Over-treatment in metastatic breast cancer

The Breast xxx (2016) 1e9

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The Breast journal homepage: www.elsevier.com/brst

Original article

Over-treatment in metastatic breast cancer _ Elzbieta Senkus a, *, Aleksandra Łacko b a b

 sk, De˛ binki 7, 80-211, Gdan  sk, Poland Department of Oncology & Radiotherapy, Medical University of Gdan Department of Clinical Oncology, Wroclaw Medical University, Borowska 213, 50-556, Wrocław, Poland

a r t i c l e i n f o

a b s t r a c t

Article history: Received 17 April 2016 Received in revised form 25 June 2016 Accepted 30 June 2016 Available online xxx

Metastatic breast cancer is an incurable disease and the main goals of treatment are prolongation of survival and preservation/improvement of quality of life. Thus the main philosophy of treatment should be to use the least toxic methods, as long as they provide sufficient disease control. In ER-positive tumours this can be in many cases achieved by endocrine therapy; in HER2-positive cancers efficacy of backbone therapy can be enhanced by an anti-HER2 agent. In patients requiring chemotherapy, consecutive single agent regimen provide disease control of a duration at least comparable to multidrug regimen, at a cost of significantly lower toxicity and are a preferred strategy in the majority of cases. Available data demonstrate, however, that aggressive chemotherapy is still overused in many metastatic breast cancer patients. The objective of this manuscript is to critically review available data on treatment choices and sequence in metastatic breast cancer across all breast cancer subtypes in relation to possible overtreatment, including therapies which are not recommended by current guidelines or not even approved. Our aim is to provide guidance on applying these data to clinical practice, but also to describe various, often non-scientific factors influencing therapeutic decisions in an aim to identify areas requiring educational and possibly political actions. © 2016 Elsevier Ltd. All rights reserved.

Keywords: Breast cancer Metastatic Chemotherapy Endocrine therapy Targeted therapy Overtreatment

Metastatic breast cancer (MBC) is an incurable disease. That means that realistic therapy goals do not include cure, no matter how aggressive is the treatment. What can be achieved in most of cases is the prolongation of life and improvement or preservation of its quality. This last objective means symptomatic improvement at the cost of minimal toxicity. These principles are simple and clear, but unfortunately seem to be often forgotten by oncologists. Another wording of this general rule of cancer treatment states that toxicity should not outweigh the efficacy. In incurable diseases, the efficacy by definition is limited and gives no justification for aggressive therapies with high toxic death rate (an extreme example being high dose chemotherapy (ChT) with bone marrow/ stem cell support). Although in the vast majority of cases MBC is fatal, many patients, in particular those with luminal or human epidermal growth factor receptor 2 (HER2)-positive (HER2þ) tumors, may live for years [1] e continuously or intermittently receiving antineoplastic treatment and experiencing its toxicities. Therefore at some points

* Corresponding author. Fax: þ48 58 3492210. E-mail addresses: [email protected] (A. Łacko).

(E.

Senkus),

[email protected]

of the disease course majority of MBC patients may be exposed to overtreatment and oncologists need to know more about how to do less. Any treatment benefit needs to be weighed against its sideeffects and realistic therapy goals together with patient’ preferences must be always kept in mind. The treatment decision-making is additionally hurdled by the paucity of quality of life (QoL) data for particular compounds and treatments and over-time risk-benefit ratio fluctuations [2]. In symptomatic patients initial response to therapy results in symptomatic relief and improvement of QoL. With prolonged treatment, however, toxicities may accumulate and symptoms of disease may be replaced by those caused by therapy. In view of limited data on comparative efficacy of available strategies, major role in treatment choices is unfortunately played by prejudices demonstrated both by patients and often e their physicians. Patients frequently expect to get “strong” treatment for their “deadly” disease and being treated less aggressively often becomes a source of anxiety related to fear of receiving suboptimal therapy. Similar attitude is unfortunately also frequently represented by oncologists, particularly in non-academic setting and in developing countries. On the other hand, physicians, even reluctant to choose more aggressive and toxic therapy are sometimes under pressure to do so because of patient preferences. Many patients accept much lower chance of benefit than the healthy individuals

http://dx.doi.org/10.1016/j.breast.2016.06.024 0960-9776/© 2016 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Senkus E, Łacko A, Over-treatment in metastatic breast cancer, The Breast (2016), http://dx.doi.org/10.1016/ j.breast.2016.06.024

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and health professionals, and are willing to undergo even serious toxicity of therapy for a relatively small objective gain [3]. Another important issue is the overuse and misuse of new therapies. Unfortunately, only a handful of recently approved agents substantially impact the course of disease. The consequence of accelerated approval of new agents is not only poor recruitment to confirmatory trials, but also possible overuse of expensive treatments without sufficient evidence on their efficacy and toxicity. Additionally, many drugs are easily used off-label based on the early results of clinical trials. It is important to remember that promising activity seen in early studies does not necessarily translate into survival benefit, and signals about significant toxicity may arise late. Geographical differences in the management of MBC are partially caused by availability and access to new agents and differences in reimbursement policy in particular countries. Overuse of new drugs is typical for high per capita income countries. As shown in multiple surveys and market research studies, clinical practice often differs from evidence based data and existing guidelines [4e7]. The objective of this manuscript is to critically review available data on treatment choices and sequence in MBC across all breast cancer (BC) subtypes in relation to possible overtreatment, including therapies which are not recommended by current guidelines or not even approved. Our aim is to provide some guidance on applying these data to current clinical practice, but also to describe various, often non-scientific factors influencing therapeutic decisions in an aim to identify areas requiring educational and possibly political actions.

Luminal HER-2 negative breast cancer Luminal HER2-negative (HRþ/HER2-) BC in 2010 in the US made up for 61.2% of primary stage IV BC and, as it constitutes almost three quarters of all newly diagnosed BC, remains also the most prevalent subtype among patients who relapse following treatment for early disease [8]. The most important issues regarding treatment of luminal HER-2 negative MBC is: (i) the binary choice between ET and ChT as initial therapy; (ii) the optimal sequence of ET; and (iii) combining ET with molecularly targeted agent to enhance efficacy and prolong ChT free interval. The main decision point for metastatic patients from this subgroup is the choice between endocrine therapy (ET) and ChT. These decisions are difficult and there are limited data directly supporting that choice. The few available randomized trials directly addressing this question were conducted in the 1970's and 1980's, and compared tamoxifen, progestins or androgens against ChT combinations which today are largely abandoned or considered suboptimal [9]. In a Cochrane review of these studies higher tumor response rate was observed in those treated with ChT, but this did not translate into any difference in overall survival (OS) [9]. No studies in MBC are available for comparisons between aromatase inhibitors or fulvestrant and modern chemotherapeutic agents, such as taxanes, capecitabine, vinorelbine or eribulin. Lack of high level of evidence data supporting treatment choices in metastatic luminal BCs forces oncologists to rely on indirect evidence from retrospective studies or prospective non-comparative data. Although comparisons of patients treated with ChT and ET outside studies randomizing subjects between these options are impossible, in general those treated with first line ET achieve longer PFS and OS. Obviously, populations selected for ChT and ET are different, but these differences are smaller than could be expected: in general the percentage of ER/PgR-positive patients in ChT studies ranges between 70 and 80%, whereas visceral involvement is present in about 50e80% of patients undergoing ChT and in about 50% of those treated with ET.

In spite of clear recommendations ET continues to be underused in MBC. A retrospective German study of patients treated between 2002 and 2004 showed that less than half of women with hormone-receptor positive MBC (48%) received ET in any line of treatment [4] e Table 1. Combination ChT was preferred in first-line treatment of MBC irrespective of the number of organs involved and hardly any patient received ET only [5]. In a large MarketScan based American study of almost 20 thousand post-menopausal patients with ERþ/HER2- MBC on first line therapy, ET was used first in 60%, but the average number of ET lines was only 1.36 [5]. In a Dutch study of metastatic luminal HER2- BC patients treated in eight mostly non-academic institutions, 24% received initial ChT: these patients tended to be younger, have less comorbidities, were more often exposed to adjuvant ChT and ET, and were more likely to have visceral metastases. Not surprisingly, long term outcomes were significantly better in those selected for ET; this effect, however, remained also after adjusting for known prognostic factors [6]. In another study of “real life” data from 5 European countries (France, Germany, The Netherlands, Belgium, and Sweden), among 355 patients with HRþ/HER2- advanced BC who progressed on 1 line of ET (adjuvant or advanced) and completed 1 line of ChT (advanced), 69% received ET in first line setting, whereas only 7% continued with 2nd line ET. The most frequent explanations for the choice of ChT were rapid disease progression and heavy tumor burden, irrespective of the line of treatment [7]. Although there are no such pattern of care studies available for other parts of the world, informal sources and personal communications suggest that the percentage of metastatic luminal BC patients beginning their treatment with ChT, at least in some parts of the world, is remarkably high. One of major misunderstandings among many, mostly community oncologists is confounding visceral metastases and visceral crisis as an indication for ChT, resulting in not even considering ET in any case of visceral involvement. Indeed, as demonstrated in data from 1396 patients from 4 phase III studies of 1st line ET, the response rate is higher in non-visceral metastases, but if disease control is achieved, its duration is equal in patient with and without visceral involvement [10]. In view of lack of good evidence of the superior efficacy of either of the two treatment choices, therapeutic decisions need to rely rather on toxicity profiles and patient preferences. In a cross-sectional survey of 360 post-menopausal women from the US and Europe, with HRþ/HER2 MBC, currently using ET or ChT, ET users reported better health-related quality of life, greater satisfaction with treatment, better feelings about side-effects, less bother with treatment side-effects and less activity impairment than ChT users [11]. Importantly, among luminal MBC patients on ET response is not a surrogate for long term benefit and similar OS is observed in those achieving an objective tumour regression or long term disease stabilization [12]. It thus needs to be kept in mind that, as most patients undergoing early lines of treatment for MBC are

Table 1 “Real life” patterns of treatment of metastatic luminal HER2- breast cancer. Study

Number of patients

% ET-treated 1st line

2nd line

United States MarketScan databases 2002e2012 [5] Southeast Netherlands Breast Cancer Consortium [6] European (5 countries) [7] German (Organgruppe Mamma der Arbeitsgemeinschaft Gynaekologische Onkologie) [4]

19,120

60

26

482

76

e

355 703

e 69 48% (any line)

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asymptomatic or mildly symptomatic and do not require rapid symptomatic improvement, the aim of the treatment in majority of them is delaying disease progression (prolonging progression-free survival- PFS) and not necessarily obtaining tumor shrinkage. An aspect which is often underestimated and possibly misunderstood by some physicians is that not all BCs are equally sensitive to ChT and that in some patients ET may actually be more active. As demonstrated in neoadjuvant studies, the frequency of complete pathological remissions varies significantly between BC phenotypes, being the lowest for HRþ/HER2- patients, in particular in lobular cancers [13e15]. Additionally, some of the effect of ChT in ER-positive premenopausal patients may not necessary come from its cytotoxiceantineoplastic activity. As demonstrated in adjuvant NSABP B-30 and IBCSG 13e93 studies, long term outcomes are superior in patients who became amenorrheic as a result of ChT [16,17], so that it can be hypothesized that at least some of the therapeutic effect in this population is actually executed by the endocrine mechanism of action. Unfortunately, no biomarkers predictive of ET benefit beyond ER and PgR have been identified for luminal HER2- BC. Some help may be provided by analysis of clinical factors, although results are often inconsistent. Various studies suggest largest benefit from endocrine therapy in patients aged 65 or more, with lower tumor grade or tumor proliferation rate (identified by Ki67 expression), strong expression of ER and PgR, longer disease free interval, lack of liver, CNS or multiple-site involvement, no history of adjuvant therapy and presence of clinical benefit from 1st line ET [18e24]. A number of novel molecular factors potentially predictive of endocrine responsiveness were described, but none has been properly validated. A multigene “sensitivity to ET (SET) index” was proposed as being predictive of response to adjuvant ET [25]. Recently, the prognostic role of the 21-gene Recurrence Score (Oncotype DX) for both TTP and 2-year OS in HRþ/HER2- patients was demonstrated in a prospective series of de novo stage IV BC [26]. The optimal sequence of endocrine treatments has not been established. The main principle is continuing with next hormonal therapy lines in patients who have benefited from the previous endocrine treatments and switching to ChT only in those with proven resistance to multiple lines of endocrine manoeuvres or with rapidly progressive visceral disease. This strategy and the position of ET as the treatment of choice in luminal BC is endorsed by international guidelines, such as those of Advanced Breast Cancer Consensus Conference (ABC) and National Comprehensive Cancer Network (NCCN) [27e29]. The efficacy of ET may be enhanced by combining the hormonal “backbone” with targeted therapies, which may prolong “chemotherapy-free” survival. Two most promising pathways to be targeted in combination with ET in ERþ/HER2- patients are the PI3KAkt-mTOR and cell-cycle regulation. The first approved targeted treatment in combination with ET in luminal MBC is mTOR (mammalian target of rapamycin) inhibitor everolimus and exemestane. In the randomized phase III study clinically significant PFS prolongation has been demonstrated for this combination; unfortunately this has not translated into OS benefit and the treatment was associated with significant toxicities [30], often leading to treatment interruptions and dose reductions, occasionally requiring permanent drug discontinuation [30,31]. The addition of cyclin-dependent kinase (CDK) 4/6 inhibitor palbocyclib to ET in patients with advanced HRþ/HER2- BC resulted in an impressive PFS prolongation in two randomized trials [32,33]. This has led to accelerated FDA approval of this compound in patients with ER-positive advanced BC as initial endocrine-based therapy for metastatic disease and recently also for the second line therapy. Unfortunately, no OS benefit has been so far observed

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and results of the confirmatory phase III PALOMA-2 study are eagerly awaited [33]. Although an advantage of palbocyclib and (and hopefully other agents in this class) is its favourable toxicity profile, widespread use of new targeted agents generate significant costs to the healthcare systems and predictive factors are eagerly needed to identify patients who derive most benefit from these expensive therapies. HER2 positive breast cancer HER2 is overexpressed in approximately 20%e25% of invasive BCs and tumors with HER2 alterations tend to be more aggressive. In the past two decades, the developments in HER2þ disease significantly improved prognosis in this population. Since introduction of trastuzumab in 1990., other HER2-directed agents: lapatinib, pertuzumab, trastuzumab-emtansine (T-DM1) were approved; sequential use of these agent in many patients changed the natural history of HER2þ BC transforming rapidly progressing disease to chronic illness. However HER2þ BC is as clinically and biologically heterogeneous as the other subsets of BC and alike in HER2- disease one of the factors determining prognosis is HR status. In spite of this biological heterogeneity in vast majority of cases the partner for anti-HER2 therapy remains ChT. HER2þ, non-luminal breast cancer Both trastuzumab and lapatinib have only modest single agent activity [34,35] and ChT became a standard partner for anti-HER2 agents based on preclinical data on synergistic effects between trastuzumab and several cytotoxic agents [36]. In pivotal clinical trials the combination of trastuzumab and ChT impressively outperformed ChT alone [37,38]. The concept of ChT combined with HER2 blockage was further developed and used in the subsequent studies with newer anti-HER2 agents such pertuzumab [39] and this approach is recommended by guidelines and used in clinical practice [27e29,40]. As most of toxic effects associated with anti-HER2 treatment are caused by cytotoxic component of the regimen, there is a number of relevant question with respect to potential overtreatment: (i) what is the optimal ChT partner for combined therapy; (ii) is there a benefit of using multidrug ChT with anti-HER2 therapy; (iii) what is the optimal duration of ChT in combination with anti-HER2 agent; and (iv) can anti-HER2 agent or agents be used alone, without ChT backbone. One of the key questions is the choice of cytotoxic agent in combination with anti-HER2 agent. Preclinical studies in HER2overexpressing BC cell lines demonstrated synergistic activity of trastuzumab plus vinorelbine and trastuzumab plus docetaxel, and additive activity of trastuzumab plus paclitaxel. There are number of cytotoxic agents which can be partner with trastuzumab, but preferred first-line agents for use in combination are paclitaxel, docetaxel, vinorelbine, and capecitabine. Based on the survival advantage observed in pivotal trials, taxanes are the most commonly used [37,38]. Although reasonably well-tolerated, taxanes are associated with alopecia, peripheral neuropathy, hypersensitivity reactions and requirements for corticosteroid premedication. Additionally fatigue, haematological toxicity and febrile neutropenia are more frequent in patients treated with taxanes than with vinorelbine or capecitabine. Two randomized phase III trials comparing vinorelbine and trastuzumab with docetaxel and trastuzumab confirmed similar efficacy of both regimens, with significantly fewer grade 3 and 4 toxicities in the vinorelbine arm [41,42]. There are no data supporting intensification of ChT in combination with trastuzumab by using combination of cytotoxic drugs [43e45]. Although addition of carboplatin to paclitaxel plus

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trastuzumab [43] and addition of capecitabine to docetaxel plus trastuzumab [45] significantly increased PFS, triplet combinations were associated with more grade 3 to 4 toxicity and no OS benefit. Current guidelines recommend continuing chemotherapy for 4e6 months or longer in the absence of disease progression [40]. This is solely based on the design of clinical trials with anti-HER2 agents. Majority of trials recommended that patients received at least six cycles of ChT but preferably to disease progression or unacceptable toxicity. In case of discontinuation of ChT for toxicity, anti-HER agents were continued until disease progression or development of unacceptable toxic effects. In fact, significant proportion of patients in these studies continued ChT beyond 6 cycles. In one of the pivotal studies about 33% received more than 6 cycles of docetaxel [38]. In the CLEOPATRA study evaluating pertuzumab with trastuzumab and docetaxel, patients in both groups received docetaxel for a median of 8 cycles, with a range of 1e35 in the pertuzumab group [39]. With the lack of data assessing the impact of ChT duration on outcome in patients continuing anti-HER2 therapy, some patients may well be ovetreated. Tempting, though insufficiently explored option is the use of HER2 directed agents in ChT free regimens. Substantial activity of the dual HER2 blockade without ChT backbone was demonstrated both in neoadjuvant and metastatic setting. In phase II Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation (NeoSPHERE) 12 weeks combination of pertuzumab and trastuzumab without ChT achieved a pCR rate of 16.8% [46]. As it was consistently demonstrated in neoadjuvant trials with anti-HER2 agents, pCR rate largely depended on HR status with pCR of 5.9% and 27.3% in patients with HR-positive and HR-negative tumors, respectively. In the phase II neoadjuvant TBCRC (Translational Breast Cancer Research Council) 006 study dual HER2 blockage with trastuzumab and lapatinib resulted in a pCR rate of 27%. (36% in ER-negative group) [47]. Three trials in trastuzumab-pretreated patients tested the role of dual HER-2 blockage in second line. In a phase II study, patients progressing on trastuzumab who received combination of trastuzumab and pertuzumab enjoyed a CBR of 50% [48]. In another study, in patients who developed progression on single-agent pertuzumab, addition of trastuzumab to pertuzumab resulted in CBR of 41.2% [49]. In phase III EGF104900 study, trastuzumab in combination with lapatinib compared to lapatinib alone prolonged PFS and offered significant OS benefit of 4.5 months [50]. These data suggest that a fraction of HER2þ patients (about 20%e25%) might be treated with dual HER2 blockade without ChT and biomarkers which identify this subgroup are urgently needed. Before that ChT free regimens cannot be recommended as a standard option, but may be considered in asymptomatic patients with low volume disease. The evidence is also sufficient to justify the use of anti-HER2 therapy alone or with ET in patients for whom ChT is contraindicated. The results of recent studies assessing combination strategies with novel targeted agents to reverse or prevent resistance to antiHER2 agents are disappointing. Two phase III trials assessed the effectiveness of adding everolimus to standard ChT-trastuzumab combination in HER2þ advanced BC. In BOLERO-1 study, everolimus was used in the first line in combination with paclitaxel and trastuzumab. Although the 7.2 months PFS improvement was observed in the HR-negative subpopulation, overall the study did not meet its prespecified level of significance [51]. The BOLERO-3 study assessing the addition of everolimus to trastuzumab plus vinorelbine in women resistant to trastuzumab demonstrated modest PFS benefit of 2.2 months. Although formally statistically significant, clinically this result seems to be of limited value, given the significant toxicities and excess number of treatment related deaths contributed to everolimus, as well as the significant cost of this treatment [52].

Luminal B HE2-positive breast cancer Approximately half of BCs with HER2 overexpression also coexpress HR. Molecular description of luminal HER2 positive tumors show that their mutation and gene expression profile is similar to that of luminal HER2- tumors [53]. However HER2 overexpression is an independent adverse prognostic factor for all subtypes of BC and luminal B HER2þ tumors tend to be more aggressive, and less sensitive to ET compared to their HER2counterparts, suggesting that HER2 signalling causes partial endocrine resistance [54]. On the other hand ER modulates the response to ChT and to HER2-targeted agents [13e15,55]. Neoadjuvant studies with anti-HER2 based therapy show that response to ChT-based treatment depends on HR status and pCR rates are significantly lower in ER-positive population [46,47,56]. The relevance of ER signalling and adding ET to the treatment in patients with HER2þ/HRþ disease is recognized, but the optimal use of combined ET and anti-HER2 agents remains to be determined. As pivotal studies demonstrating OS benefit for combinations of ChT and HER2-targeted agents enrolled both HR-positive and HRnegative patients, combination of ChT and anti-HER2 therapy became the preferred first-line option for most patients with HER2þ disease, regardless of HR status [27,28,40], and ET with HER-2 directed agents is not perceived as a real alternative. Clinically relevant questions regarding management of metastatic BC co-expressing HER2 and HR include: (i) the feasibility of sparing ChT in selected patients using combination of ET and HER2directed agents; (ii) the use of ET combined with ChT and HER2targeting agents (either sequentially or concomitantly). The role of combination of ET and anti-HER2 therapy was addressed in three first-line trials. The TAnDEM (Trastuzumab and Anastrozole Directed Against ER-Positive HER2-Positive Mammary Carcinoma) study comparing anastrozole vs. trastuzumab plus anastrozole demonstrated median PFS prolongation of 2.4 months [57]. The overall response rate (RR), as well as the clinical benefit rate were also significantly higher with the combination. Although, despite 70% crossover rate at disease progression, median overall survival was prolonged by 4.6 months in patients in the combination arm, this was not statistically significant. In the EGF100151 study, in the HER2þ subgroup the addition of lapatinib to letrozole prolonged PFS by 5.2 months and increased overall RR, without significant overall survival benefit [58]. The eLEcTRA (Study of the Efficacy and Safety of Letrozole Combined With Trastuzumab) study was closed prematurely due to poor recruitment and analysis was performed in 92 patients only. Again, adding trastuzumab to letrozole resulted in longer TTP, but this was not statistically significant [59]. Based on the substantial PFS benefit of ET with antiHER2 treatment compared to ET alone, the ESO-ESMO guidelines recommend that for patients with ERþ/HER2þ MBC for whom ET was chosen over ChT, anti-HER-2 therapy should be considered with the initiation of ET, provided that further anti-HER-2 therapy is available [27,28]. Alike in HR-/HER2þ patients, a promising perspective is the ChT-free dual HER2 blockade. In phase II neoadjuvant TBCRC 006 study, adding letrozole to lapatinib and trastuzumab, resulted in a pCR rate of 21%. Because TBCRC 006 is a small single-arm trial, these results should be interpreted rather as hypothesis generating data. However, indirect comparison pCR in TBCRC 006 study with pCR rate observed in the subset of HER2þ/ERþ tumours treated in the trastuzumab/pertuzumab arm of the NEOSPHERE trial indicates that ET added to dual HER2 blockage increases pCR rate more than 3 folds (21% vs 5,9%) [46,47], suggesting that blocking both HER2 and ER receptors may allow for sparing ChT in selected patients. There is no direct comparison of ET plus HER2-targeted therapy with ChT plus HER2-targeted therapy and indirect comparisons

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indicate superiority of ChT-based combinations. In contrast to ChT studies, OS benefit was not demonstrated for combination of ET and HER2-directed agent [57e59]. Importantly, however, long term follow up was not collected in these trials so the real impact of ETanti HER2-therapy combination on OS remains unknown. Even accounting for those limitations, the combination of ET with HER2-targeted agent is underused and most patients, independent on clinical factors, still receive ChT. RegistHER, prospective, observational study reflecting a real-world practice in the United States, shows that about 70% of HRþ/HER2þ BC patients receive ChT as first line treatment, and only about 10% are given ET and trastuzumab [60]. Nevertheless, with the current evidence, in women with mildly symptomatic, indolent, low-volume disease combining ET with anti-HER2 agent is one of the valid options [27,28,40]. ET may be also used in combination with HER2 targeted agent as a maintenance, after the cytotoxic component of ChT/HER2directed regimen was stopped. Despite lack of data from randomised trials, with only evidence coming from retrospective or observational studies, this is fairly common and reasonable practice, minimizing treatment toxicity and potentially prolonging the time to subsequent ChT. Data from RegistHER study shows that patients on first-line chemotherapy and trastuzumab who also received ET either concomitantly with ChT or sequentially as a maintenance therapy had longer median PFS (20.4 vs. 9.5 months HR: 0.53) and OS (adjusted HR: 0.50). Sequential use of ChT and ET was associated with improved OS when compared with concurrent use (adjusted PFS HR: 0.81; adjusted OS HR: 0.48) [60]. Currently there are no biomarkers which could predict benefit from ChT-free regimens in luminal HER2þ BC patients and the selection of candidates to this approach is based on clinical factors such age, comorbidities, volume and kinetics of disease and disease-free interval. Future research should concentrate on identifying tumours with strong addiction to HER2 and/or ER pathways, in which the role of cytotoxic treatments may be less critical. Triple-negative disease and luminal HER2- cancers requiring chemotherapy Metastatic triple-negative BC (TNBC) is associated with shorter median time to relapse, higher likelihood of visceral metastases and inferior survival outcomes compared to the other subtypes. Due to the aggressive course of disease and lack of targeted therapy, palliative treatment represents a real challenge and standard treatment options are limited to ChT. ChT also remains a mainstay of treatment in all other subtypes of MBC, even with the advent of ET and molecularly targeted therapy, therefore the discussion regarding ChT applies to the its use regardless of the molecular subtype. Importantly, for many women with MBC, ChT is given for months and years. “Chemotherapy holidays” with intermittent treatment and/or periods of minimally intensive therapy may offer them not necessarily shorter - and most likely better life. There are several issues regarding potential overtreatment in this patient population: (i) ChT regimen (single vs combination); (ii) ChT duration (prolonged vs short); (iii) combining ChT with molecularly targeted agents. Few appropriately powered randomized clinical trials have addressed the question of the sequential use of single cytotoxic agents versus combination chemotherapy for MBC. Additionally, most studies failed to evaluate the impact of these strategies on patients' QoL. In the modern era, two phase III clinical trials in patients pretreated with anthracyclines demonstrated improvement in RR, TTP and OS with a taxane-based combination regimen (12, 47), at the expense of greater toxicity. Unfortunately, alike in the majority of trials of combination vs. single agent chemotherapy,

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cross-over to the second agent following progression in the monotherapy arm was not mandated and very few patients in the single agent arms were later exposed to the second drug, thus limiting the generalizability of the survival benefit reported. To date, 12 randomized studies have directly addressed the comparison of sequential single agents vs. combination chemotherapy. Importantly, some of these studies started treatment with a second agent following a predefined number of cycles of initial drug, rather than following the standard clinical practice of switching therapy at disease progression. A Cochrane Review of these trials demonstrated no difference in overall survival, with an overall HR of 1.04. This result was consistent irrespective of line of chemotherapy, type of schema of ChT (planned sequence vs. switch at progression), and relative dose intensity. Interestingly, slightly higher risk of progression was observed in the combination arm (HR 1.11). As expected, overall tumour response rates were higher in the combination arm (RR 1.16). In the seven trials that reported treatment-related deaths, there was a non-significant trend for increased treatment-related mortality (RR 1.53) and higher risk of febrile neutropenia (RR 1.32) in the combination arm [61]. Depending on the clinical situation, both combination and sequential single agent chemotherapy may be appropriate as firstline systemic therapy. Combination therapies often achieve higher response rates, which may be particularly important for patients with rapidly progressing or symptomatic disease. Sequential single agent therapy should be the preferred choice for most MBC patients in the absence of rapid clinical progression, life-threatening visceral metastases, or the need for rapid symptom/disease control [27,28]. The meta-analysis examining the duration of first-line ChT showed significant improvement in PFS and quite modest OS improvement in patients receiving longer first-line ChT duration. Although value of this meta-analysis is limited by heterogeneity of study design, it reflects findings from most individual trials, consistently showing that prolonging treatment is associated with extended TTP but has little effect on OS [62]. However, in recently published trial conducted by the Korean Cancer Study Group (KCSG) continuation of paclitaxel and gemcitabine in patients who achieved objective response or disease stabilization resulted in modest 3.7-month improvement in median PFS, which translated into clinically impressive 11-month improvement in median OS, without negative impact on patients' QoL [63,64]. The group of patients who most benefited from prolonged ChT were young, premenopausal, HRenegative women with high volume disease, with at least partial response after first 6 cycles of ChT. It needs to be remembered, that continuation of ChT until progression, even if it offers better disease control and OS improvement, may compromise QoL, leaving the patients without time free of treatment related side effects. A reasonable alternative could be maintenance therapy with single well tolerated agent such as capecitabine, vinorelbine or gemcitabine. Although not supported by data from clinical trials, this concept has been already incorporated into clinical practice. In fact, in the MANTA1 (Maintenance Paclitaxel 1) trial, continuing paclitaxel as a maintenance ChT for eight cycles after response to a first-line paclitaxel plus anthracycline combination failed to prolong median PFS and OS [65]. Metronomic chemotherapy means chronic, equally spaced administration of (generally) low doses of various chemotherapeutic drugs without extended rest periods. Such dosing, characterised by very low toxicity, exerts its anti-tumour efficacy via tumour endothelial cells (antiangiogenic effect) [66]. As most patients prefer oral therapy, metronomic ChT is convenient, inexpensive alternative to conventional ChT. In multiple studies it was shown to induce durable disease control, also in heavily pretreated patients. Cytotoxic agents most frequently used in metronomic regimens include: cyclophosphamide, methotrexate, oral

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vinorelbine, capecitabine and pegylated liposomal doxorubicin. In MBC patients pretreated with anthracyclines and taxanes administered metronomic capecitabine and cyclophosphamide, median TTP was 5.2 months and median OS was 16.9 months [67]. Other promising partner for capecitabine is oral vinorelbine. In recently published phase II study of capecitabine and oral vinorelbine the clinical benefit rate was 58.1%. Treatment was well tolerated in the whole study population, specifically in elderly with 2.2% of patients experiencing grade 3 and 4 side effects [68]. Due to the different mechanism of action there are rationales to combine metronomic ChT with ET. Fulvestrant with capecitabine in luminal MBC resulted in median PFS of 15 months and OS of 28.7 months [69]. Combination of metronomic ChT with molecularly targeted agents such as trastuzumab and bevacizumab was also investigated with encouraging results. Various anti-angiogenic agents alone or in combination with ChT were intensively studied in MBC, but none of them was shown to impact OS. Bevacizumab, a monoclonal antibody against VEGF is often discussed among treatments enhancing the efficacy of ChT. Individual trials with ChT and bevacizumab, as well as metaanalysis of published studies consistently demonstrated that bevacizumab provides improvements in RR and PFS, but fails to improve OS [70]. Impressive PFS benefit (prolongation of median PFS by 5.9 months) in the registration E2100 study was not confirmed by further ChT-bevacizumab studies, both in first and second line stetting trials, in which median PFS prolongation ranged from 1.1 to 2.9 months, making it, albeit statistically significant, of disputable clinical value [71e75]. The evidence also highlights increased risks of severe adverse effects such as febrile neutropenia, hypertension, proteinuria, cardiac events and bleedings. In light of these data, in 2011 FDA formally withdrew bevacizumab's BC indication. Bevacizumab is still labelled and used in many countries including the European Union. There is no convincing data that this anti-angiogenic agent has any special properties in TNBC compared with other subtypes. With the absence of survival benefit, and small, but still substantial risk of severe, life threatening side effects, the use of bevacizumab in BC in most cases represents overtreatment [76]. The ESO-ESMO Guidelines clearly state that bevacizumab can only be considered as an option only in selected cases [27,28]. The use of bevacizumab in BC significantly decreased following FDA suggestions on risks exceeding the benefit and the resultant withdrawal of approval in November 2011 [77,78]. Few data exist for other parts of the world, however, surprisingly, in a survey among over 500 mostly non-American oncologists majority believed PFS to be a surrogate for OS, that cost played a role in the FDA's decision, and that the decision would adversely affect the future of newer drugs currently being investigated for MBC. Almost half of responders declared that they will continue to use bevacizumab for TNBC [79] although it obviously represents “overtreatment” or “mis-treatment” in view of the efficacy, toxicity and cost-effectiveness data available. Specific population of MBC patients demanding more individual approach are elderly patients. Paradoxically, they are at risk of both undertreatment and overtreatment. Phenomena of undertreatment of elderly patients is well documented [80]. In contrast, there is paucity of data when it comes to overtreatment in this group. Especially in frail patients, or those with multiple comorbidities aggressive treatment may not result in benefit, as elderly women compared to their younger counterparts are at greater risk of complications including cardiac toxicity associated with anthracyclines and trastuzumab, and arterial thromboembolic events associated with bevacizumab [81,82]. As poor functional status correlates with worse outcomes regardless of the tumor biology, and competing causes of death may influence prognosis, standard

therapy may have less effect on survival in elderly [83]. Protecting not only quality of life, but also functional status and independence are key issues. Because ET has favourable toxicity profile, it should be continued in HR positive patients for as long as possible until evident progression. Use of ChT should be limited to disease unresponsive to ET and single agent ChT is a preferred option [84]. Due to convenience and low incidence of adverse effects metronomic ChT may be considered. Treatment regimens and dosing can be adjusted to improve safety. Using lower doses of cytotoxic agents may enable longer treatment and extend disease control. An extreme example of overtreatment is antineoplastic therapy at the end of life. According to available guidelines for patients with solid tumors who did not benefit from prior evidence based intervention and patients with low performance status, cancerdirected therapy is not recommended [1e3]. One of the major measures of poor quality of end-of-life cancer care is institution of new anticancer therapies or continuation of ongoing treatments in patients with end-stage cancer [85]. However evidence confirms that treatment of cancer patients near the end of life is becoming more and more aggressive [86]. There are multiple reasons explaining overtreatment near death, including insufficient information regarding prognosis and expected benefits, overestimation of prognosis, lack of knowledge about consequnces of treatment and limited options regarding possible further care. In making treatment decisions near the end of life functional communication between doctor and patient is essential. It has to be stressed that in reality, n-line therapy in patients with refractory MBC neither prolongs life, nor improves its quality. Final remarks “The treatment should not be worse than the disease” is one of the key rules which should guide our practice. Treating chronic, incurable disease is always challenging. We often face dilemmas regarding trade-off between quality and quantity of life. Biology of MBC offers unique opportunities of therapy such as ET or anti-HER2 agents which are effective and well tolerated. However, some patients are not candidates for targeted therapy and other finally become resistant. The real measure of treatment benefit in MBC patients is time without symptoms of disease and treatment toxicities. That is why ET backbone or single agent ChT should be considered first in all patients, unless contraindications exist. The absolute contraindications for ET are quite limited and include: lack of oestrogen receptor expression, extensive/symptomatic visceral involvement resulting in directly life-threatening disease (visceral crisis) and demonstrated endocrine resistance expressed by lack of benefit from multiple ET lines [27,28]. Similar rules guide the use of more intense versus less intense ChT. It is clear, that treatment is individualized according to tumor, patient and disease associated factors, but choosing more aggressive and toxic option if better tolerated and at least equally effective therapies are available should be considered as overtreatment. Overuse of certain treatments has multiple consequences: toxicity and its impact on quality of life are the most important, but financial sequelae should not be ignored. Endocrine therapies are generally cheaper and generate much less costs related to parenteral administration and management of complications [87]. Such financing may actually lead some physicians to choose better paid options, as demonstrated in extremo by the disgraceful case of dr Farid Fata from Michigan, US, who pleaded guilty for giving unnecessary therapy to hundreds of patients. The treatment of MBC can be depicted as a deck of cards e we have a definite number of possibilities and to achieve the best results we need to get as much of them, as possible. To achieve this, each treatment option should be used optimally, starting with less

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aggressive approaches, such as ET and proceeding to more aggressive ones as the effects of the former therapies cease and the disease becomes more advanced. Switching this order and starting with ChT (often multidrug) may mean that with progressing malignancy there will never be a chance to go back to less aggressive and less toxic options. As a consequence e some of the most valued treatment possibilities may be missed. To conclude, one of the most important aims of MBC treatment is to provide patients with a chance to have as much “normal” life as possible, and this can be best achieved with low toxicity treatments, such as ET, targeted therapies and single agent ChT.

Conflict of interest statement Elzbieta Senkus: honoraria from AstraZeneca, Celgene, Pfizer and Roche; travel support from AstraZeneca, Pfizer and Roche. Aleksandra Łacko: honoraria from AstraZeneca, Novartis and Roche; travel support from Roche. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Ethical approval None.

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Please cite this article in press as: Senkus E, Łacko A, Over-treatment in metastatic breast cancer, The Breast (2016), http://dx.doi.org/10.1016/ j.breast.2016.06.024