Hormone receptor positive, HER2 negative metastatic breast cancer: Future treatment landscape

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1 Asia-Pacific Journal of Clinical Oncology 2016; 12(Suppl.1): doi: /ajco SUPPLEMENT ARTICLE Hormone receptor positive, HER2 negative metastatic breast cancer: Future treatment landscape Andrew REDFERN, 1 Katie BURSLEM, 2 Natasha WOODWARD, 3 Jane BEITH, 4 Nicole MCCARTHY, 5 Richard DE BOER 6 and Richard BELL 7 1 Fiona Stanley Hospital, Perth, Western Australia, 2 WriteSource Medical Pty Ltd, Sydney, New South Wales, 3 Mater Health Services/Mater Research Institute, South Brisbane, Queensland, 4 Chris O Brien Lifehouse, Camperdown, New South Wales, 5 Wesley Medical Centre, Auchenflower, and University of Queensland, Queensland, 6 Royal Melbourne Hospital, Parkville, Victoria, and 7 Deakin University, Warun Ponds, Victoria, Australia Abstract Endocrine therapy is an established and effective treatment strategy for hormone receptor positive metastatic breast cancer. The clinical utility of endocrine therapy is lost over time due to evolving changes in tumor biology and the development of endocrine resistance. Many agents targeting the intracellular signaling pathways associated with endocrine resistance are in development. Encouraging early results have been seen for agents which directly target the estrogen receptor (ER), inhibitors of co-signaling pathways, inhibitors of ER chaperones, ER antagonists able to inhibit mutated or otherwise activated ERs, and modulators of histone acetylation restoring synthesis of ER signaling components. Following our systematic review of treatments with established benefits in this supplement, we review some of the more promising new strategies for overcoming endocrine resistance, looking at the impact on disease control and quality of life for women with hormone receptor positive, HER2 negative breast cancer. We also examine the biomarkers that may guide selection of the best therapy for the individual. Key words: breast cancer, disease-free survival, hormone receptor positive, metastatic, review ABBREVIATIONS PFS HR mtor Pi3K progression-free survival hazard ratio mammalian target of rapamycin phosphoinositol-3-kinase Correspondence: Andrew Redfern, Fiona Stanley Hospital, Murdoch Drive, Murdoch, Perth, WA 6150, Australia. andrew.redfern@health.wa.gov.au Funding: Novartis Pharmaceuticals Australia Pty Limited provided funding to Wiley for development of this publication. Conflicts of interest: AR has participated in advisory boards for Pfizer and Roche and received travel funding from Amgen and Roche. NW, NM and JB have participated in advisory boards and received funding for travel from Roche and Novartis. NM and JB have also participated in a Pfizer focus group. RB has participated in advisory boards for Roche. RDB has received honoraria from Novartis. KB was funded by Wiley. Accepted for publication 1 March PiK3CA Pi3K gene FGFR1 fibroblast growth factor receptor-1 PTEN phosphatase and tensin homolog LKB1 liver kinase B1 Pakt phosphorylated Ak-transforming eif4e eukaryotic translation initiation factor 4E S6RP phosphorylated S6 ribosomal protein p4ebp1 phosphorylated 4E-binding protein 1 HDAC histone deacetylase CDK 4/6 cyclin dependant kinase 4/6 PR progesterone receptor AR androgen receptor IGFR1 insulin-like growth factor receptor-1 EGFR epidermal growth factor receptor HER3 human EGFR3, SRC3 steroid receptor coactivator 3 HER2 human EGFR2 ERK extracellular signal-regulated kinases VEGFR vascular endothelial growth factor receptor

2 20 A. Redfern et al. INTRODUCTION Traditionally, endocrine therapy has been an effective treatment strategy with acceptable toxicity for the treatment of hormone receptor positive metastatic breast cancer, and when used serially can delay the use of chemotherapy. 1,2 Manipulating the estrogen signaling pathway in hormone receptor positive metastatic breast cancer represents the earliest successful targeted therapy in cancer, with recorded benefits dating back more than a century. However, as recently as four years ago, all the therapeutic agents in common use for this type of breast cancer interacted directly or indirectly with the hormone receptors. 3 Beyond the use of luteinizing hormone releasing hormone (LHRH) agonists in premenopausal patients, all standard therapies employed single agents in sequence. While the use of endocrine monotherapy remains an effective treatment option for many women, both in the first and second line settings, the usefulness of endocrine therapy over time becomes limited by changes in tumor biology and consequent endocrine resistance. Increasing understanding of the complexity of endocrine receptor signaling and interactions with multiple signaling pathways provide a framework for the development and evaluation of new agents for use in combination with standard endocrine therapy. The variety and complexity of potential pathways highlights the need for the molecular characterization of tumors to define mechanisms of resistance to endocrine therapy and for predictive biomarkers to enable rational selection of optimal treatment strategies for the individual patient. 2 An increasing body of preclinical data supports the role of multiple signaling pathways in the development of endocrine resistance and has led to a broad range of clinical trials using dual and triple blockade strategies. Improved outcomes were seen in the BOLERO-2 study, 4 with improved progression-free survival (PFS) following the addition of everolimus to standard anti-estrogen therapy, expanding the therapeutic paradigm in this area, and with many trials of similar design subsequently initiated. We consider emerging opportunities to improve therapy in patients with hormone receptor positive, HER2 negative metastatic breast cancer, and explore the practical issues facing clinicians treating this condition. Our review focuses on: the relationship between overall survival (OS) and overall response rate (ORR), clinical benefit rate (CBR) and PFS in hormone receptor positive metastatic breast cancer guiding interpretation of efficacy outcomes as potential surrogates for OS. the latest strategies to address endocrine resistance, examining agents in the later stages of development that have the most potential to further expand standard-ofcare options for this patient group. the impact on quality of life (QoL) resulting from the addition of targeted agents to endocrine treatment potential predictors of response that may allow optimal treatment for each patient Overall survival as a study end-point Pragmatically, data collection for OS analysis is largely driven by the FDA requirements for drug registration. 5 Prolonging life is intuitively the gold standard by which to judge patient benefit. However, in practice the relatively long survival typically experienced by this subpopulation of women, along with the use of multiple lines of subsequent cancer therapy, including chemotherapy and investigative treatment, delay and confound survival analyses. 5 In addition, the length of follow-up associated with collecting data for an OS endpoint restricts the reliability of these analyses. Results from our systematic review show the extent to which the PFS benefit (measured by hazard ratio) is retained in OS is not sufficiently consistent to show a trend. While this may often reflect a lack of mature data for OS, other reasons may include: 1. Treatment switching post-progression 2. Induction of more aggressive tumor phenotypes postprogression, leading to an accelerated disease course after treatment discontinuation 3. The relatively short duration of survival improvement relative to the long median OS period for this subpopulation Supporting the latter, PFS extension tended to be fairly well reflected at the OS level on a month by month basis with the exception of the HDAC inhibitor, entinostat where OS improved more than PFS, and some bevacizumab trials where the reverse was true, potentially reflecting specifics of target biology. CBR, which considers stable disease in addition to the ORR, is often used because the survival benefit for patients on drugs that may induce tumor dormancy rather than cytotoxicity is often of a similar magnitude to the survival benefit for patients with an objective response. However, in our review, increased ORR (i.e. tumor shrinkage) but not improved CBR appeared to reflect improvements in OS, supporting ORR rather than CBR as a useful end-point for future studies. Asia-Pac J Clin Oncol 2016; 12(Suppl. 1): 19 31

3 HR+ HER2-metastatic breast cancer 21 Resistance Effective endocrine therapy generally requires the presence of hormone receptors but a proportion of these tumors will not respond, demonstrating de novo (primary) endocrine resistance. Furthermore, where an initial response is achieved, acquired (secondary) resistance with progressive disease eventually develops in the majority of patients. A variety of molecular alterations have been associated with development of endocrine resistance. Many of these molecular alterations involve phenotypic cellular changes: alterations in expression or post-transcriptional modification of components of both the estrogen signaling pathway and alternate signaling routes. Less common genotypic changes may include DNA mutations altering these same components of estrogen and other signaling pathways, and epigenetic changes. The consequences of these changes in relation to ER signaling can be assigned to basic mechanistic categories, including: 1. Signaling bypass or cross-talk pathway activation contributing to loss of reliance on estrogen receptor (ER) signaling or post-translational modification of ER. 2. Alterations in ER interacting proteins, including chaperones affecting ER trafficking and degradation. 3. ER mutation with constitutive activation or alteration in SERM binding. 4. Loss of ER or aromatase expression by histone methylation or deacetylation. Potential future additions to current standard therapies Reflecting the varied mechanisms of escape from antiestrogen control, there are a wide range of treatment strategies currently in development (Table 1) including: dual non-cross-resistant direct ER targeting; inhibitors of a range of co-signaling pathways; inhibitors to other ER signaling components including chaperones; alternate ER antagonists able to inhibit mutated or otherwise activated ERs; and modulators of histone acetylation restoring synthesis of ER signaling components. Dual ER pathway targeting Ongoing expression of ERs is observed in most hormone receptor positive breast cancers, even on progression. This maintained expression, associated with a lack of absolute cross-resistance between agents allows for potential gains from second and subsequentline sequential endocrine therapies. 6 This raises the possibility of potentially greater efficacy with combination therapies. Discrepant results have been seen for the addition of the selective estrogen receptor degrader (SERD) fulvestrant to AIs. The SWOG-S0226 trial showed both PFS and OS benefits for the addition of fulvestrant to anastrozole, a benefit confined to patients not previously given adjuvant endocrine therapy. 7 In contrast, the FACT study showed no benefit for the same addition of fulvestrant although a substantially greater proportion of patients had received prior adjuvant endocrine therapy. 8 A meta-analysis of the two studies did not show an overall benefit. 9 Targeting co-signaling pathways One of the main mechanisms of endocrine resistance is upregulation of alternative signaling pathways. Such pathways contain receptor-ligand systems, such as the HER growth factor pathways and IGF-1R pathways. These pathways interact with downstream signal transduction elements such as Pi3K/AKT/mTOR and SRC/RAS/RAF systems (Fig. 1). 11 It follows that combining endocrine therapy with growth factor signaling pathway inhibitors, such as HER, IGF-1R, Pi3K and SRC inhibitors offers the potential to reduce endocrine resistance. Tumor signaling network elucidation in individual patient tumors will still be required to understand which component is contributing to tumor growth and so allow treatment selection to optimize outcomes. Targeting co-signaling pathways: Receptor components A range of upstream receptor signaling systems interact with the downstream transduction systems Pi3K, SRC, JAK and RAS systems and can influence the outcomes of estrogen blockade, including EGFR, fibroblast growth factor receptor (FGFR), and insulin-like growth factor 1 receptor (IGF-1R) systems. Targeting EGFR Studies adding the EGFR-TKI gefitinib to standard antiestrogen treatment have shown mixed results. A small study in combination with anastrozole showed a significant PFS advantage, but no benefit was seen when gefitinib was used in combination with tamoxifen. 12,13 Larger studies would be needed to determine if this is due to the different anti-estrogen partner or the small number of patients in each of the trials. Targeting FGFR FGF receptor mutation or amplification is a relatively common event in breast cancer. 14 Various studies Asia-Pac J Clin Oncol 2016; 12(Suppl. 1): 19 31

4 22 A. Redfern et al. Table 1 Ongoing clinical trials of targeted agents in combination with endocrine therapy for hormone receptor positive, HER2 negative metastatic breast cancer 10 Targets Study title Phase Study status Estimated primary completion date Clinicaltrials.gov identifier mtor / SERD A Randomized Study of AZD2014 +/ Fulvestrant in Metastatic or Advanced Breast Cancer (MANTA) Study of Fulvestrant +/ Everolimus in Post-Menopausal, Hormone-Receptor + Metastatic Breast Ca Resistant to AI (PrE0102) Pi3K / SERD A Phase III Study of BKM120 (buparlisib) +/ Fulvestrant in Patients With HR+,HER2-, AI Treated, Locally Advanced or Metastatic Breast Cancer Who Progressed on or After mtori (BELLE-3) Phase III Study of BKM120 (buparlisib) / Placebo With Fulvestrant in Postmenopausal Patients With Hormone Receptor Positive HER2-negative Locally Advanced or Metastatic Breast Cancer Refractory to Aromatase Inhibitor (BELLE-2) SANDPIPER Study: A Study Of Taselisib / Placebo with Fulvestrant In Patients With Advanced or Metastatic Breast Cancer Who Have Disease Recurrence or Progression During or After Aromatase Inhibitor Therapy Study Assessing the Efficacy and Safety of Alpelisib / Placebo Plus Fulvestrant in Men and Postmenopausal Women With Advanced Breast Cancer Which Progressed on or After Aromatase Inhibitor Treatment. (SOLAR-1) Study of GDC-0941 (pictilisib) or GDC-0980 (apitolisib) With Fulvestrant Versus Fulvestrant in Advanced or Metastatic Breast Cancer in Patients Resistant to Aromatase Inhibitor Therapy 2 Recruiting June 2016 NCT Ongoing, recruitment completed October 2017 NCT Recruiting March 2017 NCT Recruiting October 2017 NCT Recruiting June 2018 NCT Recruiting July 2019 NCT Ongoing, not January 2016 NCT BKM120 (buparlisib) and Fulvestrant for Treating Postmenopausal 1 Ongoing, not September 2015 NCT Patients With Estrogen Receptor-Positive Stage IV Breast Cancer Pi3K / SERM Trial of BKM120 (buparlisib)/tamoxifen-combination in Patients With 2 Recruiting June 2017 NCT HR-pos, HER2-neg Breast Cancer (PIKTAM) Pi3K / AI BYL719 and Letrozole in Post-Menopausal Patients With Hormone 1 Recruiting October 2017 NCT Receptor-Positive Metastatic Breast Cancer Pi3K / CDK4/6 Study of LEE011, BYL719 and Letrozole in Advanced ER+ Breast Cancer 1b/2 Recruiting May 2017 NCT Study of LEE011 With Fulvestrant and BYL719 or BKM120 (buparlisib) 1b/2 Recruiting February 2019 NCT in Advanced Breast Cancer Dose Escalation Study of LEE011 in Combination With Buparlisib and December 2015 NCT Letrozole in HR+, HER2-negative Post-menopausal Women With Advanced Breast Cancer. (LeeBLet) AKT / SERD Fulvestrant +/ AKT Inhibition in Advanced Aromatase Inhibitor Resistant Breast Cancer (FAKTION) 1 Ongoing, not 1b/2 Recruiting May 2016 NCT JAK / AI Ruxolitinib in Estrogen Receptor Positive Breast Cancer 2 Recruiting October 2017 NCT FGFR / AI AZD4547 & Anastrozole or Letrozole (NSAIs) in ER+ Breast Cancer 2a Recruiting March 2016 NCT Patients Who Have Progressed on NSAIs (RADICAL) Dovitinib Plus an Aromatase Inhibitor for Metastatic Breast Cancer 1/2 Ongoing, not December 2015 NCT Asia-Pac J Clin Oncol 2016; 12(Suppl. 1): 19 31

5 HR+ HER2-metastatic breast cancer 23 Table 1 Continued Targets Study title Phase Study status Estimated primary completion date Clinicaltrials.gov identifier FGFR-VEGF Study of Oral Lucitanib (E-3810), a Dual VEGFR-FGFR Tyrosine Kinase Inhibitor, in Patients With Solid Tumors A Phase II Trial Testing Oral Administration of Lucitanib in Patients With Fibroblast Growth Factor Receptor (FGFR)1-amplified or Non-amplified Estrogen Receptor Positive Metastatic Breast Cancer (FINESSE) CDK4/6 / mtor Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of Hormone Receptor Positive HER2 Negative Advanced Breast Cancer CDK4/6 / AI Study of Efficacy and Safety of letrozole +/ LEE011 in Postmenopausal Women With Advanced Breast Cancer (MONALEESA-2) A Study of Nonsteroidal Aromatase Inhibitors Plus Abemaciclib (LY ) / Placebo in Postmenopausal Women With Breast Cancer (MONARCH 3) CDK4/6 / SERD A Study of Abemaciclib (LY ) / Placebo Combined With Fulvestrant in Women With Hormone Receptor Positive HER2 Negative Breast Cancer (MONARCH 2) Study of Efficacy and Safety of fulvestrant plus LEE011 / Placebo in Postmenopausal Women With Advanced Breast Cancer (MONALEESA-3) CDK4/6 / SERM or AI A Phase III Randomized, Double-blind, Placebo-controlled Study of LEE011 or Placebo in Combination With Tamoxifen and Goserelin or a Nonsteroidal Aromatase Inhibitor (NSAI) and Goserelin for the Treatment of Premenopausal Women With Hormone Receptor Positive, HER2-negative, Advanced Breast Cancer (MONALEESA-7) SERD / AI A Global Study to Compare the Effects of Fulvestrant with Arimidex in women with metastatic Breast Cancer. (FALCON) ESR1 / SERD A Study of GDC-0810 Versus Fulvestrant in Women With Advanced or Metastatic Breast Cancer Resistant to Aromatase Inhibitor Therapy (HydranGea) A Study of ARN-810 (GDC-0810) in Postmenopausal Women With Locally Advanced or Metastatic Estrogen Receptor Positive Breast Cancer HDAC Study of Panobinostat Monotherapy in Women With HER2 Negative Locally Recurrent or Metastatic Breast Cancer HDAC / AI Exemestane With or Without Entinostat in Treating Patients With Recurrent Hormone Receptor Positive Breast Cancer That is Locally Advanced or Metastatic Panobinostat (LBH589) and Letrozole in Treating Patients With Metastatic Breast Cancer 1/2 Ongoing, not December 2015 NCT Recruiting May 2016 NCT b/2 Recruiting November 2016 NCT Ongoing, not 3 Ongoing, not 3 Ongoing, not August 2019 NCT June 2017 NCT February 2017 NCT Recruiting April 2020 NCT Recruiting February 2018 NCT Ongoing, not January 2016 NCT Recruiting April 2018 NCT Recruiting July 2017 NCT Completed April 2015 NCT Recruiting July 2017 NCT /2 Ongoing, not July 2016 NCT Asia-Pac J Clin Oncol 2016; 12(Suppl. 1): 19 31

6 24 A. Redfern et al. Figure 1 Targets for drug development in combination with endocrine therapy. support the role of the FGFR pathway in endocrine resistance. A study of estrogen receptor positive patients showed that FGFR1 amplification corresponded with a significantly poorer survival. 15 In patients with hormone positive breast cancer treated with tamoxifen, high FGFR4 mrna levels were associated with poor clinical benefit and shorter PFS. 16 Lucitanib, an oral inhibitor of FGFR 1 and 2, VEGFR and PGFR demonstrated a 50% partial response rate (6 of 12 patients) with a median PFS of 40.4 weeks in breast cancer patients with FGF-pathway aberrations. 17 The FGFR inhibitor, dovitinib was well tolerated, and partial responses or stable disease for more than 24 weeks were observed in 25% of evaluable patients (5 of 20) with hormone receptor positive FGFR1-amplified breast cancer. These data have led to the initiation of a phase 2 study of dovitinib in combination with fulvestrant in postmenopausal patients with hormone receptor positive, HER2 negative breast cancer. 18 Targeting IGFR In contrast to other upstream signaling systems, antibody blockade of IGFR targets has not produced clinically useful results to date. Ganitumab, dalotuzumab and figitumumab have all failed to significantly influence outcomes when added to anti-estrogens, as detailed in our recent review. Targeting co-signaling pathways: Signal transduction mtor Inhibition Considering first the mtor component of the Pi3K / AKT / mtor pathway, the combination of tamoxifen with the mtor inhibitor, everolimus, increased CBR, time to progression (TTP) and OS compared with tamoxifen alone in postmenopausal women with AI-resistant metastatic breast cancer. 19 The addition of everolimus to exemestane also markedly prolonged PFS in patients with hormone receptor positive advanced breast cancer with disease recurrence or progression following prior treatment with a nonsteroidal aromatase inhibitor (NSAI). 4 In contrast a first line study adding temsirolimus to letrozole failed to show benefit, raising the possibilities of treatment line-specific activity, or different efficacy between agents of this drug class. 20 This result also highlighted the need to understand the degree and type of endocrine resistance that may be present in each patient. Stratification of type of endocrine resistance could allow for a better understanding of the benefit, or lack thereof, of certain agents. Asia-Pac J Clin Oncol 2016; 12(Suppl. 1): 19 31

7 HR+ HER2-metastatic breast cancer 25 Pi3K inhibition Recent data from trials with Pi3K inhibitors have shown that the addition of the pan-pi3k inhibitor buparlisib to fulvestrant in the Phase 3 BELLE-2 trial improved PFS (hazard ratio [HR] 0.78 [95% CI 0.67, 0.89]; n = 1,147) and showed that characterizing Pi3KCA mutation in circulating tumor DNA (ctdna) identified patients with endocrine resistant hormone receptor positive metastatic breast cancer. Buparlisib addition resulted in a greater PFS benefit for these patients (HR 0.56 [95% CI 0.39, 0.80] n = 200). 21 This result was not seen in the total patient population where the Pi3KCA activation status was determined using mainly archival tissue from the breast cancer primary. This highlights the need to assess tumor at the time of relapse or progression, rather than relying on the molecular characteristics of the tumor at initial early stage diagnosis. In addition, the Phase 2 FERGI study where fulvestrant was combined with the pan-pi3k inhibitor pictilisib, which predominantly inhibits Pi3Kα/δ activity, showed a trend to PFS improvement for dual treatment from 3.8 to 6.2 months (HR 0.77 [95% CI 0.50, 1.19]). 22 The Pi3Kα inhibitor taselisib in combination with fulvestrant is in phase 3 development for patients with hormone receptor positive locally advanced or metastatic breast cancer enriched with PiK3CA-mutant tumors. 23 AKT inhibition Downstream of Pi3K, continued AKT phosphorylation has been seen in AI-resistant cell lines with synergy observed for dual therapy with an AI and the AKT inhibitor MK Following a successful Phase I study the combination of anastrozole and MK-2206 has entered a Phase II trial. 25,26 SRC inhibition The SRC non-receptor tyrosine kinase pathway interacts with a range of up- and downstream elements including ER and HER family systems as well as the Pi3K RAS/RAF/MEK network. SRC activation correlates with tamoxifen resistance in vitro and poor prognosis in vivo. 27 In adjuvant patients SRC activity was associated with increased relapse after tamoxifen completion. 28 Preclinical in vitro and in vivo studies of the SRCspecific tyrosine-kinase inhibitor (TKI) saracatinib show dual blockade with fulvestrant or AIs, can overcome anti-estrogen resistance, and improve tumor control compared to either drug alone. 29 The randomized ARISTACAT trial comparing an AI alone with an AI in combination with saracatinib completed recruitment in 2015 with results anticipated shortly. 30 JAK inhibition Janus kinases (JAKs) mediate cytokine and growth hormone signaling. 31 The JAK1/JAK2 inhibitor, ruxolitinib, is currently in Phase 2 trial in combination with exemestane in advanced estrogen receptor positive breast cancer. 10 Targeting cell cycle entry CDK4/6 inhibition Cyclin-dependent kinase (CDK)4/6 is a downstream target of ER signaling, regulating cell entry into the cell cycle. Inhibitors of CDK4/6 are being extensively studied. Many of these studies include subgroup analyses to identify those patients mostly likely to respond. The addition of a selective CDK4/6 inhibitor palbociclib to letrozole showed a significant improvement in PFS (20.2 vs 10.2 months; HR 0.49 [95% CI 0.32, 0.75]) in the fırstline treatment of hormone receptor positive advanced breast cancer. 32 Subsequently, a comparable benefit was seen with palbociclib in combination with fulvestrant (PFS 9.5 vs 4.6 months; HR 0.46 [95% CI 0.36, 0.59]) in more advanced settings with a similar toxicity profile in each arm. 33 Looking at other molecules in the class, a phase 3 trial of ribociclib, used first or second line in combination with fulvestrant (MONALEESA-3) is currently ongoing. 34 Abemaciclib in combination with an NSAI is also in phase 3 development in the MONARCH 3 trial. 35 Targeting ER-associated proteins HSP90 inhibition Molecular chaperones are proteins that guide the movement of regulators of cell growth, differentiation and survival. 36 HSP90 is a core chaperone of estrogen receptors and other key oncogenic proteins. Many other tumorigenic proteins, including HER2 and AKT, are HSP90 clients and may also be inhibited, potentially conferring benefits across multiple pathways simultaneously. 37 HSP90 inhibitors have anti-cancer activity in both tamoxifen-sensitive and tamoxifen-resistant cells. 37,38 The HSP90 inhibitor, ganetesipib showed modest clinical activity in breast cancer overall, but with useful response rates in ER positive, HER2 positive tumors. 39 Targeting mutated ERs An emerging mechanism of anti-estrogen resistance is the mutation of the estrogen receptor gene ESR1, seen in approximately 20% of endocrine resistant metastatic cancers. 40 The novel estrogen receptor degrader GDC- 0810, is now being compared to fulvestrant in a Asia-Pac J Clin Oncol 2016; 12(Suppl. 1): 19 31

8 26 A. Redfern et al. randomized Phase II trial in women with AI-resistant advanced breast cancer. 10 Targeting histone acetylation to restore anti-estrogen sensitivity The HDAC inhibitor, entinostat showed an improvement in PFS (4.3 vs 2.3 months; HR 0.73 [95% CI 0.50, 1.07]), and a significant improvement in OS (28.1 vs 19.8 months; HR 0.59 [95% CI 0.36, 0.97]) in the EN- CORE 301 phase 2 study in patients previously treated with an NSAI. The follow-on phase 3 E2112 trial in the same patient population is ongoing. 41,42 Complex novel agent combination Observed benefits for the addition of novel agents to standard endocrine therapy look set to improve OS. The inevitable question that arises is whether still greater benefits may be achieved by rational drug combinations and the extent to which such benefits may be tempered by additive toxicities. The triplet combination of the CDK4/6 inhibitor ribociclib with the Pi3K-α inhibitor, alpelisib and letrozole has demonstrated preliminary clinical activity in heavily pre-treated patients with hormone receptor positive advanced breast cancer with an acceptable safety profile. 43 In contrast, the combination of an IGFR inhibitor in combination with an mtor inhibitor and an AI was stopped early due to a stomatitis rate of 68%. 44 Further attempts to address the low activity of IGF-1R inhibitors as single agents by combination with MEK, mtor and NOTCH inhibitors have been met with high toxicity limiting feasibility going forward, 45 demonstrating that complex trials and cautiously incremental dosage schedules will be required as we move forward with further complex combinations. Quality of life Women with hormone receptor positive, HER2 negative metastatic breast cancer can be considered to have a chronic disease requiring continued therapy, as survival has increased. 46 Toxicities associated with treatment impact on the QoL of these women. The chronicity of these therapies results in persistent impacts on QoL. Such treatment-related detriment may be countered by QoL improvements ensuing from treatment response. Currently, limited data are available to evaluate the direct impact of newer agents on patient reported QoL outcomes. By way of illustration, of the 32 studies in our systematic review, QoL data were only available for two studies, BOLERO-2 and PALOMA-3. This is disappointing, given that QoL is a critically important aspect influencing treatment selection in women contemplating these potentially long duration therapies. 47 Everolimus is associated with stomatitis, fatigue, hyperglycaemia and pneumonitis and these known effects need to be balanced with the individual patient circumstances and comorbidities. 11 Direct QoL results from BOLERO- 2, 48 however, show that the addition of everolimus to exemestane did not adversely impact QoL overall. Patients who did not drop out early maintained QoL, whereas patients who dropped out early, and those randomized to the standard arm of exemestane plus placebo, had worsening QoL over time. Hematological toxicities have been reported with CDK4/6 inhibitors in clinical trials, albeit with a very low rate of co-existing sepsis. Correspondingly, in the PALOMA-3 trial, global QoL was maintained on treatment at significantly higher levels with the CDK4/6 inhibitor, palbociclib plus fulvestrant, along with a significant improvement in emotional functioning and pain control, compared to placebo plus fulvestrant. 49 The ongoing BELLE-2 buparlisib study includes patient reported outcomes for global health status and QoL as a secondary endpoint. 8 The E2112 entinostat trial includes a secondary endpoint to evaluate the differences in overall health-related QoL. 41,42 Careful selection of patients and management of toxicities or judicious dose-reduction can ensure the efficacy benefit can be achieved in concert with maintained or improved QoL for the patient. As data continue to accrue and efficacy is established for a broader range of agents, more QoL data are expected to emerge. We recommend that QoL and other patient reported outcomes are included in clinical trial protocols as a priority. Predictive markers and individualized therapy Predictive biomarkers of both acquired and de novo (primary) resistance are required to improve patient selection and identify poor-responders who may benefit from alternative first and later-line treatments. Some patients may respond optimally with anti-estrogen therapy alone while others perform poorly despite combination therapy. The additional toxicity and financial burden of adding a novel agent addition can be avoided in such patients. The use of predictive biomarkers would reserve expensive and potentially toxic combination treatments for those most likely to experience substantial additional benefit. Although this simple premise has been extensively explored across the majority of recent trials in this area (Table 2), Asia-Pac J Clin Oncol 2016; 12(Suppl. 1): 19 31

9 HR+ HER2-metastatic breast cancer 27 Table 2 Biomarkers of response Target Agent Trial Phase N overall biomarker Overall PFS significance for trial Potential biomarkers with no association Potential biomarkers with significant association mtor Everolimus BOLERO Everolimus TAMRAD PI3K Buparlisib BELLE Pictilisib FERGI NR EGFR Gefitinib Gefitinib Nolvadex-Iressa HER1/2 Lapatinib EGF Lapatinib CALGB VEGF Cediranib D8480C NR CDK 4/6 Palbociclib PALOMA Palbociclib PALOMA HDAC Entinostat Encore Androgen receptor Abiraterone BCA < Mutation: PI3K, FGFR1, p53, cyclin D1, Activity: PI3K Expression: PTEN, pakt, eif4e, S6RP, and ps6rp High versus low cumulative mutations across FGFR1/2, cyclin D, PI3K HR = 0.62 (p = non-sig) versus 0.39 (p = sig) High versus low p4ebp1 HR = 0.35 (p = 0.02) versus 0.88 (p = 0.8) High versus low Pi3K HR = 1.09 (p = 0.83) versus 0.15 (p = 0.008) High versus low LKB1 HR = 0.67 (p = 0.32) versus 0.33 (p = 0.02) <0.001 Activity: Pi3K PiK3CA mutation versus no mutation in ctdna benefit HR = 0.56 (p<0.01) versus 1.05 (p = 0.642) PIK3CA mutation versus wt HRs 0.73 versus 0.72 ORR higher muts (16 versus 2%) NR Expression: IGFR-1, EGFR, HER3, SRC3, p27, HER2, EGF serum, pakt Expression: EGFR, p27, pakt, perk PR pos versus PR neg HR = 0.44 versus 1.22, p = for association Lum A versus Lum B HR = 0.6 versus NR Trends to better HR HER2 pos HR = 0.54 (p = 0.11) Low ER versus high ER sig better (HR NR, p NR) NR NR HER2 pos versus neg HR = 0.71 (p = 0.019) versus 0.90 (p = 0.188) 0.37 HER 2 interaction p = Expression: bfgf, serum VEGF & VEGFR NR NR NR Cyclin D1 amp/p27 loss present versus absent HR = 0.37 versus 0.19 (p NR) <0.001 Expression: PR NR Expression: PR Cycle 1 B cell acetylation positive: HR 0.32 (95% CI ) within experimental arm Expression: AR PR pos versus PR neg HR = 1.14 versus (p NR) visceral versus bone only HR = 0.51 versus 2.09 (p = 0.009) All HRs are for PFS and are for the comparison between added trial agent and placebo. Asia-Pac J Clin Oncol 2016; 12(Suppl. 1): 19 31

10 28 A. Redfern et al. many mechanistically plausible biomarkers did not turn out to predict benefit. Potentially useful predictors that have emerged include: low mutational load and low PI3K expression for mtor inhibitors, PR positivity for PI3K inhibitors, PR negativity for anti-androgens, and lower ER in EGFR inhibitors, although all require further validation. The only biomarkers currently confirmed to carry enough predictive power for routine clinical practice remain estrogen, progesterone and HER2 receptors. The sensitivity of ER positive tumors to endocrine therapy may reflect the extent to which individual tumors are dependent on ER pathways, their dependency on estrogen for activation of ERs, or the potential for activation of co-signaling pathways. 6 The failure of biomarker studies thus far to identify useful predictors of response likely relates to three factors. Firstly, the majority of studies interrogated the archived primary breast tumor tissue rather than a contemporary tumor sample, and thus may poorly reflect the biology of the metastatic deposits being treated. A number of phenotypic and genotypic changes can occur between primary excision and relapse, particularly with the widespread application of adjuvant hormonal therapy. Further, serial studies looking at post-treatment compared to pre-treatment tumor tissue may be required as data on the changes induced by treatment are unlikely to be derived from pre-therapy tissue alone. Studies using CTC s and circulating tumor DNA, if informative, may prevent the need for repeated biopsy. Secondly, it may be that simple mutational or expression studies on fixed tissue are insufficiently dynamic to capture the required predictive information. Novel paradigms may be required such as studies employing complex assays of phosphorylation reactions in ex vivo cultured patient cells exposed to putative treatments. New imaging modalities such as estradiol-labeled PET scanning to investigate biomarker expression in tumors in vivo across treatments may also aid the collection of predictive information. Finally, tumor biomarker studies fail to take account of drug pharmacokinetics commencing with the assumption that sufficient active drug is present in the tumor to achieve benefit in sensitive tumors. Surrogate pharmacodynamic studies should be considered such as those employed in ENCORE 301, showing white blood cell deacetylation correlated with efficacy. Additionally, correlation of toxicity with efficacy such as studies correlating hot flushes with tamoxifen benefit and incidence of hypertension with bevacizumab benefit may give early indications of benefit or lack thereof as well as potentially guiding dose adjustment. DISCUSSION The introduction of more targeted agents to the Australian market is likely to raise questions for many clinicians when considering patient outcomes in terms of survival benefit relative to QoL. Current European guidelines recommend the use of an AI, tamoxifen or high-dose fulvestrant (i.e. 500 mg every 4 weeks) first line, with the addition of everolimus to an AI in the second line. Alternative second line options include tamoxifen, another AI (with a different mechanism of action), fulvestrant, and megestrol acetate. Chemotherapy should largely be reserved for cases of rapidly progressive disease, high burden visceral disease or proven endocrine resistance. 11 With positive data and potential near term approval on the horizon for combination therapies including CDK4/6 inhibitors, and with initial promising data awaiting confirmation for HDAC and Pi3K inhibitors, clinical decisions and advice to patients will need to balance added toxicity and the need for increased toxicity monitoring with improved efficacy with these agents. The overall QoL benefit to patients on combination agents such as mtor inhibitors and CDK4/6 inhibitors, considering the additional toxicities, will need to be balanced against the QoL gained from use of an AI or tamoxifen alone in uncomplicated patients. Current drug development for endocrine resistant tumors aims to test new combinations in clinically resistant populations, broadly defined by disease progression on prior endocrine therapy. The lack of tools to define mechanisms of resistance in individual patients has led to the scattered development of targeted agents in unselected populations. But effective strategies for low frequency resistance mechanisms may not produce a signal in these populations. In addition, heterogeneity of resistance mechanisms between metastases within an individual patient may confound RECIST evaluation of response and progression. Defining populations with a specific alteration in a given signaling pathway would improve the likelihood of benefit from a targeted agent and limit unnecessary exposure to toxicity. Correlative biological studies are needed for predictive tests to emerge and define these populations. Strategies to prevent the emergence of resistance are a priority for drug development, particularly in high-risk patients, and in the adjuvant setting. Without the availability of predictive tests we face the prospect of having multiple strategies available to clinicians and their patients without clear evidence to guide the choice and sequencing of these promising novel therapies. Asia-Pac J Clin Oncol 2016; 12(Suppl. 1): 19 31

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