- Email: [email protected]
Clinical outcome of patients with brain metastases from HER2-positive breast cancer treated with lapatinib and capecitabine
original article
Annals of Oncology 22: 625–630, 2011 doi:10.1093/annonc/mdq434 Published online 19 August 2010
Clinical outcome of patients with brain metastases from HER2-positive breast cancer treated with lapatinib and capecitabine G. Metro1, J. Foglietta2, M. Russillo1, L. Stocchi2, A. Vidiri3, D. Giannarelli4, L. Crino`2, P. Papaldo1, M. Mottolese5, F. Cognetti1, A. Fabi1 & S. Gori2* 1
Division of Medical Oncology, Regina Elena Cancer Institute, Rome; 2Division of Medical Oncology, Ospedale S. Maria della Misericordia, Azienda Ospedaliera di Perugia; 3Diagnostic Imaging; 4Biostatistic Core; 5Department of Pathology, Regina Elena Cancer Institute, Rome, Italy
from human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) treated with lapatinib and capecitabine (LC). Methods: Of 81 HER2+ metastatic BC patients treated with LC at two Italian institutions, 30 patients with BMs eligible for the analysis were identified. All patients were pretreated with trastuzumab for metastatic disease. No patients had received prior lapatinib and/or capecitabine. Results: Median age was 45 years (range 24–75) and 26 of 30 patients (86.7%) had received prior cranial radiotherapy. In the 22 patients with BMs evaluable for response, 7 partial responses (31.8%) and 6 disease stabilizations (27.3%) were observed. Overall, the median brain-specific progression-free survival was 5.6 months (95% confidence interval 4.4–6.8). Patients treated with LC had a median overall survival (from the time of development of BMs) significantly longer compared with 23 patients treated with trastuzumab-based therapies only beyond brain progression (27.9 months versus 16.7 months, respectively, P = 0.01). Conclusions: LC is active for BMs from HER2+ BC in patients not pretreated with either lapatinib or capecitabine. The introduction of LC after the development of BMs may further improve survival compared with trastuzumab-based therapies only beyond brain progression. Key words: brain metastases, capecitabine, central nervous system, HER2, lapatinib, metastatic breast cancer
introduction Human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) is a disease with distinct clinicopathological features, which accounts for up to one third of all invasive breast tumors [1]. Clinically, HER2+ disease is characterized by a particularly aggressive course whose natural history, however, has been dramatically improved since the introduction of the anti-HER2 monoclonal antibody trastuzumab [2]. Interestingly, HER2 overexpression has recently emerged as a clear risk factor for the development of brain metastases (BMs) [3, 4], and trastuzumab treatment, despite its positive effect on overall prognosis, appears to substantially contribute to this risk [5–7]. In fact, trastuzumab does not fully cross the blood–brain barrier (BBB) [8, 9], thus making the brain a ‘sanctuary’ site for the development of metastases. In addition, several retrospective analyses of HER2+ metastatic BC patients treated with trastuzumab-based therapies showed that *Correspondence to: Dr S. Gori, Division of Medical Oncology, Ospedale S. Maria della Misericordia, Azienda Ospedaliera Perugia, via Dottori, 1, 06122 Perugia, Italy. Tel: +39-075-5784212; Fax: +39-075-5279082; E-mail: [email protected]
about one third of these patients develop BMs [6, 7, 10–14], and in more than half of these cases BMs occur in patients with either responsive or stable disease at extracranial sites. These results support the hypothesis that trastuzumab has limited ability to penetrate the BBB and highlight the importance of developing novel systemic strategies beyond local standard approaches of cranial radiotherapy to more effectively prevent or treat BMs from HER2+ BC. Lapatinib is a small molecule, dual HER1/HER2 inhibitor with a theoretical ability to cross the BBB. Preclinical evidence supports the activity of lapatinib against cerebral nervous system (CNS) disease [15], which could explain, in an unplanned exploratory analysis of the phase III study of lapatinib plus capecitabine (LC) versus capecitabine alone, the fewer CNS relapses as site of first progression associated with combination therapy (25% versus 6%, respectively; P = 0.045) [16]. For patients with established CNS metastases, two phase II studies investigated the activity of lapatinib monotherapy in HER2+ BC pretreated with trastuzumab who had developed BMs and had progressed after cranial radiation. These studies reported a modest activity of lapatinib monotherapy but
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
Background: In the present study, we investigated the clinical outcome of patients with brain metastases (BMs)
Downloaded from http://annonc.oxfordjournals.org/ at Aga Khan University on January 2, 2015
Received 13 May 2010; revised 2 July 2010; accepted 2 July 2010
original article showed a volumetric reduction in brain burden in additional patients in exploratory analyses [17, 18]. In the second international phase II trial, a cohort of 50 patients whose CNS disease had progressed on lapatinib monotherapy entered an extension phase involving treatment with both LC obtaining an overall response rate in the brain of 20% [18]. In the present analysis, the clinical outcome of patients with BMs from HER2+ BC treated with LC was evaluated and it was compared with that of a cohort of patients treated with trastuzumab-based therapies only beyond brain progression.
patients and methods
statistical analysis Response of BMs to LC was evaluated according to the World Health Organization (WHO) criteria [19]. Response of BMs was evaluated every 3 months by using the same radiological method of assessment as baseline. Duration of response in the brain was calculated from the first documented response until brain progression or death in the absence of brain progression. Progression-free survival (PFS) was the time elapsed from the date of initiation of LC to the date of first evidence of disease progression or death in the absence of disease progression. The
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Table 1. Characteristics of the 30 patients with BMs from HER2+ breast cancer treated with LC Characteristics Median age, years (range) 45 (24–75) ECOG PS, n (%) 0 7 (23.3) 1 14 (46.7) 2 9 (30) ER and/or PgR positive, n (%) 20 (66.7) HER2 positivity, n (%) IHC: 3+ 24 (80) FISH amplified 6 (20) Localized stage at initial diagnosis, n (%) 25 (83.3) Median time from initial diagnosis to the 37.5 (0–92) development of BMs, months (range) Median time from metastatic disease to the 12.4 (0–52.5) development of BMs, months (range) Median time from the development of BMs 8.8 (1–53) to treatment start, months (range) Median number of prior trastuzumab-based 2 (1–5) therapies for metastatic disease (range) Extracranial metastases, n (%) No 1 (3.3) Yes 29 (96.7) Visceral metastases 23/29 (79.3) Number of BMs, n (%) >3 12 (40) £3 18 (60) Local treatment for BMs, n (%) None 4 (13.3) Radiotherapy (WBRT and/or SRS) 21 (70) Neurosurgery with WBRT and/or SRS 5 (16.7) First systemic option after the development of BMs, n (%) LC 6 (20) Trastuzumab-based therapy 24 (80) Trastuzumab + chemotherapy 21/24 (87.5) Trastuzumab + endocrine therapy 3/24 (12.5) ECOG PS, Eastern Cooperative Oncology Group performance status; ER, estrogen receptor; PgR, progesterone receptor; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemical; FISH, fluorescence in situ hybridization; BMs, brain metastases; SRS, stereotactic radiosurgery; WBRT, whole brain radiotherapy; LC, Lapatinib plus capecitabine.
BPFS was defined as the time from the start of LC to the date of documented brain progression or death in the absence of disease progression in the brain. The OS time was measured from the start of LC (OS1) and from the time of development of BMs (OS2) to the date of death for any cause. In the absence of brain progression or death, BPFS, OS1 and OS2 were censored at the time of the last visit. Time to event (BPFS, OS1 and OS2) was analyzed according to Kaplan–Meier method and survival curves were compared using the log-rank test. Given the retrospective nature of the study, statistical significance should be used in an exploratory view and median time estimation with their 95% confidence interval (CI) reported to better interpret the data. SPSS software version 17.0 was used for statistical analyses (SPSS Inc., Chicago, IL).
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patient population Using medical records, 81 patients with HER2+ metastatic BC who were treated with lapatinib (1250 mg orally once daily) plus capecitabine (1000 mg/m2 orally twice per day for days 1–14 every 3 weeks) until disease progression at two Italian institutions from June 2006 to September 2009 were identified. Retrospective chart review was approved by the institutional review boards of both institutions. HER2 positivity was determined locally and defined as immunohistochemical staining of 3+ (HercepTest Dako A/S; Glostrup, Denmark) or 2+ with evidence of gene amplification at fluorescence in situ hybridization (PathVision HER2 DNA probe kit; Vysis Inc., Downers Grove, IL). Of these 81 patients, 30 patients who had developed BMs confirmed by magnetic resonance imaging or computed tomography scan before the start of treatment with LC were eligible for analysis (Table 1). All 30 patients had received prior treatment with a taxane, an anthracycline and trastuzumab. No patient had previously received either lapatinib or capecitabine. Response of BMs, the brain-specific progression-free survival (BPFS) and the overall survival (OS) (from the start of LC) of these 30 patients treated with LC were evaluated. Patients were considered evaluable for response of BMs: (i) in the presence of progressive BMs, (ii) in the presence of one or more measurable BMs ‡1 cm in diameter, (iii) in case of prior neurosurgery residual disease had to be documented radiologically, (iv) if cranial radiotherapy (whole brain radiation therapy and/or stereotactic radiosurgery) had been completed ‡2 months before the start of LC. In a second step, the OS from the time of development of BMs of patients treated with LC was compared with the OS of 23 patients who were treated consecutively with trastuzumabbased therapies only beyond brain progression at our institutions in the pre-lapatinib era [13, 14].
Annals of Oncology
original article
Annals of Oncology
results patient characteristics The characteristics of the 30 patients with BMs treated with LC are reported in Table 1. Median age was 45 years (range 24–75) and 21 patients (70%) had a performance status 0–1. All patients had received prior trastuzumab-based therapies for metastatic disease. Twenty-six patients (86.5%) had received prior cranial radiotherapy for BMs. No local treatment had been delivered in four patients (13.3%). In six patients (20%),
LC was administered as first systemic option after the development of BMs.
clinical outcome of patients with BMs treated with LC The median follow-up time from the initiation of LC was 9 months (range 2–31). The median duration of treatment with LC was 4 months (range 2–25). Twenty-two patients were evaluable for response in the brain: 7 partial responses (31.8%) and 6 disease stabilizations (27.3%) were observed (Table 2).
Table 2. Activity of LC for BMs according to the local treatment delivered Best response for BMs
3 (75) 1 (25) —
Radiotherapy (WBRT and/or SRS) (n = 17), n (%)
Neurosurgery with WBRT and/or SRS (n = 1), n (%)
3 (17.6) 5 (29.4) 9 (53)
1 (100) — —
Total patients (n = 22), n (%) 7 (31.8) 6 (27.3) 9 (40.9)
BMs, brain metastases; SRS, stereotactic radiosurgery; WBRT, whole brain radiotherapy.
Figure 1. The case of a 55-year-old woman with two brain metastases (BMs) from HER2+ breast cancer responding to LC (A, B). No local treatment was delivered before the initiation of LC. Moreover, LC was administered as first systemic option after the development of BMs. Duration of response in the brain lasted 14 months (C, D) and BMs were still responding at the time of treatment discontinuation due to extracranial disease progression.
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Partial response Stable disease Progressive disease
Local treatment for BMs None (n = 4), n (%)
original article
responses after 5 and 21 months of treatment, respectively. The third patient discontinued LC after 14 months of treatment due to extracranial only progression of disease (Figure 1). All 30 patients were considered for the analysis of PFS, BPFS and OS from the start of LC (OS1): the median PFS was 5.1 months (95% CI 2.6–7.5) and the median BPFS was 5.6 months (95% CI 4.4–6.8) (Figure 2A). At the time of this analysis, 5 of 30 patients had not yet experienced either intra- or extracranial disease progression and are still receiving LC. In the remaining 25 patients, treatment was discontinued due to disease progression: 4 patients for extracranial-only disease progression and 21 patients for disease progression both at intra- and extracranial sites. Eighteen patients have died and the median OS from the start of LC (OS1) was 11 months (95% CI 4.3– 17.6) (Figure 2B). Treatments after LC in the 25 progressive patients were trastuzumab-based in 11 patients, chemotherapy without trastuzumab in 9 patients and symptomatic therapy only in 5 patients.
Figure 2. Patients treated with LC (n = 30): Kaplan–Meier estimates of median brain-specific progression-free survival (2A) and median overall survival from the start of LC (OS1) (2B). OS, overall survival.
Figure 3. Kaplan–Meier estimates of overall survival from the development of brain metastases (BMs) (OS2). Median OS2 in the 30 patients treated with LC was 27.9 months (95% CI 25.6–30.1) versus 16.7 months (95% CI 8.6-24.8) in the 23 patients treated only with trastuzumab-based therapy beyond brain progression (P = 0.01) (3A). In the six patients treated with LC as first systemic option after the development of BMs, median OS2 was not reached at a median follow-up of 26 months (range 5–71) (3B). OS, overall survival; CI, confidence interval.
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The median duration of brain response was 6 months (range 3–25): it was 18 months (range 7–25) in the three patients who had not received any prior local treatment for BMs, while it was 4.5 months (range 3–6) in the four patients who had received prior local therapy. At 6 months, 57% of responsive patients were alive and free from brain progression compared with 27% of patients with stable or progressive BMs (P = 0.02). At 1 year, 67% of responsive patients were alive compared with 33% of patients with stable or progressive BMs (P = 0.02). Response of BMs was related to the local treatment delivered prior to LC (Table 2): three responses (75%) and one disease stabilization (25%) in the brain were observed in the four patients who did not receive any local treatment for BMs. The three responding patients had £3 brain lesions and received LC as first systemic option after the development of BMs. At the time of the analysis, two of these three patients had not yet experienced disease progression, with confirmed brain
Annals of Oncology
original article
Annals of Oncology
discussion Due to their high incidence, BMs represent an important cause of morbidity and mortality in HER2+ metastatic BC patients. In our retrospective analysis, patients naı¨ve for both lapatinib and capecitabine reported a 31.8% of response rate in BMs according to WHO criteria. As single agents, lapatinib and capecitabine have shown to be active for BMs in patients with HER2+ disease [17, 18] or unselected for HER2 status, respectively [20, 21]. More in detail, an international phase II study, which enrolled 242 patients pretreated with trastuzumab and with progressive BMs after radiotherapy, showed only a 6% response rate in the brain (defined by composite criteria) for single-agent lapatinib, but a 20% response rate in the brain was observed in additional patients with radiographically documented CNS progression who had entered the LC extension phase of the study [18]. For this reason, it is likely that the LC combination might act synergistically against BMs. This hypothesis has been confirmed by the results reported in the LC expanded access programs: 18% of responses in the brain were reported by Boccardo et al. [22] and 21% of responses were observed by Sutherland et al. [23], despite the fact that prior capecitabine had been administered in 42% and 35% of patients, respectively. Interestingly, previous treatment with capecitabine reduced the objective response rate in the brain: in the Sutherland study, the rate of brain response was lower in patients previously treated with capecitabine (16.7%) compared with the capecitabine-naı¨ve group (30%) (P = 0.2) [23]. These results are close to the 31.8% of responses obtained in our analysis, which was conducted in a similarly naı¨ve population for both lapatinib and capecitabine. Nevertheless, this comparison is limited by the different criteria used for CNS response assessment (RECIST in the Sutherland study versus WHO in our experience). However, at the present time, there are no standard neurooncology criteria to evaluate response in BMs. To this regard, Lin et al. [18] employed a CNS composite
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Table 3. Characteristics of the 23 patients with HER2+ breast cancer treated only with trastuzumab-based therapy beyond brain progression Characteristics Median age, years (range) ECOG PS, n (%) 0 1 2 ER and/or PgR positive, n (%) HER2 positivity, n (%) IHC: 3+ FISH amplified Localized stage at initial diagnosis, n (%) Median time from initial diagnosis to the development of BMs, months (range) Median time from metastatic disease to the development of BMs, months (range) Median no. of prior trastuzumab-based therapies for metastatic disease, months (range) Extracranial metastases, n (%) No Yes Visceral metastases Number of BMs, n (%) >3 £3 Local treatment for BMs, n (%) None Radiotherapy (WBRT and/or SRS) Neurosurgery with WBRT and/or SRS First systemic option after the development of BMs Trastuzumab-based therapy Trastuzumab + chemotherapy Trastuzumab + endocrine-therapy
41 (32–70) 12 8 3 14 18 5 17 34.9
(52.2) (34.8) (13) (60.9) (78.3) (21.7) (73.9) (7–128)
10.3 (3–65) 1 (1–5)
1 (4.3) 22 (95.7) 20/22 (90.9) 14 (60.9) 9 (39.1) 3 (13) 19 (82.6) 1 (4.4) 23 (100) 20/23 (87) 3/23 (13)
ECOG, Eastern Cooperative Oncology Group; ER, estrogen receptor; PgR, progesterone receptor; IHC, immunohistochemical; FISH, fluorescence in situ hybridization; BMs, brain metastases; SRS, stereotactic radiosurgery; WBRT, whole brain radiotherapy; LC, Lapatinib plus capecitabine.
response criteria where CNS objective response was defined as ‡50% volumetric reduction of CNS in the absence of increasing steroid use, progressive neurological signs and symptoms or progressive extra-CNS disease. Remarkably, we observed three partial responses with LC in four patients who had not received any local treatment for BMs (Figure 1). This finding might suggest that systemic treatment with LC is active on BMs in patients who have not been previously treated with cranial radiotherapy. Continuation of anti-HER2 treatments in patients progressing during trastuzumab-based therapies is associated with improved clinical outcome in patients with HER2+ metastatic BC [16, 24–26]. Similarly, continuation of trastuzumab-based therapies beyond brain progression has been associated with an improvement in survival [13, 14, 27, 28], which appears to be mainly function of an increased control of extracranial disease [13, 14]. In a recent retrospective analysis, treatment with lapatinib after the development of BMs
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OS from the time of development of BMs At a median follow-up of 26 months (range 5–71) from the diagnosis of BMs, median OS from the time of the development of BMs (OS2) evaluated in all 30 patients treated with LC was 27.9 months (95% IC 25.6–30.1) (Figure 3A). Median OS2 was not reached in the 6 patients who received LC as first systemic option after the development of BMs, while it was 27.1 months in the 24 patients who received LC after at least one trastuzumab-based therapy following the development of BMs (Figure 3B). Two-year OS2 was 66% for responsive patients compared with 44% for patients with stable or progressive BMs (P = 0.11). Median OS2 of the 30 patients treated with LC was then compared with the median OS2 of 23 patients who received only trastuzumab-based therapies beyond brain progression [13, 14]. The characteristics of these 23 patients were similar to those of the LC group (Table 3). In patients treated with LC, median OS2 was significantly higher than that of patients treated only with trastuzumab-based therapies beyond brain progression (27.9 months versus 16.7 months, respectively, P = 0.01) (Figure 3A).
original article
disclosure The authors declare no conflict of interest.
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8. Pestalozzi BC, Brignoli S. Trastuzumab in CSF. J Clin Oncol 2000; 18: 2349–2351. 9. Stemmler HJ, Schmitt M, Willems A et al. Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood-brain barrier. Anticancer Drugs 2007; 18: 23–28. 10. Bendell JC, Domchek SM, Burstein HJ et al. Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 2003; 97: 2972–2977. 11. Clayton AJ, Danson S, Jolly S et al. Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer. Br J Cancer 2004; 91: 639–643. 12. Stemmler HJ, Kahlert S, Siekiera W et al. Characteristics of patients with brain metastases receiving trastuzumab for HER2 overexpressing metastatic breast cancer. Breast 2006; 15: 219–225. 13. Gori S, Rimondini S, De Angelis V et al. Central nervous system metastases in HER-2 positive metastatic breast cancer patients treated with trastuzumab: incidence, survival, and risk factors. Oncologist 2007; 12: 766–773. 14. Metro G, Sperduti I, Russillo M et al. Clinical utility of continuing trastuzumab beyond brain progression in HER-2 positive metastatic breast cancer. Oncologist 2007; 12: 1467–1469. 15. Gril B, Palmieri D, Bronder JL et al. Effect of lapatinib on the outgrowth of metastatic breast cancer cells to the brain. J Natl Cancer Inst 2008; 100: 1092–1103. 16. 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: 533–543. 17. 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 breast cancer. J Clin Oncol 2008; 26: 1993–1999. 18. Lin NU, Die´ras V, Paul D et al. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res 2009; 15: 1452–1459. 19. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981; 47: 207–214. 20. Fabi A, Vidiri A, Ferretti G et al. Dramatic regression of multiple brain metastases from breast cancer with Capecitabine: another arrow at the bow? Cancer Invest 2006; 24: 466–468. 21. Ekenel M, Hormigo AM, Peak S et al. Capecitabine therapy of central nervous system metastases from breast cancer. J Neurooncol 2007; 85: 223–227. 22. Boccardo F, Kaufman B, Baselga J et al. Evaluation of lapatinib (Lap) plus capecitabine (Cap) in patients with brain metastases (BM) from HER2+ breast cancer (BC) enrolled in the Lapatinib Expanded Access Program (LEAP) and French Authorisation Temporaire d’Utilisation (ATU). Proc Am Soc Clin Oncol 2008; 26: abstract 1094. 23. Sutherland S, Ashley S, Miles D et al. Treatment of HER2-positive metastatic breast cancer with lapatinib and capecitabine in the lapatinib expanded access programme, including efficacy in brain metastases—the UK experience. Br J Cancer 2010; 102: 995–1002. 24. Fabi A, Metro G, Ferretti G et al. Do HER-2 positive metastatic breast cancer patients benefit from the use of trastuzumab beyond disease progression? A mono-institutional experience and systematic review of observational studies. Breast 2008; 17: 499–505. 25. von Minckwitz G, du Bois A, Schmidt M et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a German breast group 26/breast international group 03-05 study. J Clin Oncol 2009; 27: 1999–2006. 26. Blackwell KL, Burstein HJ, Storniolo AM et al. Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumabrefractory metastatic breast cancer. J Clin Oncol 2010; 28: 1124–1130. 27. Bartsch R, Rottenfusser A, Wenzel C et al. Trastuzumab prolongs overall survival in patients with brain metastases from Her2 positive breast cancer. J Neurooncol 2007; 85: 311–117. 28. Park IH, Ro J, Lee KS et al. Trastuzumab treatment beyond brain progression in HER2-positive metastatic breast cancer. Ann Oncol 2009; 20: 56–62.
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was one of the factors associated with prolonged survival from the diagnosis of BMs [7]. In our study, we reported a significantly longer OS from the development of BMs (OS2) for patients who had also received LC compared with a similar population treated only with trastuzumab-based therapies beyond brain progression (27.9 months versus 16.7 months; P = 0.01; Figure 3A). This highlights the potential impact of an additional anti-HER2 therapy with LC in patients with CNS progression on prior trastuzumab. Furthermore, the observation that the 2-year OS2 was higher in patients with responding BMs compared with those with stable or progressive CNS disease (66% versus 44%) provides evidence that the achievement of brain response is important for further improving the outcome of patients with BMs from HER2+ BC. Finally, the fact that patients who received LC as first systemic option after the development of BMs derived the greatest benefit from treatment (Figure 3B) might suggest that patients who develop BMs during trastuzumab-based therapies should undergo early initiation of LC in order to derive the greatest benefit from treatment. In conclusion, this retrospective analysis shows that LC is an active combination against BMs from HER2+ BC in patients naı¨ve for both lapatinib and capecitabine. Treatment with lapatinib and capecitabine after the development of BMs may further improve the prognosis of patients with BMs from HER2+ BC compared with the exclusive use of trastuzumabbased therapies beyond brain progression. This positive effect on survival can be at least in part attributed to the higher activity of LC on BMs compared with trastuzumab-based therapies beyond brain progression. Further evaluation of systemic strategies including LC in HER2+ BC patients with BMs is advocated.
Annals of Oncology
Annals of Oncology 22: 625–630, 2011 doi:10.1093/annonc/mdq434 Published online 19 August 2010
Clinical outcome of patients with brain metastases from HER2-positive breast cancer treated with lapatinib and capecitabine G. Metro1, J. Foglietta2, M. Russillo1, L. Stocchi2, A. Vidiri3, D. Giannarelli4, L. Crino`2, P. Papaldo1, M. Mottolese5, F. Cognetti1, A. Fabi1 & S. Gori2* 1
Division of Medical Oncology, Regina Elena Cancer Institute, Rome; 2Division of Medical Oncology, Ospedale S. Maria della Misericordia, Azienda Ospedaliera di Perugia; 3Diagnostic Imaging; 4Biostatistic Core; 5Department of Pathology, Regina Elena Cancer Institute, Rome, Italy
from human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) treated with lapatinib and capecitabine (LC). Methods: Of 81 HER2+ metastatic BC patients treated with LC at two Italian institutions, 30 patients with BMs eligible for the analysis were identified. All patients were pretreated with trastuzumab for metastatic disease. No patients had received prior lapatinib and/or capecitabine. Results: Median age was 45 years (range 24–75) and 26 of 30 patients (86.7%) had received prior cranial radiotherapy. In the 22 patients with BMs evaluable for response, 7 partial responses (31.8%) and 6 disease stabilizations (27.3%) were observed. Overall, the median brain-specific progression-free survival was 5.6 months (95% confidence interval 4.4–6.8). Patients treated with LC had a median overall survival (from the time of development of BMs) significantly longer compared with 23 patients treated with trastuzumab-based therapies only beyond brain progression (27.9 months versus 16.7 months, respectively, P = 0.01). Conclusions: LC is active for BMs from HER2+ BC in patients not pretreated with either lapatinib or capecitabine. The introduction of LC after the development of BMs may further improve survival compared with trastuzumab-based therapies only beyond brain progression. Key words: brain metastases, capecitabine, central nervous system, HER2, lapatinib, metastatic breast cancer
introduction Human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) is a disease with distinct clinicopathological features, which accounts for up to one third of all invasive breast tumors [1]. Clinically, HER2+ disease is characterized by a particularly aggressive course whose natural history, however, has been dramatically improved since the introduction of the anti-HER2 monoclonal antibody trastuzumab [2]. Interestingly, HER2 overexpression has recently emerged as a clear risk factor for the development of brain metastases (BMs) [3, 4], and trastuzumab treatment, despite its positive effect on overall prognosis, appears to substantially contribute to this risk [5–7]. In fact, trastuzumab does not fully cross the blood–brain barrier (BBB) [8, 9], thus making the brain a ‘sanctuary’ site for the development of metastases. In addition, several retrospective analyses of HER2+ metastatic BC patients treated with trastuzumab-based therapies showed that *Correspondence to: Dr S. Gori, Division of Medical Oncology, Ospedale S. Maria della Misericordia, Azienda Ospedaliera Perugia, via Dottori, 1, 06122 Perugia, Italy. Tel: +39-075-5784212; Fax: +39-075-5279082; E-mail: [email protected]
about one third of these patients develop BMs [6, 7, 10–14], and in more than half of these cases BMs occur in patients with either responsive or stable disease at extracranial sites. These results support the hypothesis that trastuzumab has limited ability to penetrate the BBB and highlight the importance of developing novel systemic strategies beyond local standard approaches of cranial radiotherapy to more effectively prevent or treat BMs from HER2+ BC. Lapatinib is a small molecule, dual HER1/HER2 inhibitor with a theoretical ability to cross the BBB. Preclinical evidence supports the activity of lapatinib against cerebral nervous system (CNS) disease [15], which could explain, in an unplanned exploratory analysis of the phase III study of lapatinib plus capecitabine (LC) versus capecitabine alone, the fewer CNS relapses as site of first progression associated with combination therapy (25% versus 6%, respectively; P = 0.045) [16]. For patients with established CNS metastases, two phase II studies investigated the activity of lapatinib monotherapy in HER2+ BC pretreated with trastuzumab who had developed BMs and had progressed after cranial radiation. These studies reported a modest activity of lapatinib monotherapy but
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
Background: In the present study, we investigated the clinical outcome of patients with brain metastases (BMs)
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Received 13 May 2010; revised 2 July 2010; accepted 2 July 2010
original article showed a volumetric reduction in brain burden in additional patients in exploratory analyses [17, 18]. In the second international phase II trial, a cohort of 50 patients whose CNS disease had progressed on lapatinib monotherapy entered an extension phase involving treatment with both LC obtaining an overall response rate in the brain of 20% [18]. In the present analysis, the clinical outcome of patients with BMs from HER2+ BC treated with LC was evaluated and it was compared with that of a cohort of patients treated with trastuzumab-based therapies only beyond brain progression.
patients and methods
statistical analysis Response of BMs to LC was evaluated according to the World Health Organization (WHO) criteria [19]. Response of BMs was evaluated every 3 months by using the same radiological method of assessment as baseline. Duration of response in the brain was calculated from the first documented response until brain progression or death in the absence of brain progression. Progression-free survival (PFS) was the time elapsed from the date of initiation of LC to the date of first evidence of disease progression or death in the absence of disease progression. The
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Table 1. Characteristics of the 30 patients with BMs from HER2+ breast cancer treated with LC Characteristics Median age, years (range) 45 (24–75) ECOG PS, n (%) 0 7 (23.3) 1 14 (46.7) 2 9 (30) ER and/or PgR positive, n (%) 20 (66.7) HER2 positivity, n (%) IHC: 3+ 24 (80) FISH amplified 6 (20) Localized stage at initial diagnosis, n (%) 25 (83.3) Median time from initial diagnosis to the 37.5 (0–92) development of BMs, months (range) Median time from metastatic disease to the 12.4 (0–52.5) development of BMs, months (range) Median time from the development of BMs 8.8 (1–53) to treatment start, months (range) Median number of prior trastuzumab-based 2 (1–5) therapies for metastatic disease (range) Extracranial metastases, n (%) No 1 (3.3) Yes 29 (96.7) Visceral metastases 23/29 (79.3) Number of BMs, n (%) >3 12 (40) £3 18 (60) Local treatment for BMs, n (%) None 4 (13.3) Radiotherapy (WBRT and/or SRS) 21 (70) Neurosurgery with WBRT and/or SRS 5 (16.7) First systemic option after the development of BMs, n (%) LC 6 (20) Trastuzumab-based therapy 24 (80) Trastuzumab + chemotherapy 21/24 (87.5) Trastuzumab + endocrine therapy 3/24 (12.5) ECOG PS, Eastern Cooperative Oncology Group performance status; ER, estrogen receptor; PgR, progesterone receptor; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemical; FISH, fluorescence in situ hybridization; BMs, brain metastases; SRS, stereotactic radiosurgery; WBRT, whole brain radiotherapy; LC, Lapatinib plus capecitabine.
BPFS was defined as the time from the start of LC to the date of documented brain progression or death in the absence of disease progression in the brain. The OS time was measured from the start of LC (OS1) and from the time of development of BMs (OS2) to the date of death for any cause. In the absence of brain progression or death, BPFS, OS1 and OS2 were censored at the time of the last visit. Time to event (BPFS, OS1 and OS2) was analyzed according to Kaplan–Meier method and survival curves were compared using the log-rank test. Given the retrospective nature of the study, statistical significance should be used in an exploratory view and median time estimation with their 95% confidence interval (CI) reported to better interpret the data. SPSS software version 17.0 was used for statistical analyses (SPSS Inc., Chicago, IL).
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patient population Using medical records, 81 patients with HER2+ metastatic BC who were treated with lapatinib (1250 mg orally once daily) plus capecitabine (1000 mg/m2 orally twice per day for days 1–14 every 3 weeks) until disease progression at two Italian institutions from June 2006 to September 2009 were identified. Retrospective chart review was approved by the institutional review boards of both institutions. HER2 positivity was determined locally and defined as immunohistochemical staining of 3+ (HercepTest Dako A/S; Glostrup, Denmark) or 2+ with evidence of gene amplification at fluorescence in situ hybridization (PathVision HER2 DNA probe kit; Vysis Inc., Downers Grove, IL). Of these 81 patients, 30 patients who had developed BMs confirmed by magnetic resonance imaging or computed tomography scan before the start of treatment with LC were eligible for analysis (Table 1). All 30 patients had received prior treatment with a taxane, an anthracycline and trastuzumab. No patient had previously received either lapatinib or capecitabine. Response of BMs, the brain-specific progression-free survival (BPFS) and the overall survival (OS) (from the start of LC) of these 30 patients treated with LC were evaluated. Patients were considered evaluable for response of BMs: (i) in the presence of progressive BMs, (ii) in the presence of one or more measurable BMs ‡1 cm in diameter, (iii) in case of prior neurosurgery residual disease had to be documented radiologically, (iv) if cranial radiotherapy (whole brain radiation therapy and/or stereotactic radiosurgery) had been completed ‡2 months before the start of LC. In a second step, the OS from the time of development of BMs of patients treated with LC was compared with the OS of 23 patients who were treated consecutively with trastuzumabbased therapies only beyond brain progression at our institutions in the pre-lapatinib era [13, 14].
Annals of Oncology
original article
Annals of Oncology
results patient characteristics The characteristics of the 30 patients with BMs treated with LC are reported in Table 1. Median age was 45 years (range 24–75) and 21 patients (70%) had a performance status 0–1. All patients had received prior trastuzumab-based therapies for metastatic disease. Twenty-six patients (86.5%) had received prior cranial radiotherapy for BMs. No local treatment had been delivered in four patients (13.3%). In six patients (20%),
LC was administered as first systemic option after the development of BMs.
clinical outcome of patients with BMs treated with LC The median follow-up time from the initiation of LC was 9 months (range 2–31). The median duration of treatment with LC was 4 months (range 2–25). Twenty-two patients were evaluable for response in the brain: 7 partial responses (31.8%) and 6 disease stabilizations (27.3%) were observed (Table 2).
Table 2. Activity of LC for BMs according to the local treatment delivered Best response for BMs
3 (75) 1 (25) —
Radiotherapy (WBRT and/or SRS) (n = 17), n (%)
Neurosurgery with WBRT and/or SRS (n = 1), n (%)
3 (17.6) 5 (29.4) 9 (53)
1 (100) — —
Total patients (n = 22), n (%) 7 (31.8) 6 (27.3) 9 (40.9)
BMs, brain metastases; SRS, stereotactic radiosurgery; WBRT, whole brain radiotherapy.
Figure 1. The case of a 55-year-old woman with two brain metastases (BMs) from HER2+ breast cancer responding to LC (A, B). No local treatment was delivered before the initiation of LC. Moreover, LC was administered as first systemic option after the development of BMs. Duration of response in the brain lasted 14 months (C, D) and BMs were still responding at the time of treatment discontinuation due to extracranial disease progression.
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Partial response Stable disease Progressive disease
Local treatment for BMs None (n = 4), n (%)
original article
responses after 5 and 21 months of treatment, respectively. The third patient discontinued LC after 14 months of treatment due to extracranial only progression of disease (Figure 1). All 30 patients were considered for the analysis of PFS, BPFS and OS from the start of LC (OS1): the median PFS was 5.1 months (95% CI 2.6–7.5) and the median BPFS was 5.6 months (95% CI 4.4–6.8) (Figure 2A). At the time of this analysis, 5 of 30 patients had not yet experienced either intra- or extracranial disease progression and are still receiving LC. In the remaining 25 patients, treatment was discontinued due to disease progression: 4 patients for extracranial-only disease progression and 21 patients for disease progression both at intra- and extracranial sites. Eighteen patients have died and the median OS from the start of LC (OS1) was 11 months (95% CI 4.3– 17.6) (Figure 2B). Treatments after LC in the 25 progressive patients were trastuzumab-based in 11 patients, chemotherapy without trastuzumab in 9 patients and symptomatic therapy only in 5 patients.
Figure 2. Patients treated with LC (n = 30): Kaplan–Meier estimates of median brain-specific progression-free survival (2A) and median overall survival from the start of LC (OS1) (2B). OS, overall survival.
Figure 3. Kaplan–Meier estimates of overall survival from the development of brain metastases (BMs) (OS2). Median OS2 in the 30 patients treated with LC was 27.9 months (95% CI 25.6–30.1) versus 16.7 months (95% CI 8.6-24.8) in the 23 patients treated only with trastuzumab-based therapy beyond brain progression (P = 0.01) (3A). In the six patients treated with LC as first systemic option after the development of BMs, median OS2 was not reached at a median follow-up of 26 months (range 5–71) (3B). OS, overall survival; CI, confidence interval.
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The median duration of brain response was 6 months (range 3–25): it was 18 months (range 7–25) in the three patients who had not received any prior local treatment for BMs, while it was 4.5 months (range 3–6) in the four patients who had received prior local therapy. At 6 months, 57% of responsive patients were alive and free from brain progression compared with 27% of patients with stable or progressive BMs (P = 0.02). At 1 year, 67% of responsive patients were alive compared with 33% of patients with stable or progressive BMs (P = 0.02). Response of BMs was related to the local treatment delivered prior to LC (Table 2): three responses (75%) and one disease stabilization (25%) in the brain were observed in the four patients who did not receive any local treatment for BMs. The three responding patients had £3 brain lesions and received LC as first systemic option after the development of BMs. At the time of the analysis, two of these three patients had not yet experienced disease progression, with confirmed brain
Annals of Oncology
original article
Annals of Oncology
discussion Due to their high incidence, BMs represent an important cause of morbidity and mortality in HER2+ metastatic BC patients. In our retrospective analysis, patients naı¨ve for both lapatinib and capecitabine reported a 31.8% of response rate in BMs according to WHO criteria. As single agents, lapatinib and capecitabine have shown to be active for BMs in patients with HER2+ disease [17, 18] or unselected for HER2 status, respectively [20, 21]. More in detail, an international phase II study, which enrolled 242 patients pretreated with trastuzumab and with progressive BMs after radiotherapy, showed only a 6% response rate in the brain (defined by composite criteria) for single-agent lapatinib, but a 20% response rate in the brain was observed in additional patients with radiographically documented CNS progression who had entered the LC extension phase of the study [18]. For this reason, it is likely that the LC combination might act synergistically against BMs. This hypothesis has been confirmed by the results reported in the LC expanded access programs: 18% of responses in the brain were reported by Boccardo et al. [22] and 21% of responses were observed by Sutherland et al. [23], despite the fact that prior capecitabine had been administered in 42% and 35% of patients, respectively. Interestingly, previous treatment with capecitabine reduced the objective response rate in the brain: in the Sutherland study, the rate of brain response was lower in patients previously treated with capecitabine (16.7%) compared with the capecitabine-naı¨ve group (30%) (P = 0.2) [23]. These results are close to the 31.8% of responses obtained in our analysis, which was conducted in a similarly naı¨ve population for both lapatinib and capecitabine. Nevertheless, this comparison is limited by the different criteria used for CNS response assessment (RECIST in the Sutherland study versus WHO in our experience). However, at the present time, there are no standard neurooncology criteria to evaluate response in BMs. To this regard, Lin et al. [18] employed a CNS composite
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Table 3. Characteristics of the 23 patients with HER2+ breast cancer treated only with trastuzumab-based therapy beyond brain progression Characteristics Median age, years (range) ECOG PS, n (%) 0 1 2 ER and/or PgR positive, n (%) HER2 positivity, n (%) IHC: 3+ FISH amplified Localized stage at initial diagnosis, n (%) Median time from initial diagnosis to the development of BMs, months (range) Median time from metastatic disease to the development of BMs, months (range) Median no. of prior trastuzumab-based therapies for metastatic disease, months (range) Extracranial metastases, n (%) No Yes Visceral metastases Number of BMs, n (%) >3 £3 Local treatment for BMs, n (%) None Radiotherapy (WBRT and/or SRS) Neurosurgery with WBRT and/or SRS First systemic option after the development of BMs Trastuzumab-based therapy Trastuzumab + chemotherapy Trastuzumab + endocrine-therapy
41 (32–70) 12 8 3 14 18 5 17 34.9
(52.2) (34.8) (13) (60.9) (78.3) (21.7) (73.9) (7–128)
10.3 (3–65) 1 (1–5)
1 (4.3) 22 (95.7) 20/22 (90.9) 14 (60.9) 9 (39.1) 3 (13) 19 (82.6) 1 (4.4) 23 (100) 20/23 (87) 3/23 (13)
ECOG, Eastern Cooperative Oncology Group; ER, estrogen receptor; PgR, progesterone receptor; IHC, immunohistochemical; FISH, fluorescence in situ hybridization; BMs, brain metastases; SRS, stereotactic radiosurgery; WBRT, whole brain radiotherapy; LC, Lapatinib plus capecitabine.
response criteria where CNS objective response was defined as ‡50% volumetric reduction of CNS in the absence of increasing steroid use, progressive neurological signs and symptoms or progressive extra-CNS disease. Remarkably, we observed three partial responses with LC in four patients who had not received any local treatment for BMs (Figure 1). This finding might suggest that systemic treatment with LC is active on BMs in patients who have not been previously treated with cranial radiotherapy. Continuation of anti-HER2 treatments in patients progressing during trastuzumab-based therapies is associated with improved clinical outcome in patients with HER2+ metastatic BC [16, 24–26]. Similarly, continuation of trastuzumab-based therapies beyond brain progression has been associated with an improvement in survival [13, 14, 27, 28], which appears to be mainly function of an increased control of extracranial disease [13, 14]. In a recent retrospective analysis, treatment with lapatinib after the development of BMs
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OS from the time of development of BMs At a median follow-up of 26 months (range 5–71) from the diagnosis of BMs, median OS from the time of the development of BMs (OS2) evaluated in all 30 patients treated with LC was 27.9 months (95% IC 25.6–30.1) (Figure 3A). Median OS2 was not reached in the 6 patients who received LC as first systemic option after the development of BMs, while it was 27.1 months in the 24 patients who received LC after at least one trastuzumab-based therapy following the development of BMs (Figure 3B). Two-year OS2 was 66% for responsive patients compared with 44% for patients with stable or progressive BMs (P = 0.11). Median OS2 of the 30 patients treated with LC was then compared with the median OS2 of 23 patients who received only trastuzumab-based therapies beyond brain progression [13, 14]. The characteristics of these 23 patients were similar to those of the LC group (Table 3). In patients treated with LC, median OS2 was significantly higher than that of patients treated only with trastuzumab-based therapies beyond brain progression (27.9 months versus 16.7 months, respectively, P = 0.01) (Figure 3A).
original article
disclosure The authors declare no conflict of interest.
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was one of the factors associated with prolonged survival from the diagnosis of BMs [7]. In our study, we reported a significantly longer OS from the development of BMs (OS2) for patients who had also received LC compared with a similar population treated only with trastuzumab-based therapies beyond brain progression (27.9 months versus 16.7 months; P = 0.01; Figure 3A). This highlights the potential impact of an additional anti-HER2 therapy with LC in patients with CNS progression on prior trastuzumab. Furthermore, the observation that the 2-year OS2 was higher in patients with responding BMs compared with those with stable or progressive CNS disease (66% versus 44%) provides evidence that the achievement of brain response is important for further improving the outcome of patients with BMs from HER2+ BC. Finally, the fact that patients who received LC as first systemic option after the development of BMs derived the greatest benefit from treatment (Figure 3B) might suggest that patients who develop BMs during trastuzumab-based therapies should undergo early initiation of LC in order to derive the greatest benefit from treatment. In conclusion, this retrospective analysis shows that LC is an active combination against BMs from HER2+ BC in patients naı¨ve for both lapatinib and capecitabine. Treatment with lapatinib and capecitabine after the development of BMs may further improve the prognosis of patients with BMs from HER2+ BC compared with the exclusive use of trastuzumabbased therapies beyond brain progression. This positive effect on survival can be at least in part attributed to the higher activity of LC on BMs compared with trastuzumab-based therapies beyond brain progression. Further evaluation of systemic strategies including LC in HER2+ BC patients with BMs is advocated.
Annals of Oncology