Target therapy in elderly breast cancer patients

Critical Reviews in Oncology/Hematology 83 (2012) 422–431

Target therapy in elderly breast cancer patients Paolo Carli a,∗ , Elisa Turchet b , Daniela Quitadamo b , Antonella Spada b , Gianmaria Miolo c , Elda Lamaj a , Simon Spazzapan a , Vincenzo Di Lauro a , Riccardo Dolcetti d , Andrea Veronesi a , Diana Crivellari a a

b

Division of Medical Oncology C, National Cancer Institute, Centro di Riferimento Oncologico via Franco Gallini 2, 33081 Aviano, Italy Biological Sc, Scientific Directorate, National Cancer Institute, Centro di Riferimento Oncologico via Franco Gallini 2, 33081 Aviano, Italy c Division of Medical Oncology B, National Cancer Institute, Centro di Riferimento Oncologico via Franco Gallini 2, 33081 Aviano, Italy d Cancer Bio-Immunotherapy Unit, National Cancer Institute, Centro di Riferimento Oncologico via Franco Gallini 2, 33081 Aviano, Italy Accepted 22 December 2011

Contents 1. 2. 3. 4. 5. 6. 7. 8. 9.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biologic aspect: targeting ER and HER2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Trastuzumab in the adjuvant setting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Trastuzumab in the metastatic setting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lapatinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Targeting HER2 and hormone receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Targeting VEGF: bevacizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Looking forward . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

422 423 423 425 425 426 427 428 428 429 429 429 431

Abstract Substantial progress has been made in the management of breast cancer by targeting HER2 and VEGF pathways. Although the efficacy and safety of target therapy in breast cancer have been established, no specific phase III trial has addressed these issues in the elderly population and the only data available derive from subanalyses or retrospective series. The aim of this review is to summarize the available evidence in this special population and to encourage further well designed studies in elderly breast cancer patients. © 2011 Elsevier Ireland Ltd. All rights reserved. Keywords: Elderly; Breast cancer; Bevacizumab; Trastuzumab; Lapatinib

1. Introduction Breast cancer is the leading contributor to cancer incidence among women in Europe and in the United States. ∗

Corresponding author. Tel.: +39 0434659214. E-mail address: [email protected] (P. Carli).

1040-8428/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2011.12.004

Two thirds of all newly diagnosed breast cancer are older than 55 years and the peak incidence occurs in women aged 70–74 years [1]. Late mortality depends in a large part also from the impact of comorbidities in older patients. In the USA, as in most western countries, hypertension, diabetes, mental disorders and obesity are common in aging patients and have prevalence rates of about 46%,

P. Carli et al. / Critical Reviews in Oncology/Hematology 83 (2012) 422–431

20%, 31% and 6%, respectively in breast cancer patients [2,3]. Several studies demonstrate an association between cancer, comorbidities and outcome. In a longitudinal observational study carried out in the Detroit metropolitan area among women aged 40–84 years, patients with 3 or more comorbidities had a 20-fold higher rate of mortality from causes other than breast cancer and a 4-fold higher rate of all-cause mortality when compared to patients without comorbidity [4]. The hazard ratio for dying for patients with high grade comorbidities was almost 3 times higher in a study conducted in Holland by Houterman et al. [5]. In stages I and II breast cancer, according to the experience of Yancik, age was a statistically significant determinant of decreased survival. Concomitant renal failure, liver disease and stroke or transient ischemic attack increased the risk ratio by 2-fold or greater as compared with patients without these comorbidities. In patients older than 75 years old (y/o), fewer than half the deaths in the first 30 months period of follow-up were due to breast cancer. On the contrary, age group was not a statistically significant determinant of survival in stages III and IV [1] where probably the bulk of disease plays a major role. Huge effort has to be made to coniugate knowledge of treatment options with the best choice for the specific patient, otherwise the risk of under or over treatment is consistent [6]. In a retrospective MD Anderson Cancer Center study overall and disease free survival were not significantly associated with frequently observed undertreatment in older than 80 years old breast cancer patients with respect of treatment recommendation for stage. However, when stratified by treatment administered, outcomes of hormonal therapy only versus combined chemo-endocrine therapy and of partial mastectomy without radiation treatment versus the combination of them were inferior in terms of disease specific survival and local regional recurrence, respectively [7]. In France one institution reported a significant influence (82%) of a comprehensive geriatric evaluation on treatment decision when it was performed in older than 70 y/o patients [8]. Anyway these results were not confirmed by other institutions [9]. In France pilot units for oncogeriatric coordination emerged and were incorporated into the national cancer control strategy [10]. There were few trials that specifically evaluated comorbidities and outcome in elderly breast cancer patients. Data from large cooperative groups have shown that only 22–36%, 65 years of age or older, participates in trials for cancer therapy even though they represent nearly 60% of the population with cancer [11,12]. With the advent of the new approaches of the so called target therapies, new ways of treatment have opened. The aim of this review is to discuss efficacy and safety of available target based therapy in elderly breast cancer patients.

423

2. Biologic aspect: targeting ER and HER2 Several studies pointed to an association between increasing age and a favorable histologic profile. From a joint analysis from SEER and San Antonio database in patients 55 y/o or older with a diagnosis of invasive breast cancer, more tumors express steroid receptors, have lower proliferative rates, diploidy, normal p53, and do not express epidermal growth factor receptor and HER2 [13]. A reduced aggressiveness of disease with advancing age was demonstrated by a tissue microarray analysis of 575 breast cancer tissue of over 70 y/o patients. An increased expression of ER and cell differentiation markers and a decreased expression of proliferation markers were observed in this elderly population, comparing the expression of ER, PR, HER4, E-cadherin, p53, CK (5/6, 7/8, 14, 17, 18 and 19), BRCA1, Ki67, MUC1, HER2 with data derived from younger patients (<70 y/o) [14]. Unfortunately, about 20% of patients present with aggressive features with a lower rate of response to endocrine therapy [15]. In general HER expression is associated with a poorer response to hormone treatment. A higher risk of relapse in HER2+ breast cancer, independently of the type of endocrine adjuvant therapy used, was observed by translational research data in ATAC and in BIG 1–98 trials [16,17]. At the Breast Center, Baylor College of Medicine in the United States, it was possible to review the outcome from more than 50,000 early breast cancer patients. Among patients treated with Tamoxifen only, HER1 or HER2 positive status confers a higher risk of recurrence than that noted in patients with HER1, HER2 negative tumors. A higher risk of death was observed only in HER2+ versus HER2 negative tumors [18]. There are many ways to interact with HER2 but the main two available are Trastuzumab and Lapatinib. Trastuzumab, the most effective target therapy developed in breast cancer so far, is a monoclonal antibody directed towards the extracellular domain of HER2. Its mechanism of action has not yet been fully determined and may involve the inhibition of HER2 shedding and of PI3K-AKT pathway, attenuation of cell signaling, antibody dependent cellular cytotoxicity and inhibition of tumor angiogenesis [19]. Lapatinib is an orally available small molecule, reversible inhibitor of both EGFR and HER2. It works intracellularly, directly targeting the TK domain and preventing receptor phosphorylation and activation. Thanks to its ability to bind also to the truncated form of HER2 that lacks the extracellular domain, Lapatinib might be active in HER2+ tumors that are resistant to Trastuzumab [20].

3. Trastuzumab in the adjuvant setting Six large randomized trials (NSABP B31 and N9831 [21], HERA [22], BCIRG 006 [23], FINHER [24], PACS04 [25]) were designed to test the role of Trastuzumab as adjuvant therapy after surgical treatment. Despite differences in patient populations and design, all these studies apart from

Over 60 All

0.64 (0.54–0.76) p < 0.0001 0.48 (0.39–0.59) p < 0.0001 0.61 (0.37–0.65) p < 0.0001; 0.67 (0.47–0.79) p 0.0002 0.42 (0.21–0.83) p = 0.001 0.86 (0.61–1.22) p = 0.41 Anthra CT → Obs; Tx12 mos; Tx24 mos ACx4 → Px4(w12); ACx4 → Px4(w12) → T; ACx4 → PTx4(w12) → T ACx4 → Dx4 → Obs; ACx4 → Dx4 + T(w52); DCTx6 → T(w up to 1 year) Dx3 or Vinx9 + T(w9) → FECx3; Dx3 or Vinx9 → FECx3 FECx6 or EDx6 → Obs; T 544 (16%) 535 (16%) NR NR NR HERA [26] 5102 NSABP-B31/N9831 [21] 3351 BCIRG 006 [23] 3222 FinHER [24] 232 PACS-04 [25] 528

DFS HR (95% CI) Arms Over 60 Pts all Study

one (PACS trial) showed similar results, namely a significant improvement of disease free survival, with a hazard ratio (HR) of 0.46–0.67 for women receiving Trastuzumab. Only PACS trial did not demonstrate any benefit from Trastuzumab following adjuvant antracycline based chemotherapy with or without docetaxel. A possible reason is that is an underpowered study [25]. Study design, main characteristics of patients and outcome have been outlined in Table 1. There was no evidence of substantial heterogeneity in the relative treatment effect on disease free survival in HERA trial and in the joint NSABP-B31/N9831 also for patients older than 60 years [21,26]. Age (≤40 vs. >40) was not an independent predictor of risk of early recurrence in HERA trial [27]. Cardiotoxicity was the major side effect emerged during Trastuzumab therapy even if in all these trials patients with history of cardiac heart failure, cardiomyopathy, myocardial infarction, angina or arrhythmia or poorly controlled hypertension were excluded. In NSABP B-31, NCCTG N9831 and in HERA trial the cumulative incidence of a cardiac event (CE) defined as New York Heart association (NIHA) class III/IV congestive heart failure (CHF) were about 3.8%, 3.0%, 0.6% in the Trastuzumab arm versus about 0.9%, 0.3%, 0% in the control arm [28]. The reported number of cardiac deaths in patients treated with Trastuzumab was 0 in HERA trial [26], 1 in NCCTG N9831 and 0 in NSABP B-31 [21]. Update of the cardiac safety data after a median follow-up of 5 years in NSABP B-31 [29] demonstrated that the cumulative incidence of CEs with Trastuzumab did not increase. The great majority of cardiac adverse events were reported within 1 year in N9831 trial at 3 year safety cardiac analysis [30]. In HERA trial and in the joint analysis of NSABP B-31 and NCCTG N9831 only 16% of patients were older than 60 years. However, some risk factors for Trastuzumab related cardiotoxicity have been identified in age >50 y/o (in >60 y/o the risk is about 5%), namely need for hypertension medication at entry (risk about 5%), and baseline LVEF (left ventricular ejection fraction) within the normal range but <55% (3 years cumulative risk was 14.5% in the NSABP B-31 and about 5% in the NCCTG N9831) [28]. Higher cumulative doses of Doxorubicin, a lower screening LVEF and a higher body mass index were risk factors for cardiac dysfunction in HERA trial [31]. The majority of patients recovered from cardiac toxicity. However, in NSABP B-31 15% of patients who underwent a CE, followed for at least 6 months remained symptomatic for CHF and 60% remained on medication [28]. In HERA trial 20% remained symptomatic [31]. With these data in mind, a phase 3 randomized trial of The Breast Cancer International Research Group (BCIRG 006 study) was designed to assess the role of anthracyclines and Trastuzumab in early HER2+ breast cancer patients and, most important, if it was possible to avoid anthracyclines by using a Carboplatin-Taxotere (TC) regimen. No statistically

0.91 (0.59–1.41) 0.41 (0.24–0.68) NR NR NR

P. Carli et al. / Critical Reviews in Oncology/Hematology 83 (2012) 422–431 Table 1 Trastuzumab adjuvant phase III trials: principal characteristics and clinical outcome: Anthra (anthracycline); T (Trastuzumab); A (Adriamycin); C (Cyclophospamide); P (Paclitaxel); D (Docetaxel); DC (Docetaxel plus Carboplatin), Vin (Vinorelbine), F (5-fluorouracil), E (Epirubicin), Obs (observation), w (weekly), NR (not reported), CT (chemotherapy).

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P. Carli et al. / Critical Reviews in Oncology/Hematology 83 (2012) 422–431

significant difference in hazard ratio for disease free survival was observed between the two Trastuzumab containing regimens even though a better hazard ratio for disease free survival was achieved with AC-TH arm. Cardiac toxicity was significantly lower in the TCH arm compared with the ACTH arm (8.6% patients with >10% relative decline in LVEF compared with 18% in the AC-TH arm; p = 0.0001). These results suggest that the clear advantage of TCH relative to AC-TH in terms of reduced cardiac toxicity may be offset by a small reduction in efficacy [23]. No data are reported unfortunately in order to understand if older patients experienced different and more severe toxicities. As recommended by SIOG guidelines, in the absence of cardiac contraindications, adjuvant Trastuzumab should be offered to older patients with HER2-positive breast cancer when chemotherapy is indicated, but cardiac monitoring is essential [32].

4. Trastuzumab in the metastatic setting A pivotal and landmark phase III study randomized 469 patients to receive CT (either paclitaxel or antracycline based chemotherapy) alone or concomitant with Trastuzumab and demonstrated an improved survival in the Trastuzumab arm, despite a crossover design that resulted in 65% of control patients receiving Trastuzumab at disease progression (HR 0.80; p = 0.046). In this trial patients treated with concurrent antracyclines and Trastuzumab experienced a cardiac adverse event at a rate of 27% compared with 8% in patients treated with the antracyclines combination alone, an unacceptable toxic rate in a palliative treatment setting. Conversely, paclitaxel combination was well tolerated and time to disease progression was significantly higher in the Taxol plus Trastuzumab arm (6.9 vs. 3 months, HR 0.38; 95% CI 0.27–0.53) [33]. In a sub-analysis of this trial the survival benefit seen with the addition of Trastuzumab was maintained in patients older than 60 y/o. In the group >60 y/o, the addition of Trastuzumab to chemotherapy improved response rate (RR) from 28% to 44% and median overall survival (OS) from 14 to 19 months. Cardiac dysfunction in the Trastuzumab plus Taxol arm occurred in 11% of the <60 y/o vs. 21% of the >60 y/o [34]. The benefit of Trastuzumab added to chemotherapy in first line metastatic breast cancer (MBC) was confirmed in another phase II trial comparing Trastuzumab plus docetaxel versus docetaxel alone in terms of RR (61% vs. 34%; p = 0.0002), OS (median 31.2 vs. 22.7 months; p = 0.0325), time to disease progression (median 11.7 vs. 6.1 months; p = 0.0001) [35]. Other trials have explored the optimal chemotherapy regimen with Trastuzumab in first line MBC. No one study has demonstrated a clear advantage in OS. Vinorelbine versus docetaxel combination with Trastuzumab showed no difference in median time to treatment progression (TTP) (12.4 vs. 15.3 months, HR 0.94; 95% CI 0.71–1.42; p = 0.67) [36].

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More treatment related grades III–IV febrile neutropenia, neuropathy, nail changes were reported with docetaxel. Considering 108 pts over 60 y/o no differences were reported in TTP, however the better toxicity profile of vinorelbine should be emphasized when treating an elderly population. Addition of Capecitabine [37] but not of Carboplatin [38] to docetaxel plus Trastuzumab showed an improvement in progression free survival (PFS) (median PFS 17.9 vs. 12.8 months, HR 0.72; 95% CI 0.53–0.99; p = 0.045). Carboplatin added to paclitaxel and Trastuzumab showed better PFS (13.8 vs. 7.6 months; p = .005; HR 0.55; 95% CI 0.46–0.64) [39]. Unfortunately no sufficient data on elderly patients were collected. At least three retrospective analyses, as shown in Table 2, have ruled out an excess of cardiac toxicity with Trastuzumab combination chemotherapy in elderly patients. Median duration of treatment with Trastuzumab was longer than 8 months in all these experiences. High frequency of relevant cardiovascular risk factors in elderly MBC patients were registered in one multicenter Italian experience [40]. Only one of these series reported an association between Trastuzumab cardiotoxicity and diabetes, BMI > 30, previous cardiac disease [41]. More data are needed to better define the role of Trastuzumab in elderly population, however age by itself should not be enough to deny Trastuzumab treatment.

5. Lapatinib The combination of Lapatinib plus paclitaxel versus paclitaxel alone used in a phase III trial (EGF30001) [42] in unknown or HER2+ MBC patients in first-line therapy demonstrated an advantage in TTP, event free survival and OS only in a subset analysis performed in HER2+ patients (n = 86). The most convincing results were derived from an openlabel phase III trial (NCT78572) [43] including 324 women with HER2+ MBC, progressing after antracyclines, taxanes and Trastuzumab. Patients were randomized to receive Lapatinib plus Capecitabine or Capecitabine alone. At the first preplanned statistical analysis a significant benefit of Lapatinib plus Capecitabine has been demonstrated (median TTP 8.4 months in the combination arm versus 4.4 months in the control arm, HR 0.49; 95% CI 0.34–0.71, p < 0.001). Thereafter crossover was allowed and a significant OS advantage [44] was not observed (median OS 75 weeks in the combination arm vs. 64.7 weeks in the monotherapy arm, HR 0.87; p = 0.210). No efficacy subgroup analysis in elderly patients has been performed [43,44]. In our experience in 68 patients (10 of them aged 65 years or more) that received a total of 608 cycles the only grade 4 hematological toxicity was noted in a patient 65 years old, the same patient experienced grade 3 diarrhea and stomatitis and refused further treatment [45]. In EGF30001 Lapatinib combined with paclitaxel was associated with a 2.7% incidence of fatal adverse events (AEs), mainly sepsis associated with diarrhea compared with

19 30.6 NR NR A/EC or P 13 Taxanes, 2 Vin, 6 no CT NR Taxanes 56%, Vin 36% NROver 60 72 75.7 73

NR 7.8 NR 8.7

Median OS Median TTP T plus CT Median age

a 0.6% incidence in the paclitaxel-placebo arm. Most of these events occurred early in the accrual period and decreased sharply thereafter. Increased experience treating these AEs and the introduction of a proactive guideline for managing Lapatinib related diarrhea likely contributed to a better safety profile [42,46,47]. In the Capecitabine plus Lapatinib arm of NCT78572 the most common side effects were diarrhea (grades III and IV 13%), hand-foot syndrome (grades III and IV 7%), nausea (grades III and IV 2%), vomiting (grades III and IV 2%), fatigue (grades III and IV 2%) and rash (grades III and IV 1%). Most adverse events were grades I–III. There were no symptomatic CEs and Lapatinib was not discontinued because of a decrease in the LVEF. However, asymptomatic CEs were identified in 4 women (2%) in the combination treatment and in only one women in the control arm (0.006%) [43]. In a pooled analysis of 3689 patients enrolled in clinical trials (25 phase I, 13 phase II, and 6 phase III) a CE was reported in 60 patients. Median age (60 y/o) and known cardiovascular risk factors were similar to the entire population. There were no obvious trends that might be predictive for decreased LVEF. The decrease in LVEF was rarely severe and 88% had a partial or full recovery [48]. An analysis of diarrhea events, derived from 11 clinical trials (phases I, II, or III) in patients with metastatic cancer treated with Lapatinib, outlined a greater incidence of grade III diarrhea AEs in elderly (over 70 y/o) MBC patients (33% vs. 19% in patients younger than 70 years) [49]. Unfortunately this population is at major risk of dehydration, renal deficiency and infection and greater attention should be paid in managing this side effect. Although no studies were identified that specifically enrolled elderly patients, 17% of patients in clinical trials of Lapatinib plus Capecitabine in MBC were aged ≥65 years, and 1% were aged ≥75 years. The effectiveness and tolerability of Lapatinib did not appear to be affected by age, although increased sensitivity in some older individuals cannot be ruled out [50].

N. of pts

109 21 20 MBC10 early BC 50 Fyfe [34] Bernardi et al. [73] Serrano et al. [41] Brunello et al. [40]

6. Targeting HER2 and hormone receptors

Authors

Table 2 Principal evidence of efficacy and safety of Trastuzumab in elderly MBC.

21% cardiac disfunction 10% LVEF drop, 5% pulmonary hypertension, 5% IMA 16.6% LVEF drop 13.5% symptomatic cardiac failure 9% LVEF drop

P. Carli et al. / Critical Reviews in Oncology/Hematology 83 (2012) 422–431

Major toxicity

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Due to the evidence of a cross-talk between epidermal growth factor receptor and hormone receptor pathways, Lapatinib [51] and Trastuzumab [52] were studied in first line MBC in two phase III trials, combined with Letrozole and Anastrozole, respectively. The combination of AI and HER2 inhibitors was generally well tolerated and no unexpected major side effects were registered. In the experimental arm progression free survival was improved in both studies in HER2+ MBC as shown in Table 3. In the same populations no statistically significant survival advantage has been reached. Median age in these trials was 62 in Letrozole plus Lapatinib trial and 55 in Trastuzumab plus Anastrozole trial. No

NR NR 0.90 (0.77–1.05) p = 0.188 NR

NR

0.74 (0.5–1.1) p = 0.113 33.3 32.3 0.71 (0.53–0.96) p = 0.019 8.2

HR 95% CI Exp arm

28.5 23.9

Control arm HR 95% CI

0.63 (0.47–0.84) p = 0.0016

Exp arm

7. Targeting VEGF: bevacizumab

4.8

Control arm

427

data can be derived regarding the elderly population subgroup.

2.4 HER2+ 3.0 HER2− NR 207/0 219/952 Ana vs T + Ana Le vs Le + La TanDem [52] EGF3008 [51]

OS (months) Median PFS (months) N. of pts HER2+/− Arm

Table 3 Principal evidence of efficacy of endocrine therapy combined with anti-HER2 therapy. Ana (Anastrozole), Le (Letrozole), La (Lapatinib), Exp (experimental).

p = 0.325

P. Carli et al. / Critical Reviews in Oncology/Hematology 83 (2012) 422–431

Bevacizumab is a humanized monoclonal antibody that specifically inhibits vascular endothelial growth factor (VEGF), a key mediator of angiogenesis [53]. Its efficacy was tested in first line MBC phase III AVADO [54], RIBBON1 [55] and E2100 [56] trials and in second/third line MBC in Miller’s [57] and in RIBBON2 [58] trials. The main characteristics and results of these trials are outlined in Table 4. In each trial a statistically significant improvement in PFS in favor of the Bevacizumab 15 mg/kg q21 days or 10 mg/kg q14 days experimental arm was demonstrated except for the study of Miller in second line. In first-line line a 23–40% reduction in the risk of disease progression was achieved with Bevacizumab combination. With respect to age (>65 y/o), hormonal status (triple negative vs. others), visceral involvement Bevacizumab maintained its benefit in PFS [59]. Although no significant gain in OS was noted, a higher percentage of patients was alive at the first year in Bevacizumab containing arm in AVADO (84% vs. 76%), E2100 (81% vs. 74%) and RIBBON1 Capecitabine cohort (81% vs. 74.4%) [59]. Of note, one 91 years old patient was treated. In RIBBON1 trial 153 patients ≥65 years were treated in arm A (Capecitabine cohort) and 124 in arm B (taxane/anthracycline cohort). Reported median PFS was 6.2 versus 4.7 months in younger patients in arm A and 8.5 versus 7.9, respectively in arm B [55]. In a joint sub-analysis of these 3 trials, patients over 65 y/o (n = 530) experienced an improvement both in median PFS from 6.9 to 9.9 months (HR 0.67%; 95% CI 0.52–0.85) and in RR from 25.5% to 32.9% in Bevacizumab arm. No advantage was noted in 1 year survival rate (73%). Hypertension was more frequent in experimental arm (11.8% vs. 3.9%) and in the same range of younger patients. Grades III–V AEs were observed in 53.4% of patients in the chemotherapy only cohort versus 65.6% of patients in the chemotherapy plus Bevacizumab group [60]. A report of the incidence and spectrum of Bevacizumab related side effects in elderly came from a large open label study in first line Bevacizumab plus taxane-based chemotherapy in a broad patient population, more closely reflecting general oncology practice. Active hypertension and diabetes were present in 48.6% and 10.6% of over 70 y/o MBC patients. Similar efficacy in different age subgroups was found through a subanalysis of 175 patients ≥70 y/o. Hypertension and proteinuria were the only grade III side effects reported more frequently in the elderly than in the younger cohort. No relationship between baseline hypertension and the presence or severity of hypertension during Bevacizumab containing therapy was found. Nevertheless, grade ≥III

0.775 (NR) p = 0.0072 5.1/7.2 NR 684

462 (26% HER2+)

1st chemonaive locally HER2+/neg rec.; MBC MBC post Anthra, taxanes, T if HER2+, no more than 2 lines for MBC MBC, pure II line, HER2 neg.

722

D, P, NabPacl, G, Vin, Cap+/−Bev15 mg/kg q21 or 10 mg/kg q14

0.98 (0.77–1.25) p = 0.857 4.17/4.86 Cap+/− Bev 15 mg/kg q21

5.9/11.8 P+/− Bev 10 mg/kg q14

5.7/8.6

55/55 25% 57/56 20% 55/56 20%; (1% HER2+) 52/51 NR 1237

D, NabPacl or AC, EC, FEC+/−Bev 15 mg/kg q21 Cap+/−Bev 15 mg/kg q21

8/9.2

DBev 15 mg/kg q21 0.77 (0.64–0.93) p = 0.006 0.64 (0.52–0.80) p < 0.001 0.69 (0.56–0.84) p < 0.001 0.60 (0.51–0.70) p < 0.001 D 8.2; DBev (7.5 mg/kg) 9; DBev (15 mg/kg) 10.1 55/55 17% 736 1st line chemo naive HER2 neg locally rec.; MBC

D; DBev 7.5 mg/kg q21; DBev 15 mg/kg q21

HR (95% CI)

adverse events occurred in 60% of elderly patients and 54% of the younger group (≤70 y/o). Bevacizumab was discontinued in the ≥70 versus <70 subgroup because of arterial or venous thromboembolism in 2.9% and 1.8% of patients, respectively. Interestingly, these side effects occurred at grade ≥III in only a small fraction of the population (0.6% over 70 years), suggesting that Bevacizumab was cautionally discontinued for grade I or II events [61]. Based on this favorable toxicity profile, age should not preclude Bevacizumab containing regimens although a complete geriatric assessment should be performed.

8. Looking forward Translational research is driving treatment choices and drug development. Luminal A and B breast cancer patients have recently shown a 60–70% partial response in the neoadjuvant setting after treatment with aromatase inhibitors alone [62]. Everolimus significantly increased Letrozole efficacy in the neoadjuvant therapy of patients with ERpositive breast cancer, targeting the cross-talk between the estrogen receptor (ER) and the phosphoinositide-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways [63]. Multiple blockade of HER2 pathway is promising [64]. The combination of Trastuzumab and Lapatinib with chemotherapy achieved a 51.3% pathological complete RR in HER2+ BC without major toxicity during neoadjuvant treatment. These results were significantly superior to Trastuzumab (29.5%) or Lapatinib (24.7%) combined with chemotherapy [65]. In the same setting Trastuzumab plus Pertuzumab, a monoclonal antibody directed towards the HER2 dimerization domain, achieved a 18% of pathologic complete responses [66]. In Trastuzumab pretreated HER2+ MBC the same combination yielded a 50% clinical benefit rate [67]. Neratinib, an irreversible inhibitor of HER2 and EGFR demonstrated a 26% overall RR in previously treated Trastuzumab patients and a 77% in a Trastuzumab naïve cohort in a phase II trial, prompting the development of several phase III trials [68]. T-DM1, an antimicrotubule agent (a derivative of maytansine) conjugated with Trastuzumab, had 25.9% objective RR in patients previously treated with Trastuzumab [69] and appears particularly attractive due to its low toxicity profile. No safety and efficacy data of these new treatments have been reported in the subgroup of elderly population.

RIBBON2 [58]

Miller [57]

E2100 [56]

RIBBON1 [55]

9. Conclusion

AVADO [54]

Median age con/Exp; pts ≥ 65 N. of pts Population

Drug tested

Median PFS Con/Exp Arm (months)

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Trial’s name or first author

Table 4 Bevacizumab (Bev) phase III trials: study design and outcomes. Con (control), Exp (experimental), NabPacl (nabpaclitaxel), rec (recurrence), G (gemcitabine), Cap (capecitabine).

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High quality translational research and target therapy have allowed huge progress in the treatment of breast cancer. Elderly breast cancer patients should not be discriminated and should have the opportunity to be treated with target therapies as their younger counterparts. It has been pointed

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out that quality of life and functional status of the patients should be assessed in clinical trials as well as if possible also in daily clinical practice in all older patients, beside the classical endpoints and these informations should help to identify those women who may derive benefit reducing the risks of serious adverse events and preventing increase in the costs of treatment [70]. Whether frail or vulnerable breast cancer patients may equally be treated with these very expensive drugs remains a matter of debate as they probably have the higher risk to have serious toxic effects that may finally prevent them to obtain eventual benefits [71]. Strong collaboration between oncologist, gastroenterologists, cardiologists and geriatricians is needed in the clinical-decision making process and mainly in the continue evaluation of the treatments [47,72]. Reviewers Silvia Dellapasqua, M.D., European Institute of Oncology, Via Ripamonti 435, Milan IT-20141, Italy. Jean-Philippe Spano, MD, PhD, Medical Oncology, PitieSalpetriere Hospital, 47 bld de l’Hopital, Paris 75 013, France. Conflict of interest statement All authors disclose any financial and personal relationships with other people or organisations that could inappropriately influence (bias) their work. References [1] Yancik R, Wesley MN, Ries LA, et al. Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older. JAMA 2001;285:885–92. [2] Zhang S, Ivy JS, Payton FC, Diehl KM. Modeling the impact of comorbidity on breast cancer patient outcomes. Health Care Manage Sci 2010;13:137–54. [3] Girones R, Torregrosa D, Diaz-Beveridge R. Comorbidity, disability and geriatric syndromes in elderly breast cancer survivors. Results of a single-center experience. Crit Rev Oncol Hematol 2010;73: 236–45. [4] Satariano WA, Ragland DR. The effect of comorbidity on 3-year survival of women with primary breast cancer. Ann Intern Med 1994;120:104–10. [5] Houterman S, Janssen-Heijnen ML, Verheij CD, et al. Comorbidity has negligible impact on treatment and complications but influences survival in breast cancer patients. Br J Cancer 2004;90:2332–7. [6] Protiere C, Viens P, Rousseau F, Moatti JP. Prescribers’ attitudes toward elderly breast cancer patients. Discrimination or empathy? Crit Rev Oncol Hematol 2010;75:138–50. [7] Van Leeuwen BL, Rosenkranz KM, Feng LL, et al. The effect of undertreatment of breast cancer in women 80 years of age and older. Crit Rev Oncol Hematol 2011;79:315–20. [8] Chaibi P, Magne N, Breton S, et al. Influence of geriatric consultation with comprehensive geriatric assessment on final therapeutic decision in elderly cancer patients. Crit Rev Oncol Hematol 2011;79: 302–7.

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Biography Dr. Carli is a physician specialized in medical oncology. His principal scientific interest is clinical research in breast cancer and he is working at the Division of Medical Oncology C, Centro di Riferimento Oncologico, National Cancer Institute, Aviano, Italy. He recently took part in a translational research unit visit in “Circulating endothelial cells and progenitors as biomarkers in anti-angiogenic therapy of cancer” at The European Institute of Oncology with Dr. Bertolini in Milan, founded by ESMO.