Prolonged survival after diagnosis of brain metastasis from breast cancer: contributing factors and treatment implications

Japanese Journal of Clinical Oncology, 2015, 45(8) 713 718 doi: 10.1093/jjco/hyv067 Advance Access Publication Date: 15 May 2015 Original Article Original Article Prolonged survival after diagnosis of brain metastasis from breast cancer: contributing factors and treatment implications Yayoi Honda*, Tomoyuki Aruga, Toshinari Yamashita, Hiromi Miyamoto, Kazumi Horiguchi, Dai Kitagawa, Nami Idera, Risa Goto, and Katsumasa Kuroi Division of Breast Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan *For reprints and all correspondence: Yayoi Honda, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan. E-mail: yayoi.honda@cick.jp Received 31 January 2015; Accepted 7 April 2015 Abstract Objective: The prognosis of breast cancer-derived brain metastasis is poor, but new drugs and recent therapeutic strategies have helped extend survival in patients. Prediction of therapeutic responses and outcomes is not yet possible, however. In a retrospective study, we examined prognostic factors in patients with breast cancer-derived brain metastasis, and we tested the prognostic utility of a breast cancer-specific Graded Prognostic Assessment in these patients. Methods: Sixty-three patients diagnosed with brain metastasis from breast cancer treated surgically and adjuvantly were included. We examined clinical variables per primary tumor subtype: ER+/HER2 (luminal), HER2+ (human epidermal growth factor receptor type 2-enriched) or ER /PR /HER2 (triple negative). We also categorized patients breast cancer-specific Graded Prognostic Assessment scores and analyzed post-brain metastasis survival time in relation to these categories. Results: The breast cancers comprised the following subtypes: luminal, n = 18; human epidermal growth factor receptor type 2-enriched, n = 27 and triple-negative, n = 18; median survival per subtype was 11, 37 and 3 months, respectively. Survival of human epidermal growth factor receptor type 2-enriched patients was longer, though not significantly (P = 0.188), than that of luminal patients. Survival of triple-negative patients was significantly short (vs. human epidermal growth factor receptor type 2-enriched patients, P < 0.001). Karnofsky performance status, HER2 status and the disease-free interval (from initial treatment to first recurrence) were shown to be significant prognostic factors (Karnofsky performance status < 70: relative risk 2.08, P = 0.028; HER2+: relative risk 2.911, P = 0.004; disease-free interval < 24 months: relative risk 1.933, P = 0.011). Breast cancer-specific Graded Prognostic Assessment scores reflected disease-free intervals and survival times. Conclusions: Our data indicate that breast cancer-specific Graded Prognostic Assessment-based prediction will be helpful in determining appropriate therapeutic strategies for patients with brain metastasis from breast cancer. Key words: breast cancer, brain metastasis, retrospective study, subtype, prognostic factor, breast cancer-specific GPA The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com 713

714 Survival after diagnosis of brain metastasis Introduction Brain metastasis (BM) is diagnosed in 10 16% of all breast cancer patients and has been reported in as many as 30% of breast cancer patients at autopsy (1 4). BM is not uncommon. It can arise from various cancer types and is associated with a poor prognosis and impaired quality of life. Both local and systemic treatments for BM are challenging. Typically, survival after whole-brain radiation therapy for BM is 3 6 months, and the prognosis in cases of triple-negative (TN) breast cancer is quite poor after central nervous system recurrence, although new treatment regimens have prolonged survival after a diagnosis of BM (5 10). It is now possible to predict the prognosis of BM on the basis of the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis index or the RTOG Graded Prognostic Assessment (GPA) (11 15), and the original GPA has been refined to include indices specific to breast cancer, lung cancer, gastrointestinal cancer, melanoma and renal cell carcinoma (16). The breast cancerspecific GPA (BS-GPA) incorporates Karnofsky performance status (KPS), the primary tumor subtype and age as prognostic factors (17,18); however, it is not yet possible to predict therapeutic responses and outcomes on the basis of the BS-GPA. Although the prognosis of BM is improving, we have encountered BMs that are resistance to treatment. Predicting prognosis after BM is important in determining the treatment strategy. Thus, we conducted a retrospective study to investigate survival after a diagnosis of BM from breast cancer, factors contributing to prolonged survival and the prognostic utility of the BS-GPA. Patients and methods Patients Between 2000 and 2012, 2673 patients were treated surgically for breast cancer at the Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital. BM from breast cancer was diagnosed in 63 of these patients (not including patients with Stage IV breast cancer). In all 63 cases, the primary tumor was identified pathologically as an invasive ductal carcinoma or invasive lobular carcinoma, and patients had undergone radical surgery and had received appropriate adjuvant therapy. Estrogen receptor (ER) expression was determined by immunohistochemistry (IHC), and ER positivity was defined as 1% or more ER-positive cells. Human epidermal growth factor receptor type 2 (HER2) expression was evaluated by means of IHC or fluorescent in situ hybridization (FISH), and tumors with a respective score of 3+ or a >2.0-fold increase in HER2 gene expression were considered positive for HER2. The primary tumor was classified by subtype as ER+/HER2 (luminal), ER+ or ER /HER2+ (HER2-enriched [HER2-E]) or ER /PR /HER2 (TN or basal-like) breast cancer. BM was diagnosed by magnetic resonance imaging (MRI) or computed tomography (CT). The study was approved by the research ethics committee of Komagome Hospital. Data obtained The following data were obtained from the patients online medical records: age at the time of initial treatment for breast cancer, TN status, ER and HER2 statuses of the primary tumor, follow-up time, the disease-free interval (DFI) from the time of initial treatment of breast cancer to the first recurrence ( 2 years vs. <2 years); site of first recurrence; extracranial disease control (no metastasis to other organs vs. controlled or uncontrolled metastasis to other organs), first indication of BM (symptoms vs. evidence upon screening), age at the diagnosis of BM, KPS at the time of BM diagnosis, characteristic of the BM (single vs. multiple lesions), brain region affected, presence or absence of carcinomatous meningitis, treatment of the BM, survival time after the diagnosis of BM and cause of death. Patients were grouped according to primary tumor subtypes, and variables were compared between these patient groups. In addition, we categorized patients BS-GPA scores as 0 1, 1.5 2, 2.5 3 or 3.5 4. A patient s BS-GPA score is calculated as the total points assigned for KPS, tumor subtype and age), as summarized in Table 1. We analyzed patient characteristics as well as survival time after BM in relation to these score categories. Statistical analyses Survival was analyzed by the Kaplan Meier method, and betweengroup differences were analyzed by log-rank test. To identify prognostic factors after a diagnosis of BM from breast cancer, variables that were shown to be significant by univariate analysis were entered into a Cox proportional hazard model. The relative risks (RRs) and 95% confidence intervals (CIs) were calculated. For all tests, significance was accepted at P < 0.05. All analyses were performed with JMP, version 9.0.0 (SAS Institute, Inc., Cary, NC, USA). Results Study data are summarized in Table 2. Median age of patients at the time of initial treatment for breast cancer was 53 years (range, 35 78 years), and the median follow-up period was 41.6 months (range, 7 188 months). The numbers of ER+/HER2 (luminal), ER+ or /HER2+ (HER2-E) and ER /PR /HER2 (TN) primary tumors were 18, 27 and 18, respectively. The sites of initial recurrence were brain (n = 21), lung (n = 25), regional lymph nodes (n = 7), bone (n = 12), liver (n = 3), uterus (n = 1) and skin (n = 1) (with some patients showing initial recurrence at multiple sites). The BM was found by MRI or CT screening in four patients who had no symptoms. Four or more brain metastases were found in 32 patients, i.e. in more than half of the patients. The brain metastases were supratentorial (n = 19), infratentorial (n = 8) or both supratentorial and infratentorial (n = 36) as the transition point. Carcinomatous meningitis was found in 13 patients. Whole-brain radiation therapy was performed in about half of the patients, and surgery, either curative or palliative, was performed in 35% of patients. HER2-targeted therapy was performed in 67% of patients with BM derived from HER2-E cancer even after the diagnosis of BM. Study variables are summarized per primary tumor subtype in Table 3. Notably, the incidence of BM among patients with HER2-E breast cancer was relatively high at 8.1%, and single lesions Table 1. BS-GPA point system a 0 0.5 1 1.5 2.0 KPS <50 60 70 80 90 100 Subtype Basal n/a LumA HER2 LumB b Age (years) <60 60 BS-GPA, breast cancer-specific Graded Prognostic Assessment; KPS, Karnofsky performance status; Subtype, breast cancer subtype; Lum, luminal. a BS-GPA points from three categories are summed for a total BS-GPA score of 0 4.0. b ER and HER2 are both positive.

Jpn J Clin Oncol, 2015, Vol. 45, No. 8 715 Table 2. Clinicopathologic characteristics of study patients (n = 63) Age, median (range) 53 (35 78) years Follow-up period, median (range) 41.6 (7 188) months Primary tumor subtype ER+/HER2 (luminal) 18 (28) ER or ER+/HER2+ 27 (43) (HER2-enrich) ER /PR /HER2 (triple 18 (28.5) negative) Median survival after BM diagnosis 12 (1 168) months Cause of death (n = 42) Related to BM a 34 Not related to BM 8 Site of initial recurrence b Brain/lung/lymph node 21 (33)/24(40)/7(11) Bone/liver/other 12 (19)/3(5)/2 (3) No. of brain metastases 1/2 3/ 4 8 (13)/23(37)/32(50) Region of BM Supratentorial/infratentorial/ 19 (30)/8(13)/36(57) both Carcinomatous meningitis Present/absent 13 (21)/50(79) First treatment for brain metastases Surgery/SRS/WBRT 22 (35)/6(9.5)/28(44) No treatment/unknown 5 (8)/2(3) Adjuvant therapy NAC/AC/HT/no treatment/ 27 (43)/30(47.5)/3(4)/2(3)/1(1.5) unknown Systemic therapy after BM Anticancer drug/ht/no 25 (39)/13(21)/32(51)/3(5) treatment/unknown HER2-targeted therapy as adjuvant therapy NAC/AC/no treatment/unknown 8 (30)/15(56)3(11)/1(4) c HER2-targeted therapy after BM Treatment/no treatment/ 18(67)/7(26)2(7) c unknown Number (and percentage) of patients are shown unless otherwise indicated. BM, brain metastasis; SRS, stereotactic radiosurgery; WBRT, whole-brain radiation therapy; NAC, neo-adjuvant chemotherapy; AC, adjuvant chemotherapy; HT, hormone therapy. a For example, decline in performance status due to BM. b Multiple sites of initial recurrence in some cases. c Number shown in ( ) is the percentage of the HER2-E-dervied BM. were found in over 20% of these patients. In addition, the incidence of carcinomatous meningitis was lowest in this group. The median DFI, which was 33 months or more in the luminal and HER2-E subgroups was only 3 months in the TN subgroup. Median survival after the diagnosis of BM for patients with luminal, HER2-E and TN tumors was 11, 37 and 3 months, respectively. The prognosis of TN tumors was significantly poor (TN vs. HER2-E, P < 0.001), and although the difference in survival time between BM derived from a HER2-E tumor and BM derived from a luminal tumor was not significant (P = 0.188), survival after BM from a HER2-E tumor tended to be >36 months (Fig. 1). Results of univariate and multivariate analyses are summarized in Table 4. According to univariate analysis, age at the diagnosis of BM, ER status, the presence of extracranial disease and the BM characteristic (single vs. multiple lesions) were not significant variables. The KPS ( 70 vs. <70), HER2 status and DFI ( 2 years vs. <2 years) were shown to have a significant effect on survival time after the diagnosis of BM (P = 0.0458, P =0.0398 and P = 0.0385, respectively). The presence of carcinomatous meningitis was of borderline significance (P = 0.052). Thus, KPS, HER2 status and DFI were entered into multivariate analysis, and the presence of carcinomatous meningitis was also entered. KPS <70, HER2+ and DFI <24 months were shown to be significant prognostic factors after a diagnosis of BM (KPS: RR 2.08, 95% CI 1.08 4.07; HER2: RR 2.911, 95% CI 1.396 6.484; DFI: RR 1.933, 95% CI 0.83 4.102). Patients were grouped per BS-GPA score categories as follows: 0 1, n = 8; 1.5 2, n = 19; 2.5 3, n = 22 and 3.5 4, n = 15. As summarized on Table 5, DFI in the poor prognosis groups (BS-GPA Score 0 1 or 1.5 2) was shorter than that in the good prognosis groups (BS-GPA Score 2.5 3 or3.5 4). Median survival times after the diagnosis of BM were 3, 8.5, 19.5 and 40 months per BS-GPA Scores 0 1, 1.5 2, 2.5 3 and 3.5 4, respectively (Fig. 2). Discussion Table 3. Characteristics of breast cancer-derived brain metastasis per primary ER plus HER2 status Prognosis after a diagnosis of BM from breast cancer has been considered poor. However, in our HER2-E group, median survival after the diagnosis of BM was 37 months. The prospect of prolonged survival in patients with BM from breast cancer naturally raises the issue of optimum treatment strategies for the primary tumor itself and then for the metastatic brain tumor. For the treatment of BM, it is Characteristic ER+/HER2 (luminal) ER or ER+/HER2+ (HER2-E) ER /PR /HER2 (TN) No. of brain lesions/total no. of surgeries for BC a 18/1972 (0.9%) 27 b /333 (8.1%) 18/368 (4.9%) Age at first treatment years, median (range) 56 (42 78) 5 (41 68) 53 (35 70) Survival months, median (range) 11 (6 68) 37 (3 167) 3 (1 18) DFI months, median (range) 35.5 (7 117) 33 (4 78) 3 (1 26) BM First/secondary 1 (11.1%)/17 (88.9%) 12 (44.4%)/15 (55.6%) 8 (44.4%)/10 (55.6%) BM characteristic Single/multiple lesions 1 (5.6%)/17 (94.4%) 6 (22.2%)/21 (77.8%) 1 (5.5%)/17 (94.5%) Carcinomatous meningitis 5 (27.7%) 3 (11.1%) 5 (27.8%) Number (and percentage of patients) are shown unless otherwise indicated. BC, breast cancer; HER2-E, HER2-enriched; TN, triple negative; DFI, disease-free interval. a Total number of patients treated surgically for BC at our institution, 2000 12. b Tumors in 4 of the 27 patients were ER+/HER2+.

716 Survival after diagnosis of brain metastasis Figure 1. Kaplan Meier curves of survival after diagnosis of brain metastasis, per estrogen receptor and human epidermal growth factor receptor type 2 status. P values were determined by log-rank test. Table 4. Results of univariate and multivariate analyses of prognostic factors in brain metastasis from breast cancer Factor No. of patients Survival after BM (months) P value RR (95% CI) Univariate Multivariate Age at diagnosis 60 years 29 18 0.4860 <60 years 34 9 Extracranial disease Yes 49 19 0.1123 No 14 18 Brain lesion Single 8 16 0.8919 Multiple 55 18 ER status Positive 25 24 0.0959 Negative 38 10 HER2 status 2.911 (1.396 6.484) Positive a 27 32 0.0398 0.039 Negative 36 12 DFI 1.933 (0.83 4.102) <24 months a 32 7 0.0385 0.011 24 months 31 18 KPS 2.08 (1.08 4.07) <70 a 30 7 0.0458 0.028 70 33 20 Meningitis 2.552 (1.240 5.414) Yes 13 9 0.0552 0.1194 No 50 17 RR, relative risk; CI, confidence interval. a Shown by multivariate analysis to be a significant prognostic factor. important to make effective combined use of systemic therapy, radiation therapy and surgical resection. We must strive to obtain an acceptable quality of life for patients that can be maintained for a long period of time. In establishing treatment guidelines for initial BM, it is necessary to clearly understand the prognosis, which is based in part on the number and size of the brain lesions, and to consider treatment

Jpn J Clin Oncol, 2015, Vol. 45, No. 8 717 protocols according to the prognosis (19). We tested the utility of the BS-GPA for determining prognosis in cases of BM. Early detection of BM, KPS, tumor subtype and age have been reported as important prognostic factors in patients with BM from breast cancer (16 18,20), and KPS and HER2 status were shown in our study to be prognostic factors. In our patient series, actual median survival times after BM were well reflected by patients BS-GPA scores, and thus BS-GPA was shown to be effective in predicting prognosis upon a diagnosis of BM from breast cancer. So the necessity of examining the treatment of breast cancer-derived BM according to both the cancer subtype and BS-GPA is clear. In our study patients, the prevalence of BM derived from HER2-E breast cancer was higher than that of BM derived from luminal or TN breast cancer, but the prognosis of HER2-E-derived BM was good. The majority of patients with HER2+ breast cancer were treated with trastuzumab as adjuvant therapy, and 67% of patients with HER2-E-deived BM underwent HER2-targeted therapy even after the diagnosis of BM. Trastuzumab treatment has been reported to increase the risk of BM from HER2+ breast cancer, but a recently reported study found no difference in the frequency of BM between the use and non-use of trastuzumab (21), and pertuzumab treatment has been described similarly (22). Trastuzumab does not easily penetrate the blood brain barrier, and thus the effect on metastatic brain lesions is thought Table 5. Variables per GPA score categories BS-GPA score No. of patients Age at first treatment (years, median) to be limited. Because treatment with trastuzumab has prolonged the lives of patients with breast cancer, cases of BM have increased in number. However, even in cases of BM, the prognosis under treatment with trastuzumab is reportedly better for HER2+ breast cancer than for HER2 breast cancer (21). An existing report supports prolongation of survival after BM by HER2-targeted treatment in cases of HER2-positive breast cancer (23). Lapatinib has shown some success in patients for whom trastuzumab has not prevented BM (24,25). Some of our patients with HER2-E-derived BM were treated with HER2-targeted therapy over the long term. We believe HER2-targeted therapy to be important for systemic treatment of BM arising from HER2+ breast cancer. Innovative cytotoxic agents did not appear to contribute toward improved clinical outcomes in our patients with BM from TN breast cancer. Survival in our TN group was only 3 months, which is not an improvement over historically reported survival times (4.9 7 months) (10,22), and the TN subtype was thus assumed to be a poor prognostic factor. In the future, it will be necessary to consider the appropriate treatment strategy for BM from TN breast cancer. In cases of BM from other cancers, the status of the BM (the number of brain metastases, for example) may be included as a prognostic factor in the GPA. The status of BM was not included in the BS-GPA used in our study. We found inclusion of the primary tumor subtype to be important, however. DFI (months, median) Median survival (months, range) 0 1 8 56.0 12.0 3.0 (1 16) 1.5 2 18 51.5 22.0 8.5 (1 67) 2.5 3 22 54.0 31.5 19.5 (4 167) 3.5 4 15 53.5 24.5 40.0 (2 144) GPA, Graded Prognostic Assessment. Figure 2. Kaplan Meier curves of survival after brain metastasis per breast cancer-specific Graded Prognostic Assessment scores.

718 Survival after diagnosis of brain metastasis Conclusion Our study was limited by its implementation as a single-institution, retrospective study. Nevertheless, we found a comparatively good prognosis for BM arising from HER2+ breast cancer, and we believe that aggressive medical treatment should be considered for such patients. The BS-GPA was shown to be effective for predicting prognosis after a diagnosis of BM, and thus BS-GPA-based prediction will be helpful in determining appropriate therapeutic strategies for any patient with BM from breast cancer. We anticipate detailed investigation into optimum treatment protocols. Conflict of interest statement None declared. References 1. Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. JClin Oncol 2004;22:2865 72. 2. Lin NU, Bellon JR, Winter EP. CNS metastases in breast cancer. JClin Oncol 2004;22:3608 17. 3. Lee YT. Breast carcinoma: pattern of metastases at autopsy. J Surg Oncol 1983;23:175 80. 4. Tsukada Y, Fouad A, Pickren JW, Lane WW. Central nervous system metastasis from breast carcinoma. Autopsy study. Cancer 1983;52:2349 54. 5. Phillips TL, Scott CB, Leibel SA, Rotman M, Weigensberg IJ. Results of a randomized comparison of radiotherapy and bromodeoxyuridine with radiotherapy alone for brain metastases: report of RTOG trial 89-05. Int J Radiat Oncol Biol Phys 1995;33:339 48. 6. Borgelt B, Gelber R, Kramer S, et al. The palliation of brain metastases: final results of the first two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1980;6:1 9. 7. Crivellari D, Pagani O, Veronesi A, et al. High incidence of central nervous system involvement in patients with metastatic or locally advanced breast cancer treated with epirubicin and docetaxel. Ann Oncol 2001;12:353 6. 8. Brufsky AM, Mayer M, Rugo HS, et al. Central nervous system metastases in patients with HER2-positive metastatic breast cancer: incidence, treatment and survival in patients from registher. Clin Cancer Res 2011;17: 4834 43. 9. Dawood S, Broglio K, Esteva FJ, et al. Defining prognosis for women with breast cancer and CNS metastases by HER2 status. Ann Oncol 2008;19: 1242 8. 10. Lin NU, Claus E, Sohl J, Razzak AR, Arnaout A, Winer EP. Sites of distant recurrence and clinical outcomes in patients metastatic triple-negative breast cancer; high incidence of central nervous system metastases. Cancer 2008;113:2638 45. 11. Gaspar L, Scott C, Rotman M, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 1997;37:745 51. 12. Speruduto PW, Berkey B, Gasper LE, Mehta M, Curran W. A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database. Int J Radiat Oncol Biol Phys 2008;70:510 14. 13. Komarnicky LT, Phillips TL, Martz K, Asbell S, Isaacson S, Urtasun R. A randomized phase III protocol for the evaluation of misonidazole combined with radiation in the treatment of patients with brain metastases (RTOG79-16). Int J Radiat Oncol Biol Phys 1991;20:53 8. 14. Sause WT, Scott C, Krisch R, et al. Phase I/II trial of accelerated fractionation in brain metastases RTOG 85-28. IntJRadiatOncolBiolPhys 1993;26:653 7. 15. Murray KJ, Scott C, Greenberg HM, et al. A randomized phase III study of accelerated hyperfractionation versus standard in patients with unresected brain metastases: a report of the Radiation Therapy Oncology Group (RTOG) 9104. Int J Radiat Oncol Biol Phys 1997;39:571 4. 16. Sperduto PW, Chao ST, Sneed PK, et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys 2010;77:655 61. 17. Sperduto PW, Kased N, Roberge D, et al. Summary report on the Graded Prognostic Assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol 2012;30: 419 25. 18. Sperduto PW, Kased N, Roberge D, et al. Effect of tumor subtype on survival and the Graded Prognostic Assessment for patients with breast cancer and brain metastases. Int J Radiat Oncol Biol Phys 2012;82:2111 17. 19. Tsao MN, Rades D, Wirth A, et al. Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): an American Society for Radiation Oncology evidence-based guideline. Pract Radiat Oncol 2012;2: 210 25. 20. Sperduto PW, Kased N, Roberge D, et al. The effect of tumor subtype on the time from primary diagnosis to development of brain metastases and survival in patients with breast cancer. J Neurooncol 2013;112:467 72. 21. Leyland-Jones B. Human epidermal growth factor receptor 2-positive breast cancer and central nervous system metastases. J Clin Oncol 2009;27: 5278 86. 22. Swain SM, Baselga J, Miles D, et al. Incidence of central nervous system metastases in patients with HER2-positive metastatic breast cancer treated with pertuzumab, trastuzumab, and docetaxel: results from the randomized phase III study CLEOPATRA. Ann Oncol 2014;25:1116 21. 23. Hines SL, Vallow LA, Tan WW, McNeil RB, Perez EA, Jain A. Clinical outcomes after a diagnosis of brain metastases in patients with estrogen-and/or human epidermal growth factor receptor 2-positive versus triple-negative breast cancer. Ann Oncol 2008;19:1561 5. 24. Cameron D, Casey M, Press M, et al. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat 2008;112:533 43. 25. Lin NU, Carey LA, Liu MC, et al. Phase II trial of lapatinib for brain metastases in patients with human epidermal growth factor receptor 2-positive with breast cancer. J Clin Oncol 2008;26:1993 9.