Meeting Highlights
2013 San Antonio Breast Cancer Symposium Valentina Rossi, Rossella Martinello, Caterina Aversa & Filippo Montemurro†
1.
Introduction
2.
Early, human epidermal growth factor 2-positive breast
†
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Fudan University on 05/14/15 For personal use only.
cancer 3.
Triple-negative breast cancer
4.
Addition of ramucirumab to chemotherapy in metastatic, HER2-negative breast cancer
5.
Chemoprevention with anastrozole
6.
Meta-analysis of the effects of bisphosphonates on survival outcomes in patients with early breast cancer
7.
Expert opinion and conclusion
Institute of Candiolo (IRCCs), Fondazione del Piemonte per L’Oncologia, Unit of Investigative Clinical Oncology, Candiolo, Italy
The San Antonio Breast Cancer Symposium is considered by researchers and physicians involved in breast cancer management as one of the most important international events on the subject. A dense program of plenary presentations of novel findings, main lectures, poster discussions and displays, it encompasses all the aspects of the rapidly evolving field of breast cancer research and treatment. This article briefly summarises some of the presentations that are expected to have an impact on the medical treatment of breast cancer. Keywords: aromatase inhibitors, bevacizumab, bisphosphonates, breast cancer, carboplatin, human epidermal growth factor 2, lapatinib, trastuzumab, triple negative breast cancer Expert Opin. Pharmacother. (2014) 15(8):1191-1195
1.
Introduction
This article will highlight some of the results presented at the 2013 San Antonio Breast Cancer Symposium which, in our opinion, are expected to have an impact both on patterns of treatment and on future research in the field of breast cancer.
Early, human epidermal growth factor 2-positive breast cancer
2.
Event-free survival results of the neo-adjuvant lapatinib and trastuzumab treatment optimisation trial
2.1
In operable breast cancer patients, comparing pathological complete remission (pCR) rates between two treatments administered preoperatively requires smaller sample sizes and shorter observation periods than those required in the classical adjuvant studies aiming at event-free survival (EFS) and overall survival (OS). For this reason, the preoperative setting is looked at as a potential platform for the accelerated approval of novel treatments in the setting of operable breast cancer [1]. However, the minimum increase in pCR rate that results in a difference in long-term outcomes between two treatments that are being compared has not yet been defined. Piccart-Gebhart et al. presented the follow-up results of the neo-adjuvant lapatinib and trastuzumab treatment optimisation (NEO-ALTTO) trial, where 455 patients with early, human epidermal growth factor 2 (HER2)-positive breast cancer were randomised to chemotherapy with trastuzumab, lapatinib or both agents [2]. In this study, compared with single agent trastuzumab, the combination of both antiHER2 drugs resulted in an absolute increase in pCR rates of 19 and 25% in women with hormone receptor-positive and -negative tumours, respectively. At a median follow up of slightly < 4 years, the significant pCR increase did not translate into a statistically significant EFS or OS advantage. A nonsignificant trend towards improved EFS (hazard ratio [HR] = 0.65, p = 0.22) was seen in the hormone receptor negative subset.
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No role for bevacizumab added to chemotherapy and trastuzumab
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2.2
The bevacizumab with trastuzumab adjuvant therapy in HER2-positive breast cancer (BETH) trial randomised about 3500 patients with operable, HER2-positive tumours to chemotherapy and trastuzumab with or without bevacizumab [3]. At a median follow up of 38 months, neither invasive diseasefree survival (IDFS) nor OS were improved by the addition of bevacizumab, which resulted in increased toxicity. An interesting finding was that the 3-year IDFS in the conventional arm was higher than expected (92%, identical to that of the experimental arm). This probably reflects a better prognostic profile of patients who are currently enrolled in adjuvant studies, compared to those who were treated in the pivotal trials. Indeed, for example, about 50% of patients enrolled in the BETH trial had lymph node-negative disease, compared to 0 -- 30% of those enrolled in the pivotal adjuvant trials. Meta-analysis in small, HER2-positive operable tumours
2.3
The outcome of patients with small (T < 2 cm), HER2positive tumours was studied in a meta-analysis that included women enrolled in the trastuzumab-containing arms of five of the pivotal adjuvant trials [4]. The main finding of this meta-analysis was that small, hormone receptor-positive tumours, with 0 or 1 positive axillary lymph node had an excellent clinical outcome (5-year DFS and OS of 91 and 97%, respectively). These high survival figures suggest that, in this patient category, further meaningful improvements with more potent strategies (i.e., double-targeting or more chemotherapy) are unlikely. Adjuvant paclitaxel and trastuzumab in small HER2-positive tumours
2.4
Tolaney et al. reported the results of a large, Phase II trial of adjuvant chemotherapy with weekly paclitaxel and trastuzumab (80 mg/m2/week and 4 mg/kg, followed by 2 mg/kg, respectively) administered for 12 weeks, followed by 13 administrations of 3-weekly trastuzumab (6 mg/kg) [5]. The target population consisted of patients with axillary lymph node-negative tumours < 3 cm and 50% of the enrolled patients had pT1a and pT1b tumours. At a median follow up of 3.6 years, 10 patients experienced a disease relapse, which was a distant metastasis in two patients only. The 3-year DFS rate was 98.7%, and approached 100% for pT1a/b tumours (99.5%). 3.
Triple-negative breast cancer
Carboplatin added to neoadjuvant chemotherapy in triple-negative breast cancer
3.1
Because high proliferation and genomic instability are common features of hormone receptor-negative, HER2-negative 1192
(triple-negative) breast cancers (TNBC) [6], DNA damaging agents such as platinum compounds and antiangiogenic drugs may be active in this subset of breast cancers. The Cancer and Leukaemia Group B (CALGB) 40603 clinical trial adopted a 2 2 factorial design to evaluate the addition of carboplatin (AUC 6 every 3 weeks), bevacizumab (10 mg/m2 every 2 weeks) or both agents to a sequence of weekly paclitaxel followed by dose-dense doxorubicin and cyclophosphamide administered as neoadjuvant chemotherapy in women with stage II -- III, non-inflammatory TNBC [7]. The primary end point was pCR rate in the breast and the study was not powered to detect survival differences. In the 427 women who underwent surgery, both bevacizumab (48 vs 59%) and carboplatin (46 to 60%) were associated with a significant increase in pCR rates. However, only carboplatin increased the pCR rate significantly in both the breast and the axilla (from 41 to 54% overall, and from 39 to 49% in the chemotherapy alone vs carboplatin alone arms). Further, no interaction was found between bevacizumab and carboplatin on pCR rate. Not unexpectedly, both drugs added significant toxicity, which resulted in frequent modification of the doses and administration of chemotherapy (paclitaxel in particular). Investigation of serial studies to predict your therapeutic response with imaging and molecular analysis 2 trial
3.2
The investigation of serial studies to predict your therapeutic response with imaging and molecular analysis 2 (I-SPY 2) is an eight-arm randomised neoadjuvant trial testing the addition of investigational new drugs (seven experimental arms) to standard neoadjuvant chemotherapy (weekly paclitaxel for 12 weeks followed by 4 cycles of doxorubicin and ciclophosphamide-AC every 3 weeks) in breast cancer. The primary end point of the trial is pCR rate in the breast and the axilla. This trial uses an adaptive randomisation methodology that is based on a pre-specified and automated algorithm. This algorithm considers response data of each regimen (response by MRI and/or pathological response) in predefined breast cancer biomarker subtypes or signatures and triggers the decision to ‘graduate’ the novel regimen after just 60 -- 120 patients are enrolled. Rugo et al. presented the results of one of the seven arms of this ongoing trial testing the addition of carboplatin (AUC 6 every 3 weeks for 4 cycles) and the poly ADP ribose polymerase inhibitor veliparib (50 mg twice a day for 12 weeks) to standard chemotherapy [8]. A total of 72 women with HER2-negative breast cancer were enrolled in the experimental arm and 62 patients, 44 of whom with HER2-negative disease, were concurrently assigned to the conventional regimen. A Bayesian model calculated that the probability of pCR was increased from 26 to 52% by the addition of carboplatin and veliparib to chemotherapy, compared with chemotherapy alone in patients with TNBC. No difference was seen in patients with hormone receptor-positive disease. Based on the I-SPY
Expert Opin. Pharmacother. (2014) 15(8)
2013 San Antonio Breast Cancer Symposium
2 calculations, the probability that the experimental regimen is actually superior to the standard comparator in TNBC is 99%, and this arm has 90% probability of being successful in a formal Phase III trial. The trade-off of this ‘graduation’ is significant increase in grade 3 or higher hematologic toxicity (febrile neutropenia, thrombocytopenia and anaemia).
Addition of ramucirumab to chemotherapy in metastatic, HER2-negative breast cancer
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4.
Ramucirumab is a monoclonal antibody that binds the extracellular domain of the VEGFR-2. This compound has shown activity in gastric and other cancers [9]. In the ramucirumab overall survival evaluation/translational research in oncology (ROSE/TRIO) trial, 1144 women with inoperable locally advanced or metastatic, HER2-negative breast cancer were randomised in a 2:1 ratio to docetaxel (100 mg/m2 every 3 weeks) plus ramucirumab (10 mg/kg every 3 weeks) or placebo. After the observation of 819 events of progression, ramucirumab resulted in a non-significant 1.3 months increase in the median investigator-assessed progression-free survival (PFS), which was the primary study end point. Among the secondary study end points, centrally assessed PFS, which was based on a fairly lower number of events, was improved in the ramucirumab arm (11.1 vs 8.5 months, p = 0.008), as was the response rate (44.7 vs 37.9%, p = 0.027). However, no survival advantage was noted and no particular subgroup of patients defined by clinical and pathological characteristics seemed to derive a differential benefit from this compound. Finally, ramucirumab resulted more frequently associated with the side effects that are typical of antiangiogenic agents (bleeding/haemorrhage, hypertension and proteinuria) and also with increased incidence of fatigue, stomatitis, lacrimation, reduced appetite and weight loss. 5.
Chemoprevention with anastrozole
The international breast cancer intervention study II (IBIS-II) is the second large randomised trial of chemoprevention with an aromatase inhibitor (AI) in post-menopausal women increased breast cancer risk [10]. In this trial, a total of 3864 women were randomised to 5 years of anastrozole or placebo. At 5 years of median follow up, anastrozole yielded 53% reduction in the risk of in-situ and invasive breast cancers (HR = 0.47) and a 58% reduction in the risk of hormone receptor-positive, invasive breast cancers (HR = 0.42). No effect was seen in preventing hormone receptor-negative breast cancers. These figures are similar to those obtained in the mammary prevention 3 (MAP.3) trial with exemestane [11]. Interestingly, the discontinuation rate at 5 years was only slightly higher in the experimental than in the placebo arm (32 vs 28%, with most of the discontinuations due to side effects). Further, comparing the incidence of typical side effects associated with aromatase inhibitors, no significant difference in the incidence of osteoporotic fractures was
observed (8.5 vs 7.7% for anastrozole and placebo, respectively) and the increase in musculoskeletal (63.9 vs 57.8%) and vasomotor symptoms (56.8 vs 49.4%) due to anastrozole was significant but small.
Meta-analysis of the effects of bisphosphonates on survival outcomes in patients with early breast cancer
6.
Although a direct anticancer activity of bisphosphonates has never been documented in clinical trials, the potentially beneficial effects that these agents have on the so-called bone vicious circle have been described [12]. Indeed, several studies conducted in the adjuvant setting provided encouraging, yet inconclusive results on a potential survival benefit [9]. Coleman et al. presented an individual patient data meta-analysis of 22 clinical trials where bisphosphonates, mostly zoledronic and ibandronic acid (89% of the cases) were administered along with adjuvant therapy in women with early breast cancer [13]. Adjuvant bisphosphonates yielded a significant reduction in the risk of bone recurrences (HR = 0.774, p = 0.0003), which translated into an absolute bone metastasis-free survival of 2.9% at 10 years. This effect was restricted to post-menopausal patients only (HR = 0.660). More importantly, and still restricted to post-menopausal women, bisphosphonates yielded a 10-year OS gain of 3.1%, including a 2.3% gain in breast cancer-specific survival. The effect was similar across the different pharmacologic classes (amino vs non-amino bisphosphonates) and different schedules (i.e., monthly administration, typical of the use in cancer patients, or more relaxed timings, typical of the bone loss prevention) of bisphosphonates. 7.
Expert opinion and conclusion
The EFS results of the NEO-ALTTO trials point out some of the limitations of the pre-surgical platform as a shortcut to approval of novel treatments in the adjuvant setting. For example, a sample size that is optimal to demonstrate significant differences in pCR may be insufficient to demonstrate small but meaningful EFS or OS differences [2]. Specifically, to robustly assess the worth of adding lapatinib to trastuzumab and chemotherapy, we must remit to the results of the 8000-patients, post-surgical ALTTO trial [14]. Although an increase in the potency of adjuvant regimens is a possible way to improve the prognosis of patients with operable, HER2-positive breast cancer, the NEO-ALTTO and BETH trials’ results also suggest that, for some patients with HER2-positive operable breast cancer, we might not really need to study more potent, but often also more toxic, treatments. The meta-analysis of small, HER2-positive tumours enrolled in the pivotal adjuvant trastuzumab therapy provides reassurance in this respect [4]. Considering also the excellent results of the Phase II clinical trial presented by Tolaney et al., it is now clear that a possible way forward to
Expert Opin. Pharmacother. (2014) 15(8)
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V. Rossi et al.
improve on the management of tumours at lower risk of relapse is to evaluate less complex (and toxic) therapeutic strategies [5]. The question of whether some patients with smaller, HER2-positive tumours could be spared treatment at all, however, still needs a reasonable answer. Breast oncologists and researchers strive to find strategies to effectively target TNBCs, and the incorporation of platinum compounds has a biological rationale. Data from the CALGB 40603 and from the previously presented GEPARSIXTO, randomised Phase II trial, showing a 20% increase in pCR rates when carboplatin was added to weekly paclitaxel and liposomal doxorubicin, suggest the inclusion of carboplatin to neoadjuvant anthracycline and taxane-based chemotherapy in TNBC [15]. Although encouraging, these results also raise a number of questions. First, and foremost, follow up of these studies is needed to evaluate whether an increase of pCR rates in the range of 10 -- 20%, which may be advantageous for surgical outcomes, translates into a survival advantage. Second, carboplatin adds significant toxicity, which is dose and schedule-dependant. Consequently, the optimal modality to include this drug in current neoadjuvant or adjuvant programs needs being established. Last, TNBC is an immunohistochemically defined entity that overlaps only partially with the molecularly defined basal-like breast cancer (BLBC) [16]. BLBC is enriched with features that may predict sensitivity to platinum compounds (i.e., frequent BRCA1 mutations or features of deficient DNA-repair mechanisms). Correlative studies are ongoing that will clarify the worth of carboplatin in molecularly defined subsets of the TNBCs treated in these trials. Along this line, the results of the I-SPY 2 trial confirm the potential of this innovative methodology to rapidly assess the worth of new drugs in biologically defined breast cancer subsets, including TNBC. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
.
2.
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Cortazar P, Zhang L, Untch M, et al. Pathological complete response and longterm clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014; published online as, doi:10.1016/ S0140-6736(13)62422-8 This FDA-funded meta-analysis was undertaken as a methodological step on the path of adopting neoadjuvant therapy as a platform for accelerated approval of regimens in early breast cancer. Piccart-Gebhart M, Holmes AP, De Azambuja E, et al. The association between event-free survival and pathological complete response to neoadjuvant lapatinib, trastuzumab or their combination in HER2-positive
.
3.
The positive results of the IBIS-II trial will fuel the debate around the value of chemoprevention with AIs, which started a couple of years ago with the MAP.3 trial results [10,11,17]. If this strategy enters the clinical practice, however, problems of adherence to treatment will become increasingly relevant [18]. The IBIS-II trial clearly shows that menopausal symptoms are common and only slightly but significantly increased by the use of AIs. Before prescribing these drugs in any setting of breast cancer, identification of baseline conditions that may predict the risk of treatment discontinuation, together with proactive measures to treat side effects such as physical activity, may be the key to maximise adherence to treatment [19,20]. On account of the meta-analysis on adjuvant bisphosphonates, there are now reasons to carefully evaluate the addition of this class of compounds in the treatment of post-menopausal, operable breast cancer patients [13]. The increase in OS, which is paralleled by an increase in bone metastasisfree survival, provides a clinical confirmation of ‘bone vicious circle’ that bisphosphonates are capable of interfering with. Further, when administered on ‘relaxed’ schedules as those use to prevent bone loss (i.e., 3- or 6-monthly), these drugs are likely to result in cost-effectiveness and with an acceptable profile of side effects.
Declaration of interest F Montemurro has received speaker’s honoraria from GlaxoSmithKline and Hoffman-La Roche. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
breast cancer. Survival follow-up analysis of the NeoALTTO study (BIG 1-06) [abstract S1-01]. San Antonio Breast Cancer Symposium; 2013 This study fails to show that a large difference in pathological complete remission (pCR) seen in the preoperative setting results in a statistically significant event-free survival (EFS) advantage in human epidermal growth factor 2-positive breast cancer. Slamon DJ, Swain SM, Geyer CE, et al. Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy and trastuzumab +/bevacizumab in patients with HER2positive, node-positive or high risk node negative breast cancer [abstract S1-03].
Expert Opin. Pharmacother. (2014) 15(8)
.
4.
.
5.
San Antonio Breast Cancer Symposium; 2013 The addition of bevacizumab in adjuvant, trastuzumab-based regimens increases toxicity but not efficacy. O’Sullivan CC, Holmes E, Spielmann M, et al. The prognosis of small HER2+ breast cancers: a meta-analysis of the randomized trastuzumab trials [abstract S6-03]. San Antonio Breast Cancer Symposium; 2013 This meta-analysis of patients enrolled in the pivotal adjuvant trial with trastuzumab shows excellent outcomes for patients with small, HER2 and hormone receptor-positive disease. Tolaney SM, Barry WT, Dang CT, et al. A Phase II study of adjuvant paclitaxel (T) and trastuzumab (H) (APT trial) for node-negative HER2+ breast cancer
2013 San Antonio Breast Cancer Symposium
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6.
.
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7.
8.
.
[abstract S1-04]. San Antonio Breast Cancer Symposium; 2013 A simplified, anthracycline-free trastuzumab-based regimens yield excellent results in small, node-negative, HER2-positive breast cancers. Carey L, Winer E, Viale G, et al. Triple-negative breast cancer: disease entity or title of convenience? Nat Rev Clin Oncol 2010;7:683-92 A complete and informative review on triple-negative breast cancer. Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of carboplatin (Cb) and/or bevacizumab (B) to neoadjuvant paclitaxel (P) followed by dose-dense AC on pathologic complete response (pCR) rates in triple-negative breast cancer (TNBC): CALGB 40603 (Alliance) [abstract S5-01]. San Antonio Breast Cancer Symposium; 2013 Rugo HS, Olopade O, DeMichele A, et al. Veliparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer: First efficacy results from the I-SPY 2 TRIAL [abstract S5-02]. San Antonio Breast Cancer Symposium; 2013 The innovative methodology used in this trial has the potential to increase our ability to establish new treatment strategies in biologically defined subsets of breast cancer.
9.
Clarke JM, Hurwitz HI. Targeted inhibition of VEGF receptor 2: an update on ramucirumab. Expert Opin Biol Ther 2013;13:1187-96
10.
Cuzick J, Sestak I, Forbes JF, et al. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet 2013; published online as, doi:10.1016/ S0140-6736(13)62292-8 This is the second Phase II large, randomised trial on aromatase
..
inhibitors in the chemoprevention setting. 11.
..
12.
13.
..
Goss PE, Ingle JN, Ales-Martinez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 2011;364:2381-91 A large, Phase III trial comparing exemestane with placebo in the chemoprevention setting in post-menopausal women with increased breast cancer risk. Santini D, Galluzzo S, Zoccoli A, et al. New molecular targets in bone metastases. Cancer Treat Rev 2010;36(Suppl 3):S6-S10 Coleman R, Gnant M, Paterson A, et al. Effects of bisphosphonates treatment on recurrence and cause-specific mortality in women with early breast cancer: a meta-analysis of individual patient data from randomised trials [abstract S4-07]. San Antonio Breast Cancer Symposium; 2013 This meta-analysis provides practice changing results on the role of bisphosphonates in post-menopausal patients with early breast cancer.
14.
Tomasello G, de Azambuja E, Dinh P, et al. Jumping higher: is it still possible? The ALTTO trial challenge. Expert Rev Anticancer Ther 2008;8:1883-90
15.
Von Minckwitz G, Schneeweiss A, Salat C, et al. A randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). ASCO Meeting Abstracts 2013;31:1004
16.
Prat A, Adamo B, Cheang MC, et al. Molecular characterization of basal-like and non-basal-like triple-negative breast cancer. Oncologist 2013;18:123-33
17.
Decensi A, Dunn BK, Puntoni M, et al. Exemestane for breast cancer prevention: a critical shift? Cancer Discov 2012;2:25-40
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18.
Chlebowski RT, Kim JS, Haque R. Adherence to endocrine therapy in breast cancer adjuvant and prevention settings. Cancer Prev Res (Phila) 2014. [Epub ahead of print]
19.
Henry NL, Kidwell K, Hayes DF, et al. Associations between baseline patient-reported symptoms and discontinuation of adjuvant aromatase inhibitor (AI) therapy [abstract S3-02]. San Antonio Breast Cancer Symposium; 2013
20.
Irwin ML, Cartmel B, Gross C, et al. Randomized trial of exercise vs. usual care on aromatase inhibitor-associated arthralgias in women with breast cancer: the hormones and physical exercise (HOPE) study [abstract S3-03]. San Antonio Breast Cancer Symposium; 2013 This study suggests that regular physical activity reduces aromatase-associated bone pain and potentially results in increased adherence to treatment.
.
Affiliation Valentina Rossi1, Rossella Martinello2, Caterina Aversa2,3 & Filippo Montemurro†1 † Author for correspondence 1 Institute of Candiolo (IRCCs), Fondazione del Piemonte per L’Oncologia, Unit of Investigative Clinical Oncology, Strada Provinciale 142, 10060, Candiolo, Italy E-mail: [email protected] 2 Institute of Candiolo (IRCCs), Fondazione del Piemonte per L’Oncologia, Division of Medical Oncology, Strada Provinciale 142, 10060, Candiolo, Italy 3 Institute for Cancer Research @Candiolo, Medical Oncology 1, Strada Provinciale 142, 10060, Candiolo, Italy
1195
2013 San Antonio Breast Cancer Symposium Valentina Rossi, Rossella Martinello, Caterina Aversa & Filippo Montemurro†
1.
Introduction
2.
Early, human epidermal growth factor 2-positive breast
†
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Fudan University on 05/14/15 For personal use only.
cancer 3.
Triple-negative breast cancer
4.
Addition of ramucirumab to chemotherapy in metastatic, HER2-negative breast cancer
5.
Chemoprevention with anastrozole
6.
Meta-analysis of the effects of bisphosphonates on survival outcomes in patients with early breast cancer
7.
Expert opinion and conclusion
Institute of Candiolo (IRCCs), Fondazione del Piemonte per L’Oncologia, Unit of Investigative Clinical Oncology, Candiolo, Italy
The San Antonio Breast Cancer Symposium is considered by researchers and physicians involved in breast cancer management as one of the most important international events on the subject. A dense program of plenary presentations of novel findings, main lectures, poster discussions and displays, it encompasses all the aspects of the rapidly evolving field of breast cancer research and treatment. This article briefly summarises some of the presentations that are expected to have an impact on the medical treatment of breast cancer. Keywords: aromatase inhibitors, bevacizumab, bisphosphonates, breast cancer, carboplatin, human epidermal growth factor 2, lapatinib, trastuzumab, triple negative breast cancer Expert Opin. Pharmacother. (2014) 15(8):1191-1195
1.
Introduction
This article will highlight some of the results presented at the 2013 San Antonio Breast Cancer Symposium which, in our opinion, are expected to have an impact both on patterns of treatment and on future research in the field of breast cancer.
Early, human epidermal growth factor 2-positive breast cancer
2.
Event-free survival results of the neo-adjuvant lapatinib and trastuzumab treatment optimisation trial
2.1
In operable breast cancer patients, comparing pathological complete remission (pCR) rates between two treatments administered preoperatively requires smaller sample sizes and shorter observation periods than those required in the classical adjuvant studies aiming at event-free survival (EFS) and overall survival (OS). For this reason, the preoperative setting is looked at as a potential platform for the accelerated approval of novel treatments in the setting of operable breast cancer [1]. However, the minimum increase in pCR rate that results in a difference in long-term outcomes between two treatments that are being compared has not yet been defined. Piccart-Gebhart et al. presented the follow-up results of the neo-adjuvant lapatinib and trastuzumab treatment optimisation (NEO-ALTTO) trial, where 455 patients with early, human epidermal growth factor 2 (HER2)-positive breast cancer were randomised to chemotherapy with trastuzumab, lapatinib or both agents [2]. In this study, compared with single agent trastuzumab, the combination of both antiHER2 drugs resulted in an absolute increase in pCR rates of 19 and 25% in women with hormone receptor-positive and -negative tumours, respectively. At a median follow up of slightly < 4 years, the significant pCR increase did not translate into a statistically significant EFS or OS advantage. A nonsignificant trend towards improved EFS (hazard ratio [HR] = 0.65, p = 0.22) was seen in the hormone receptor negative subset.
10.1517/14656566.2014.904288 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
1191
V. Rossi et al.
No role for bevacizumab added to chemotherapy and trastuzumab
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Fudan University on 05/14/15 For personal use only.
2.2
The bevacizumab with trastuzumab adjuvant therapy in HER2-positive breast cancer (BETH) trial randomised about 3500 patients with operable, HER2-positive tumours to chemotherapy and trastuzumab with or without bevacizumab [3]. At a median follow up of 38 months, neither invasive diseasefree survival (IDFS) nor OS were improved by the addition of bevacizumab, which resulted in increased toxicity. An interesting finding was that the 3-year IDFS in the conventional arm was higher than expected (92%, identical to that of the experimental arm). This probably reflects a better prognostic profile of patients who are currently enrolled in adjuvant studies, compared to those who were treated in the pivotal trials. Indeed, for example, about 50% of patients enrolled in the BETH trial had lymph node-negative disease, compared to 0 -- 30% of those enrolled in the pivotal adjuvant trials. Meta-analysis in small, HER2-positive operable tumours
2.3
The outcome of patients with small (T < 2 cm), HER2positive tumours was studied in a meta-analysis that included women enrolled in the trastuzumab-containing arms of five of the pivotal adjuvant trials [4]. The main finding of this meta-analysis was that small, hormone receptor-positive tumours, with 0 or 1 positive axillary lymph node had an excellent clinical outcome (5-year DFS and OS of 91 and 97%, respectively). These high survival figures suggest that, in this patient category, further meaningful improvements with more potent strategies (i.e., double-targeting or more chemotherapy) are unlikely. Adjuvant paclitaxel and trastuzumab in small HER2-positive tumours
2.4
Tolaney et al. reported the results of a large, Phase II trial of adjuvant chemotherapy with weekly paclitaxel and trastuzumab (80 mg/m2/week and 4 mg/kg, followed by 2 mg/kg, respectively) administered for 12 weeks, followed by 13 administrations of 3-weekly trastuzumab (6 mg/kg) [5]. The target population consisted of patients with axillary lymph node-negative tumours < 3 cm and 50% of the enrolled patients had pT1a and pT1b tumours. At a median follow up of 3.6 years, 10 patients experienced a disease relapse, which was a distant metastasis in two patients only. The 3-year DFS rate was 98.7%, and approached 100% for pT1a/b tumours (99.5%). 3.
Triple-negative breast cancer
Carboplatin added to neoadjuvant chemotherapy in triple-negative breast cancer
3.1
Because high proliferation and genomic instability are common features of hormone receptor-negative, HER2-negative 1192
(triple-negative) breast cancers (TNBC) [6], DNA damaging agents such as platinum compounds and antiangiogenic drugs may be active in this subset of breast cancers. The Cancer and Leukaemia Group B (CALGB) 40603 clinical trial adopted a 2 2 factorial design to evaluate the addition of carboplatin (AUC 6 every 3 weeks), bevacizumab (10 mg/m2 every 2 weeks) or both agents to a sequence of weekly paclitaxel followed by dose-dense doxorubicin and cyclophosphamide administered as neoadjuvant chemotherapy in women with stage II -- III, non-inflammatory TNBC [7]. The primary end point was pCR rate in the breast and the study was not powered to detect survival differences. In the 427 women who underwent surgery, both bevacizumab (48 vs 59%) and carboplatin (46 to 60%) were associated with a significant increase in pCR rates. However, only carboplatin increased the pCR rate significantly in both the breast and the axilla (from 41 to 54% overall, and from 39 to 49% in the chemotherapy alone vs carboplatin alone arms). Further, no interaction was found between bevacizumab and carboplatin on pCR rate. Not unexpectedly, both drugs added significant toxicity, which resulted in frequent modification of the doses and administration of chemotherapy (paclitaxel in particular). Investigation of serial studies to predict your therapeutic response with imaging and molecular analysis 2 trial
3.2
The investigation of serial studies to predict your therapeutic response with imaging and molecular analysis 2 (I-SPY 2) is an eight-arm randomised neoadjuvant trial testing the addition of investigational new drugs (seven experimental arms) to standard neoadjuvant chemotherapy (weekly paclitaxel for 12 weeks followed by 4 cycles of doxorubicin and ciclophosphamide-AC every 3 weeks) in breast cancer. The primary end point of the trial is pCR rate in the breast and the axilla. This trial uses an adaptive randomisation methodology that is based on a pre-specified and automated algorithm. This algorithm considers response data of each regimen (response by MRI and/or pathological response) in predefined breast cancer biomarker subtypes or signatures and triggers the decision to ‘graduate’ the novel regimen after just 60 -- 120 patients are enrolled. Rugo et al. presented the results of one of the seven arms of this ongoing trial testing the addition of carboplatin (AUC 6 every 3 weeks for 4 cycles) and the poly ADP ribose polymerase inhibitor veliparib (50 mg twice a day for 12 weeks) to standard chemotherapy [8]. A total of 72 women with HER2-negative breast cancer were enrolled in the experimental arm and 62 patients, 44 of whom with HER2-negative disease, were concurrently assigned to the conventional regimen. A Bayesian model calculated that the probability of pCR was increased from 26 to 52% by the addition of carboplatin and veliparib to chemotherapy, compared with chemotherapy alone in patients with TNBC. No difference was seen in patients with hormone receptor-positive disease. Based on the I-SPY
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2 calculations, the probability that the experimental regimen is actually superior to the standard comparator in TNBC is 99%, and this arm has 90% probability of being successful in a formal Phase III trial. The trade-off of this ‘graduation’ is significant increase in grade 3 or higher hematologic toxicity (febrile neutropenia, thrombocytopenia and anaemia).
Addition of ramucirumab to chemotherapy in metastatic, HER2-negative breast cancer
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4.
Ramucirumab is a monoclonal antibody that binds the extracellular domain of the VEGFR-2. This compound has shown activity in gastric and other cancers [9]. In the ramucirumab overall survival evaluation/translational research in oncology (ROSE/TRIO) trial, 1144 women with inoperable locally advanced or metastatic, HER2-negative breast cancer were randomised in a 2:1 ratio to docetaxel (100 mg/m2 every 3 weeks) plus ramucirumab (10 mg/kg every 3 weeks) or placebo. After the observation of 819 events of progression, ramucirumab resulted in a non-significant 1.3 months increase in the median investigator-assessed progression-free survival (PFS), which was the primary study end point. Among the secondary study end points, centrally assessed PFS, which was based on a fairly lower number of events, was improved in the ramucirumab arm (11.1 vs 8.5 months, p = 0.008), as was the response rate (44.7 vs 37.9%, p = 0.027). However, no survival advantage was noted and no particular subgroup of patients defined by clinical and pathological characteristics seemed to derive a differential benefit from this compound. Finally, ramucirumab resulted more frequently associated with the side effects that are typical of antiangiogenic agents (bleeding/haemorrhage, hypertension and proteinuria) and also with increased incidence of fatigue, stomatitis, lacrimation, reduced appetite and weight loss. 5.
Chemoprevention with anastrozole
The international breast cancer intervention study II (IBIS-II) is the second large randomised trial of chemoprevention with an aromatase inhibitor (AI) in post-menopausal women increased breast cancer risk [10]. In this trial, a total of 3864 women were randomised to 5 years of anastrozole or placebo. At 5 years of median follow up, anastrozole yielded 53% reduction in the risk of in-situ and invasive breast cancers (HR = 0.47) and a 58% reduction in the risk of hormone receptor-positive, invasive breast cancers (HR = 0.42). No effect was seen in preventing hormone receptor-negative breast cancers. These figures are similar to those obtained in the mammary prevention 3 (MAP.3) trial with exemestane [11]. Interestingly, the discontinuation rate at 5 years was only slightly higher in the experimental than in the placebo arm (32 vs 28%, with most of the discontinuations due to side effects). Further, comparing the incidence of typical side effects associated with aromatase inhibitors, no significant difference in the incidence of osteoporotic fractures was
observed (8.5 vs 7.7% for anastrozole and placebo, respectively) and the increase in musculoskeletal (63.9 vs 57.8%) and vasomotor symptoms (56.8 vs 49.4%) due to anastrozole was significant but small.
Meta-analysis of the effects of bisphosphonates on survival outcomes in patients with early breast cancer
6.
Although a direct anticancer activity of bisphosphonates has never been documented in clinical trials, the potentially beneficial effects that these agents have on the so-called bone vicious circle have been described [12]. Indeed, several studies conducted in the adjuvant setting provided encouraging, yet inconclusive results on a potential survival benefit [9]. Coleman et al. presented an individual patient data meta-analysis of 22 clinical trials where bisphosphonates, mostly zoledronic and ibandronic acid (89% of the cases) were administered along with adjuvant therapy in women with early breast cancer [13]. Adjuvant bisphosphonates yielded a significant reduction in the risk of bone recurrences (HR = 0.774, p = 0.0003), which translated into an absolute bone metastasis-free survival of 2.9% at 10 years. This effect was restricted to post-menopausal patients only (HR = 0.660). More importantly, and still restricted to post-menopausal women, bisphosphonates yielded a 10-year OS gain of 3.1%, including a 2.3% gain in breast cancer-specific survival. The effect was similar across the different pharmacologic classes (amino vs non-amino bisphosphonates) and different schedules (i.e., monthly administration, typical of the use in cancer patients, or more relaxed timings, typical of the bone loss prevention) of bisphosphonates. 7.
Expert opinion and conclusion
The EFS results of the NEO-ALTTO trials point out some of the limitations of the pre-surgical platform as a shortcut to approval of novel treatments in the adjuvant setting. For example, a sample size that is optimal to demonstrate significant differences in pCR may be insufficient to demonstrate small but meaningful EFS or OS differences [2]. Specifically, to robustly assess the worth of adding lapatinib to trastuzumab and chemotherapy, we must remit to the results of the 8000-patients, post-surgical ALTTO trial [14]. Although an increase in the potency of adjuvant regimens is a possible way to improve the prognosis of patients with operable, HER2-positive breast cancer, the NEO-ALTTO and BETH trials’ results also suggest that, for some patients with HER2-positive operable breast cancer, we might not really need to study more potent, but often also more toxic, treatments. The meta-analysis of small, HER2-positive tumours enrolled in the pivotal adjuvant trastuzumab therapy provides reassurance in this respect [4]. Considering also the excellent results of the Phase II clinical trial presented by Tolaney et al., it is now clear that a possible way forward to
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V. Rossi et al.
improve on the management of tumours at lower risk of relapse is to evaluate less complex (and toxic) therapeutic strategies [5]. The question of whether some patients with smaller, HER2-positive tumours could be spared treatment at all, however, still needs a reasonable answer. Breast oncologists and researchers strive to find strategies to effectively target TNBCs, and the incorporation of platinum compounds has a biological rationale. Data from the CALGB 40603 and from the previously presented GEPARSIXTO, randomised Phase II trial, showing a 20% increase in pCR rates when carboplatin was added to weekly paclitaxel and liposomal doxorubicin, suggest the inclusion of carboplatin to neoadjuvant anthracycline and taxane-based chemotherapy in TNBC [15]. Although encouraging, these results also raise a number of questions. First, and foremost, follow up of these studies is needed to evaluate whether an increase of pCR rates in the range of 10 -- 20%, which may be advantageous for surgical outcomes, translates into a survival advantage. Second, carboplatin adds significant toxicity, which is dose and schedule-dependant. Consequently, the optimal modality to include this drug in current neoadjuvant or adjuvant programs needs being established. Last, TNBC is an immunohistochemically defined entity that overlaps only partially with the molecularly defined basal-like breast cancer (BLBC) [16]. BLBC is enriched with features that may predict sensitivity to platinum compounds (i.e., frequent BRCA1 mutations or features of deficient DNA-repair mechanisms). Correlative studies are ongoing that will clarify the worth of carboplatin in molecularly defined subsets of the TNBCs treated in these trials. Along this line, the results of the I-SPY 2 trial confirm the potential of this innovative methodology to rapidly assess the worth of new drugs in biologically defined breast cancer subsets, including TNBC. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
.
2.
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Cortazar P, Zhang L, Untch M, et al. Pathological complete response and longterm clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014; published online as, doi:10.1016/ S0140-6736(13)62422-8 This FDA-funded meta-analysis was undertaken as a methodological step on the path of adopting neoadjuvant therapy as a platform for accelerated approval of regimens in early breast cancer. Piccart-Gebhart M, Holmes AP, De Azambuja E, et al. The association between event-free survival and pathological complete response to neoadjuvant lapatinib, trastuzumab or their combination in HER2-positive
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3.
The positive results of the IBIS-II trial will fuel the debate around the value of chemoprevention with AIs, which started a couple of years ago with the MAP.3 trial results [10,11,17]. If this strategy enters the clinical practice, however, problems of adherence to treatment will become increasingly relevant [18]. The IBIS-II trial clearly shows that menopausal symptoms are common and only slightly but significantly increased by the use of AIs. Before prescribing these drugs in any setting of breast cancer, identification of baseline conditions that may predict the risk of treatment discontinuation, together with proactive measures to treat side effects such as physical activity, may be the key to maximise adherence to treatment [19,20]. On account of the meta-analysis on adjuvant bisphosphonates, there are now reasons to carefully evaluate the addition of this class of compounds in the treatment of post-menopausal, operable breast cancer patients [13]. The increase in OS, which is paralleled by an increase in bone metastasisfree survival, provides a clinical confirmation of ‘bone vicious circle’ that bisphosphonates are capable of interfering with. Further, when administered on ‘relaxed’ schedules as those use to prevent bone loss (i.e., 3- or 6-monthly), these drugs are likely to result in cost-effectiveness and with an acceptable profile of side effects.
Declaration of interest F Montemurro has received speaker’s honoraria from GlaxoSmithKline and Hoffman-La Roche. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
breast cancer. Survival follow-up analysis of the NeoALTTO study (BIG 1-06) [abstract S1-01]. San Antonio Breast Cancer Symposium; 2013 This study fails to show that a large difference in pathological complete remission (pCR) seen in the preoperative setting results in a statistically significant event-free survival (EFS) advantage in human epidermal growth factor 2-positive breast cancer. Slamon DJ, Swain SM, Geyer CE, et al. Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy and trastuzumab +/bevacizumab in patients with HER2positive, node-positive or high risk node negative breast cancer [abstract S1-03].
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San Antonio Breast Cancer Symposium; 2013 The addition of bevacizumab in adjuvant, trastuzumab-based regimens increases toxicity but not efficacy. O’Sullivan CC, Holmes E, Spielmann M, et al. The prognosis of small HER2+ breast cancers: a meta-analysis of the randomized trastuzumab trials [abstract S6-03]. San Antonio Breast Cancer Symposium; 2013 This meta-analysis of patients enrolled in the pivotal adjuvant trial with trastuzumab shows excellent outcomes for patients with small, HER2 and hormone receptor-positive disease. Tolaney SM, Barry WT, Dang CT, et al. A Phase II study of adjuvant paclitaxel (T) and trastuzumab (H) (APT trial) for node-negative HER2+ breast cancer
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[abstract S1-04]. San Antonio Breast Cancer Symposium; 2013 A simplified, anthracycline-free trastuzumab-based regimens yield excellent results in small, node-negative, HER2-positive breast cancers. Carey L, Winer E, Viale G, et al. Triple-negative breast cancer: disease entity or title of convenience? Nat Rev Clin Oncol 2010;7:683-92 A complete and informative review on triple-negative breast cancer. Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of carboplatin (Cb) and/or bevacizumab (B) to neoadjuvant paclitaxel (P) followed by dose-dense AC on pathologic complete response (pCR) rates in triple-negative breast cancer (TNBC): CALGB 40603 (Alliance) [abstract S5-01]. San Antonio Breast Cancer Symposium; 2013 Rugo HS, Olopade O, DeMichele A, et al. Veliparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer: First efficacy results from the I-SPY 2 TRIAL [abstract S5-02]. San Antonio Breast Cancer Symposium; 2013 The innovative methodology used in this trial has the potential to increase our ability to establish new treatment strategies in biologically defined subsets of breast cancer.
9.
Clarke JM, Hurwitz HI. Targeted inhibition of VEGF receptor 2: an update on ramucirumab. Expert Opin Biol Ther 2013;13:1187-96
10.
Cuzick J, Sestak I, Forbes JF, et al. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet 2013; published online as, doi:10.1016/ S0140-6736(13)62292-8 This is the second Phase II large, randomised trial on aromatase
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inhibitors in the chemoprevention setting. 11.
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Goss PE, Ingle JN, Ales-Martinez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 2011;364:2381-91 A large, Phase III trial comparing exemestane with placebo in the chemoprevention setting in post-menopausal women with increased breast cancer risk. Santini D, Galluzzo S, Zoccoli A, et al. New molecular targets in bone metastases. Cancer Treat Rev 2010;36(Suppl 3):S6-S10 Coleman R, Gnant M, Paterson A, et al. Effects of bisphosphonates treatment on recurrence and cause-specific mortality in women with early breast cancer: a meta-analysis of individual patient data from randomised trials [abstract S4-07]. San Antonio Breast Cancer Symposium; 2013 This meta-analysis provides practice changing results on the role of bisphosphonates in post-menopausal patients with early breast cancer.
14.
Tomasello G, de Azambuja E, Dinh P, et al. Jumping higher: is it still possible? The ALTTO trial challenge. Expert Rev Anticancer Ther 2008;8:1883-90
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Von Minckwitz G, Schneeweiss A, Salat C, et al. A randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). ASCO Meeting Abstracts 2013;31:1004
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Prat A, Adamo B, Cheang MC, et al. Molecular characterization of basal-like and non-basal-like triple-negative breast cancer. Oncologist 2013;18:123-33
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Decensi A, Dunn BK, Puntoni M, et al. Exemestane for breast cancer prevention: a critical shift? Cancer Discov 2012;2:25-40
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Chlebowski RT, Kim JS, Haque R. Adherence to endocrine therapy in breast cancer adjuvant and prevention settings. Cancer Prev Res (Phila) 2014. [Epub ahead of print]
19.
Henry NL, Kidwell K, Hayes DF, et al. Associations between baseline patient-reported symptoms and discontinuation of adjuvant aromatase inhibitor (AI) therapy [abstract S3-02]. San Antonio Breast Cancer Symposium; 2013
20.
Irwin ML, Cartmel B, Gross C, et al. Randomized trial of exercise vs. usual care on aromatase inhibitor-associated arthralgias in women with breast cancer: the hormones and physical exercise (HOPE) study [abstract S3-03]. San Antonio Breast Cancer Symposium; 2013 This study suggests that regular physical activity reduces aromatase-associated bone pain and potentially results in increased adherence to treatment.
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Affiliation Valentina Rossi1, Rossella Martinello2, Caterina Aversa2,3 & Filippo Montemurro†1 † Author for correspondence 1 Institute of Candiolo (IRCCs), Fondazione del Piemonte per L’Oncologia, Unit of Investigative Clinical Oncology, Strada Provinciale 142, 10060, Candiolo, Italy E-mail: [email protected] 2 Institute of Candiolo (IRCCs), Fondazione del Piemonte per L’Oncologia, Division of Medical Oncology, Strada Provinciale 142, 10060, Candiolo, Italy 3 Institute for Cancer Research @Candiolo, Medical Oncology 1, Strada Provinciale 142, 10060, Candiolo, Italy
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