved pcr had excellent survival regardless of receptor status, but patients with and residual disease after neoadjuvant chemotherapy have significantly shorter overall and postrecurrence survival than patients with non- and residual cancer (Fig 2). This is likely due to the combination of at least two factors. First, in general has poor prognostic features, including significantly higher nuclear grade, increased incidence of visceral metastases, and shorter recurrence-free interval compared with non-. Second, chemotherapy is the only systemic treatment option for, whereas patients with non- may derive benefit from both chemotherapy and endocrine therapy and, more recently, trastuzumab as well. It is therefore not surprising that patients with non- and residual cancer after neoadjuvant chemotherapy who also received adjuvant endocrine therapy (if 1278 JOURNAL OF CLINICAL ONCOLOGY

5 Clinical Features of Triple-Negative Breast Cancer A Probability Being Progresion-Free Non D Probability of Being Alive Non B Hazard Rate of Progression Non- E Hazard Rate of Death Non C F Hazard Ratio of Progression Point Estimates 95% CI Hazard Ratio of Death Point Estimates 95% CI Fig 1. (A) Proportion of patients with triple-negative breast cancer () who remained free from disease progression compared with those with non-. (B) Hazard functions for disease progression among patients with compared with non-. (C) Progression hazard ratio (HR; v non-) as a changing function of time. (D) Proportion with who survived compared with those with non-. (E) Hazard functions for death among patients with compared with non-. (F) Death HR ( v non-) as a changing function of time. ER or PR positive) in this study showed better survival. As expected, the survival of the entire group of non- was also better than that in the group with because the majority of patients in both groups had residual cancer. It is important to recognize that the non- group is clinically heterogeneous. In general, fewer ER-positive breast cancers are sensitive to chemotherapy than ER-negative cancers. 9,1 However, some subsets of patients in the non- group may have as high, or higher, pcr rates as those with (Table A1). For example, HER-2 amplified tumors have significantly higher response rates than HER-2 normal tumors in both hormone receptor subsets. 11 HER-2 amplified tumors may be particularly sensitive to anthracycline-based chemotherapy. 12 Our results also demonstrate that the risk of recurrence is strongly time-dependent, and the hazard curves are different for and non-. The risk of relapse and death is significantly and dramatically higher for during the first 3 years of followup. After 3 years, the hazard curves run close to each other and can

6 Liedtke et al Receptor Status Table 3. Effect of ER Status and HER-2 Status on the Frequency of First Relapse in Different Organ Sites No. of Patients Bone Soft Tissue Viscera No. % No. % No. % Triple-negative status Non ER expression Positive Negative PR expression Positive Negative HER-2 expression Positive Negative Abbreviations:, triple-negative breast cancer; ER, estrogen receptor; PR, progesterone receptor; HER-2, human epidermal growth factor receptor 2. * Cox regression model. P * even cross, suggesting a possibly higher risk of relapse and death for non- in years 4 to 6. Our results corroborate previous reports on the clinical history of. Dent et al 1 described the clinical course of 1,61 women with breast cancer who received various therapies but not neoadjuvant chemotherapy. Eleven percent of women had defined by IHC, and showed an increased likelihood of distant recurrence (P.1) and death (P.1) within 5 years of diagnosis, but not thereafter (similar to our results). In that study, the recurrence risk in the non- group was constant over the period of follow-up. In another study, Carey et al 3 examined response rates to neoadjuvant anthracycline-based chemotherapy in different molecular classes of breast cancer. The investigators assigned basal-like, HER-2 positive/er-negative, and luminal subtypes to 34, 11, and 62 breast cancers, respectively. Similar to our results, they observed a high pathologic response rate in the basallike group that paradoxically had significantly decreased distant DFS and OS compared with the luminal subtype. Our results add to the previous literature in that we demonstrate in a large number of patients that the worse overall survival of is primarily determined by the worse survival of patients with residual cancer. Even though includes more patients with highly chemotherapy-sensitive disease compared with non-, these individuals still represent only a minority of all patients with. None of the previous studies correlated tumor phenotype with site of recurrence; in this article, we show that has a higher predilection for visceral metastasis and early recurrence within the first 3 years of follow-up. Our study has limitations. Almost one third of eligible patients were excluded because of the lack of complete receptor information. Those who were excluded from the analysis were diagnosed in significantly earlier time intervals (in the mid- and late 198s) and had significantly lower pt, pn, ct, and cn stages compared with those patients included in our study. There were significant differences in tumor grade, patient age, and ethnicity. How and whether the excluded patients could bias our observations is unclear. In addition, our study covered an almost 2-year period during which multiple different and increasingly effective chemotherapy regimens were used. the frequent use of earlier generation chemotherapy regimens (approximately half of the patients received 3 to 6 months of an Status Total No. of Patients Table 4. Effect of Triple-Negative Status on Postrecurrence Survival No. of Patients With Events Median Survival (years) 95% CI HR 95% CI P * All locations to Non to to 1.2 Bone to Non to to NR Soft tissue to Non to NR to NR Viscera to 3..5 Non to to 1.2 Abbreviations:, triple-negative breast cancer; HR, hazard ratio; NR, not reached. * Cox regression model. 128 JOURNAL OF CLINICAL ONCOLOGY

7 Clinical Features of Triple-Negative Breast Cancer Probability Being Alive pcr/non- pcr/ RD/non- RD/ 98% 94% 88% 68% P =.24 P = Fig 2. Overall survival as a function of response to chemotherapy (pathologic complete response [pcr] v residual disease [RD]) and triple-negative status (triple-negative breast cancer [] v non-). anthracycline-based regimen without a taxane) is reflected by the relatively low overall pcr rate (11% and 2% for and non-, respectively) compared with what some current thirdgeneration regimens that include taxanes can accomplish. 13 However, systemic treatment variables (except endocrine therapy) were equally distributed among the and the non- subgroup. The variety of regimens used in the study may even be considered a strength of the study, given that it allows for a conclusion that extends across different cytotoxic treatments. It is important to note that we excluded patients who received neoadjuvant or adjuvant trastuzumab, and more than 75% of ER-positive patients received tamoxifen rather than an aromatase inhibitor. Given that both of these modalities are now used routinely, it is possible that the prognostic gap between and non- is even wider today than in our historic cohort of patients. In conclusion, patients with have increased pcr rates compared with non-, and those with pcr have excellent survival. However, patients with RD after neoadjuvant chemotherapy have significantly worse survival, particularly in the first 3 years. Accordingly, patients with may be best treated with thirdgeneration adjuvant or neoadjuvant chemotherapy regimens that achieve the highest possible pcr rates. Given the high risk of visceral metastases, these individuals may require closer surveillance in the initial years of follow-up. However, whether earlier detection and aggressive therapy of metastatic recurrence could improve survival is yet to be demonstrated. Importantly, these and previous results illustrate the need to develop novel therapeutic alternatives for this subgroup of patients to alleviate the significantly worse PFS and OS associated with residual disease with current chemotherapies. AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Cornelia Liedtke, Chafika Mazouni, W. Fraser Symmans, Lajos Pusztai Administrative support: Gabriel N. Hortobagyi, Lajos Pusztai Collection and assembly of data: Chafika Mazouni, Jaime A. Mejia, Ana M. Gonzalez-Angulo, Bryan Hennessy, Marjorie Green, Massimo Cristofanilli Data analysis and interpretation: Cornelia Liedtke, Kenneth R. Hess, Fabrice André, Attila Tordai, W. Fraser Symmans, Ana M. Gonzalez-Angulo, Massimo Cristofanilli, Gabriel N. Hortobagyi, Lajos Pusztai Manuscript writing: Cornelia Liedtke, Ana M. Gonzalez-Angulo, Gabriel N. Hortobagyi, Lajos Pusztai Final approval of manuscript: Cornelia Liedtke, Chafika Mazouni, Kenneth R. Hess, Fabrice André, Attila Tordai, Jaime A. Mejia, W. Fraser Symmans, Ana M. Gonzalez-Angulo, Bryan Hennessy, Marjorie Green, Massimo Cristofanilli, Gabriel N. Hortobagyi, Lajos Pusztai REFERENCES 1. Dent R, Trudeau M, Pritchard KI, et al: Triplenegative breast cancer: Clinical features and patterns of recurrence. Clin Cancer Res 13: , Bauer KR, Brown M, Cress RD, et al: Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: A population-based study from the California Cancer Registry. Cancer 19: , Carey LA, Dees EC, Sawyer L, et al: The triple negative paradox: Primary tumor chemosensitivity of breast cancer subtypes. 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Oncologist 11: , 26 Appendix The Appendix is included in the full-text version of this article, available online at It is not included in the PDF version (via Adobe Reader )