Actualización de ensayos clínicos y moléculas en desarrollo en CMM, RH-positivo. Miquel Àngel Seguí Palmer

Transcripción

1 Actualización de ensayos clínicos y moléculas en Miquel Àngel Seguí Palmer

2 Selection of patients with advanced breast cancer as appropriate for endocrine manipulation according to hormone receptor status is a successful strategy. Unfortunately, the emergence of resistance is inevitable and subsequent treatment is not well defined. Numerous mechanisms have been implicated in the development of resistance; central among them is the activation of compensatory signaling pathways.

3 Endocrine resistance is a major problem, and a distinction is made between primary and secondary resistance. A significant proportion of patients have de novo or primary resistance, or they develop endocrine resistance during the course of treatment Definitions of Endocrine Resistance

4 Targetable genomic alterations under clinical investigation or with potential clinical relevance in metastatic ER+HER2 breast cancers Turner NC, et al. Lancet 2016

5 Key Pathways of Endocrine Resistance ESR1 mutations SERDs

6 1. PI3K/Akt/mTOR Pathway 2. Inhibition of CDK4/6 3. PI3K/Akt/mTOR Pathway + Inhibition of CDK4/6 4. SERDs 5. HDAC Inhibitors 6. Immune Checkpoint Inhibition

7 1. PI3K/Akt/mTOR Pathway 2. Inhibition of CDK4/6 3. PI3K/Akt/mTOR Pathway + Inhibition of CDK4/6 4. SERDs 5. HDAC Inhibitors 6. Immune Checkpoint Inhibition

8 PI3K/Akt/mTOR Pathway Most frequently mutated signaling pathway in breast carcinoma PI3K activation is associated with both de novo and also acquired endocrine resistance.

9 PI3K/Akt/mTOR Pathway mtorc1 inhibitors Dual mtorc1/2 inhibitors Everolimus Temsirolimus AZD2014 TAK-228 (MLN0128) PI3K inhibitors Wortmannin LY BYL719 (alpelisib) GDC-0032 (Taselisib) BAY (Copanlisib) NK-1117 Pan-PI3K inhibitors BKM120 (Buparlisib) XL-147 (SAR245408) PX-866 PKI-587 (Gedatolisib) GDC-0941(Pictilisib) Dual PI3K/mTOR inhibitors BEZ235 BGT226 PF GDC-0980 XL-765 AKT inhibitors MK2206

10 PI3K/Akt/mTOR Pathway mtorc1 inhibitors Everolimus BOLERO-2 TAMRAD PrRECOG 0102 BOLERO-4 BOLERO-6 DESIREE UNIRAD

11 PI3K/Akt/mTOR Pathway mtorc1 inhibitors Everolimus BOLERO-2 TAMRAD PrRECOG 0102 BOLERO-4 BOLERO-6 DESIREE UNIRAD BOLERO-4: Phase 2 Trial of First-Line Everolimus Plus Letrozole in Estrogen Receptor Positive, Human Epidermal Growth Factor Receptor 2 Negative Advanced Breast Cancer. (NCT ) This study is ongoing. Additional second-line PFS, OS, and stomatitis substudy data will be reported and first-line efficacy results will be updated at a later date

12 PI3K/Akt/mTOR Pathway mtorc1 inhibitors Everolimus BOLERO-2 TAMRAD PrRECOG 0102 BOLERO-4 BOLERO-6 DESIREE UNIRAD BOLERO-6: A Phase II Study of Everolimus in Combination With Exemestane Versus Everolimus Alone Versus Capecitabine in Advance Breast Cancer. (NCT ) Primary Outcome Measures: Progression free survival

13 PI3K/Akt/mTOR Pathway mtorc1 inhibitors Everolimus BOLERO-2 TAMRAD PrRECOG 0102 BOLERO-4 BOLERO-6 DESIREE UNIRAD UNIRAD: Safety Study of Adding Everolimus to Adjuvant Hormone Therapy in Women With High Risk of Relapse, ER+ and HER2- Primary Breast Cancer, Free of Disease After Receiving at Least One Year of Adjuvant Hormone Therapy. (NCT ) Primary Outcome Measures: To evaluate the benefit from adding everolimus to standard endocrine treatments after two years of treatment on the DFS

14 PI3K/Akt/mTOR Pathway Dual mtorc1/2 inhibitors AZD2014 MANTA TAK-228 C31006

15 PI3K/Akt/mTOR Pathway Dual mtorc1/2 inhibitors AZD2014 MANTA TAK-228 C31006 MANTA: A Randomized Study of AZD2014 in Combination With Fulvestrant in Metastatic or Advanced Breast Cancer. (NCT ) Primary Outcome Measures: Progression free survival

16 PI3K/Akt/mTOR Pathway Dual mtorc1/2 inhibitors AZD2014 MANTA TAK-228 C31006 C31006 study: MLN0128 (TAK-228) in Combination With Fulvestrant in Women With Advanced or Metastatic Breast Cancer After Aromatase Inhibitor Therapy Postmenopausal women with advanced or metastatic ER positive, HER2 negative breast cancer that has progressed during or after aromatase inhibitor therapy n=153 R Arm A: Single-agent fulvestrant. Arm B: Combination of fulvestrant+daily MLN0128. Arm C: Combination of fulvestrant+weekly MLN0128. Primary Outcome Measures: Progression free survival

17 The PI3K pathway with respective PI3K inhibitors

18 PI3K/Akt/mTOR Pathway Pan-PI3K inhibitors Buparlisib BELLE 2 BELLE 3 Pictilisib FERGI

19 PI3K/Akt/mTOR Pathway Pan-PI3K inhibitors Buparlisib BELLE 2 BELLE 3 Pictilisib FERGI Serious (grade 3 or higher) toxicity was reported in 77.3% receiving buparlisib and 61% of those receiving pictilisib in the BELLE-2 and FERGI trials, respectively. The most commonly observed adverse events are elevated liver function enzymes, rash and hyperglycemia. Psychiatric disorders such as anxiety and depression have also been noted in patients receiving buparlisib.

20 PI3K inhibition for ER+ breast cancer: limitations and possible solutions

21 PI3K/Akt/mTOR Pathway PI3K inhibitors Alpelisib Taselisib

22 PI3K/Akt/mTOR Pathway PI3K inhibitors Alpelisib PIKNIC SOLAR-1 BYLieve Taselisib LORELEI POSEIDON SANDPIPER SOLAR-1: Study Assessing the Efficacy and Safety of Alpelisib Plus Fulvestrant in Men and Postmenopausal Women With Advanced Breast Cancer Which Progressed on or After Aromatase Inhibitor Treatment. (NCT )

23 PI3K/Akt/mTOR Pathway PI3K inhibitors Alpelisib PIKNIC SOLAR-1 BYLieve Taselisib LORELEI POSEIDON SANDPIPER BYLieve: Efficacy and Safety of Treatment With Alpelisib Plus Endocrine Therapy in Patients With HR+, HER2 negative abc, With PIK3CA Mutations, Whose Disease Has Progressed on or After CDK 4/6 Treatment With an Aromatase Inhibitor or Fulvestrant. (NCT ) Primary Outcome Measures: The percentage of patients who are alive without disease progression

24 PI3K/Akt/mTOR Pathway PI3K inhibitors Alpelisib PIKNIC SOLAR-1 BYLieve Taselisib LORELEI POSEIDON SANDPIPER LORELEI: A Study of Neoadjuvant Letrozole + Taselisib Versus Letrozole + Placebo in Post-Menopausal Women With Breast Cancer. (NCT ) Primary Outcome Measures: Percentage of Participants With Objective Response (OR) Percentage of Participants with Total Pathologic Complete Response (total pcr)

25 PI3K/Akt/mTOR Pathway PI3K inhibitors Alpelisib PIKNIC SOLAR-1 BYLieve Taselisib LORELEI POSEIDON SANDPIPER SANDPIPER Study: A Study Of Taselisib + Fulvestrant Versus Placebo + Fulvestrant In Patients With Advanced or Metastatic Breast Cancer Who Have Disease Recurrence or Progression During or After Aromatase Inhibitor Therapy. (NCT ) Primary Outcome Measures: Progression free survival

26 1. PI3K/Akt/mTOR Pathway 2. Inhibition of CDK4/6 3. PI3K/Akt/mTOR Pathway + Inhibition of CDK4/6 4. SERDs 5. HDAC Inhibitors 6. Immune Checkpoint Inhibition

27 Inhibition of CDK4/6 Palbociclib Ribociclib Abemaciclib Uncontrolled cellular proliferation mediated by dysregulation of the cell-cycle and activation of CDKs is one of the hallmarks of cancer

28 Inhibition of CDK4/6 Palbociclib PALOMA-1 PALOMA-2 PALOMA-3 PALOMA-4 FLIPPER PEARL PARSIFAL PALLET PENELOPE-B PALLAS Mechanism of Action of CDK4/6 Palbociclib

29 Inhibition of CDK4/6 Palbociclib PALOMA-1 PALOMA-2 PALOMA-3 PALOMA-4 FLIPPER PEARL PARSIFAL PALLET PENELOPE-B PALLAS FLIPPER: Comparison of Efficacy and Tolerability of Fulvestrant+Placebo vs Fulvestrant+Palbociclib as First Line Therapy for Postmenopausal Women With HR+ Metastatic BC Treated With 5 Years of Hormonal Therapy Remaining Disease Free More Than 12 Months After Completion or Have de Novo Metastatic Disease. (NCT ) (GEICAM ) Primary Objective: To compare the efficacy of fulvestrant in combination with palbociclib versus fulvestrant plus placebo in terms of the rate of PFS at 1 year.

30 Inhibition of CDK4/6 Palbociclib PALOMA-1 PALOMA-2 PALOMA-3 PALOMA-4 FLIPPER PEARL PARSIFAL PALLET PENELOPE-B PALLAS PEARL: Phase III Study of Palbociclib in Combination With Endocrine Therapy (Exemestane or Fulvestrant) Versus Chemotherapy (Capecitabine) in Hormonal Receptor Positive/HER2 Negative Metastatic Breast Cancer Patients With Resistance to Nonsteroidal Aromatase Inhibitors. (NCT ) Primary Outcome Measures: PFS based on the investigator's assessment

31 Inhibition of CDK4/6 Palbociclib PALOMA-1 PALOMA-2 PALOMA-3 PALOMA-4 FLIPPER PEARL PARSIFAL PALLET PENELOPE-B PALLAS PARSIFAL: Study to Evaluate the Efficacy and Safety of Palbociclib in Combination With Fulvestrant or Letrozole in Patients With ER+, HER2- Locally Advanced or Metastatic Breast Cancer. (NCT ) Primary Outcome Measures: 1year PFS

32 Inhibition of CDK4/6 Palbociclib PALOMA-1 PALOMA-2 PALOMA-3 PALOMA-4 FLIPPER PEARL PARSIFAL PALLET PENELOPE-B PALLAS PENELOPE-B: A Study of Palbociclib in Addition to Standard Endocrine Treatment in Hormone Receptor Positive Her2 Normal Patients With Residual Disease After Neoadjuvant Chemotherapy and Surgery. (NCT ) Primary Outcome Measures: Invasive disease free survival (idfs) for palbociclib vs. placebo n = 1100

33 Inhibition of CDK4/6 Palbociclib PALOMA-1 PALOMA-2 PALOMA-3 PALOMA-4 FLIPPER PEARL PARSIFAL PALLET PENELOPE-B PALLAS PALLAS: PALbociclib CoLlaborative Adjuvant Study: A Randomized Phase III Trial of Palbociclib With Standard Adjuvant Endocrine Therapy Versus Standard Adjuvant Endocrine Therapy Alone for Hormone Receptor Positive / Human Epidermal Growth Factor Receptor 2 Negative Early Breast Cancer (NCT )

34 Inhibition of CDK4/6 Palbociclib PALOMA-1 PALOMA-2 PALOMA-3 PALOMA-4 FLIPPER PEARL PARSIFAL PALLET PENELOPE-B PALLAS Palbociclib With Fulvestrant for Metastatic Breast Cancer After Treatment With Palbociclib and an Aromatase Inhibitor (NCT ). n=100 Sidney Kimmel Comprehensive Cancer Center In this phase II trial, the primary objective is to determine the PFS of palbociclib with fulvestrant in women and men with ER/PR positive, HER2 negative metastatic breast cáncer who progressed on treatment with palbociclib and an aromatase inhibitor. The study will also determine the prevalence rate of ESR1 and PI3K mutations in the study population. BioPER: A multicenter, international, noncontrolled, phase II trial to identify the molecular mechanisms of resistance and sensitivity to palbociclib re-challenge upon progression to a palbociclib combination in ER-positive metastatic breast cancer patients. n=30 MedSir Biological objective: To characterize the molecular patterns of resistance (upon progression to palbociclib plus endocrine therapy in patients who previously achieved clinical benefit with the combination. Clinical objective: To define the clinical activity of the combination of palbociclib and endocrine therapy after prior progression to palbociclib in endocrine-sensitive patients

35 Inhibition of CDK4/6 Ribociclib MONALEESA-1 MONALEESA-2 MONALEESA-3 MONALEESA-7 COMPLEEMENT-1 EarLEE-1 EarLEE-2

36 Inhibition of CDK4/6 Ribociclib MONALEESA-1 MONALEESA-2 MONALEESA-3 MONALEESA-7 COMPLEEMENT-1 EarLEE-1 EarLEE-2 MONALEESA-3: A phase III study of Ribociclib (LEE011) with Fulvestrant for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2- negative advanced breast cancer in postmenopausal women who have received no or only one line of prior endocrine therapy (NCT )

37 Inhibition of CDK4/6 Ribociclib MONALEESA-1 MONALEESA-2 MONALEESA-3 MONALEESA-7 COMPLEEMENT-1 EarLEE-1 EarLEE-2 MONALEESA-7: Study of Efficacy and Safety in Premenopausal Women With Hormone Receptor Positive, HER2-negative Advanced Breast Cancer. (NCT )

38 Inhibition of CDK4/6 Ribociclib MONALEESA-1 MONALEESA-2 MONALEESA-3 MONALEESA-7 COMPLEEMENT-1 EarLEE-1 EarLEE-2 COMPLEEMENT 1: Study to Assess the Safety and Efficacy of Ribociclib in Combination With Letrozole for the Treatment of Men and Pre/Postmenopausal Women With HR+ HER2- abc (NCT ) n=3000 Primary Outcome Measures: The number of participants with adverse events as a measure of safety and tolerability

39 Inhibition of CDK4/6 Ribociclib MONALEESA-1 MONALEESA-2 MONALEESA-3 MONALEESA-7 COMPLEEMENT-1 EarLEE-1 EarLEE-2 EarLEE-1: Adjuvant Ribociclib With Endocrine Therapy in Hormone Receptor+/HER2- High Risk Early Breast Cancer. (NCT ) Patient who received adjuvant chemotherapy and have AJCC 8th edition Prognostic Stage Group III tumor; or patient who received neoadjuvant chemotherapy and have 1 or more ipsilateral axillary lymph nodes with residual tumor metastases greater than 2.0 mm in lymph node(s) and residual tumor greater than 10.0 mm in breast tissue n=2000 Primary Outcome Measures: Invasive DFS using STEEP criteria EarLEE-2: Adjuvant Ribociclib With Endocrine Therapy in Hormone Receptor+/HER2- Intermediate Risk Early Breast Cancer (NCT ) Patient who received adjuvant chemotherapy and have AJCC 8th edition Prognostic Stage Group II n=4000 Primary Outcome Measures: Invasive DFS using STEEP criteria

40 Inhibition of CDK4/6 Abemaciclib NEOMONARCH MONARCH 1 MONARCH 2 MONARCH 3 nextmonarch 1 monarcher Scheduling is continuous and side effect profile is slightly different from the other CDK4/6 inhibitors. Grade 3 diarrhea is seen more often, whereas neutropenia occurs less frequently.

41 Inhibition of CDK4/6 Abemaciclib NEOMONARCH MONARCH 1 MONARCH 2 MONARCH 3 nextmonarch 1 monarcher

42 Inhibition of CDK4/6 Abemaciclib NEOMONARCH MONARCH 1 MONARCH 2 MONARCH 3 nextmonarch 1 monarcher nextmonarch 1: A Study of Abemaciclib (LY ) Plus Tamoxifen or Abemaciclib Alone in Women With Metastatic Breast Cancer. (NCT ) n=225 Primary Outcome Measures: Progression free survival

43 1. PI3K/Akt/mTOR Pathway 2. Inhibition of CDK4/6 3. PI3K/Akt/mTOR Pathway + Inhibition of CDK4/6 4. SERDs + 5. HDAC Inhibitors 6. Immune Checkpoint Inhibition

44 It is probably naive to believe that targeting a solitary signaling pathway will reverse all endocrine resistance mechanisms. Blockade of any given pathway may just promote or even enhance development of other compensatory escape mechanisms that will drive resistance. Therefore, the emphasis is now shifting towards targeting networks and pathways with combinations of key signaling inhibitors, either in parallel (socalled combined horizontal blockade) or in series (combined vertical blockade). It does carry the risk of increased toxicity. This strategy is being explored in current trials exploring the tolerability and efficacy of triplet regimens (including antiestrogen/mtor/cdk inhibitor and antiestrogen/pi3k/cdk inhibitor combinations) in advanced breast cancer.

45 PI3K/Akt/mTOR Pathway + Inhibition of CDK4/6 Preclinical work aiming to understand resistance to CDK4/6 inhibition, has suggested that HR. BC cells quickly adapt to CDK4/6 inhibition by activation of PI3K. Thus, by targeting the CDK4/6/retinoblastoma and the PI3K/Akt/mTORaxis we might be able to overcome or prevent resistance to CDK4/6 inhibitors. Herrera-Abreu MT et al. Cancer Res 2016

46 PI3K/Akt/mTOR Pathway + Inhibition of CDK4/6 Phases Ib/II Palbociclib+Everolimus+Exemestane (NCT ) Ribociclib+Everolimus+Exemestane (NCT ) Ribociclib+Everolimus+Exemestane (NCT ) TRINITI1: Study of Ribociclib With Everolimus + Exemestane in HR+ HER2- Locally Advanced/Metastatic Breast Cancer Post Progression on CDK 4/6 Inhibitor. Palbociclib + Taselisib / Pictilisib (PIPA, NCT ) Palbociclib + AZD2014 (PASTOR, NCT ) Ribociclib + Alpelisib + Letrozole) (NCT ) Primary Outcome Measures: Phase I: Maximum Tolerated Dose (MTD) and/or the Recommended Phase II Dose for the triplet combination. Phase II: Clinical Benefit Rate (CBR) among subjects receiving triplet therapy

47 1. PI3K/Akt/mTOR Pathway 2. Inhibition of CDK4/6 ESR1 mutations 3. PI3K/Akt/mTOR Pathway + Inhibition of CDK4/6 4. SERDs 5. HDAC Inhibitors 6. Immune Checkpoint Inhibition SERDs

48 SERDs Selective ER Downregulators (SERDs) are competitive ERa antagonists that also induce a conformational shift of the receptor that results in ubiquitination and subsequent degradation of ER, via the ubiquitin-proteasome system. A mechanism of resistance that has been recently suggested is the development of ESR1 mutations. Early BC samples showed a low presence of ESR1 mutations in 0.5% and of ESR1 amplification in 2.5% of the cases. In contrast, ESR1 mutations have been reported in 20-50% of recurrent or MBC after ET with AIs.

49 SERDs Theoretically, a strategy of completely or nearly completely destroying the ER, may lead to a more effective inhibition of highly ER-dependent tumors. The recognition that ERα remains a viable target even in the setting of endocrine resistance and the limitations of fulvestrant led to the search for a new generation of orally bioavailable highly selective SERDs. In particular, ER degraders may have a particular advantage in tumors with ESR1 mutations, which may emerge after estrogen deprivation strategies, but could potentially be less of a problem as a mechanism of resistance if ER is degraded.

50 SERDs Antitumor activity of GDC-0810 in a tamoxifenresistant breast cancer xenograft model. Joseph JD et al. Elife 2016

51 SERDs GDC-0810 GDC-0927 LSZ102 HydranGea: A Phase II, Open Label, Randomized Study of GDC0810 Versus Fulvestrant in Postmenopausal Women With Advanced or Metastatic ER+ /HER2 Breast Cancer Resistant to Aromatase Inhibitor Therapy. (NCT ) n=71 Primary Outcome Measures: PFS for all participants and for subset of participants with Estrogen Receptor (ESR)1 mutations. An Open Label, Phase I Study of GDC0927 in Postmenopausal Women With Locally Advanced or Metastatic Estrogen Receptor Positive Breast Cancer. (NCT ) n=90 Primary Outcome Measures: Maximum Tolerated Dose (MTD)/Recommended Phase II Dose (RP2D) of GDC0927. Percentage of Participants With Adverse Events An Open label,phase Ia/Ib/IIa Study of GDC0810 Single Agent or in Combination With Palbociclib and/or an LHRH Agonist in Women With Locally Advanced or Metastatic Estrogen Receptor Positive Breast Cancer. (NCT ) n=195 Primary Outcome Measures: Phase Ib: RP2D of GDC0810 When Used in Combination With Palbociclib and/or LHRH. Phase IIa: Percentage of Participants With Confirmed Objective Tumor Response of GDC0810. Phase I/Ib Trial of LSZ102 Single Agent or LSZ102 + LEE011 or LSZ102 + BYL719 in ER+ Breast Cancers. (NCT ) n=152 Primary Outcome Measures: Incidence of dose limiting toxicities (DLTs) Safety and tolerability of LSZ102 at the recommended dose for expansion

52 1. PI3K/Akt/mTOR Pathway 2. Inhibition of CDK4/6 3. PI3K/Akt/mTOR Pathway + Inhibition of CDK4/6 4. SERDs 5. HDAC Inhibitors 6. Immune Checkpoint Inhibition

53 HDAC Inhibitors Phase II ENCORE 301

54 HDAC Inhibitors Etinostat E2112: Exemestane With or Without Entinostat in Treating Patients With Recurrent Hormone Receptor Positive Breast Cancer That is Locally Advanced or Metastatic (NCT ) Primary Outcome Measures: OS PFS

55 1. PI3K/Akt/mTOR Pathway 2. Inhibition of CDK4/6 3. PI3K/Akt/mTOR Pathway + Inhibition of CDK4/6 4. SERDs 5. HDAC Inhibitors 6. Immune Checkpoint Inhibition

56 Immune Checkpoint Inhibition Anti PD-1 Pembrolizumab Anti PD-L1 Durvalumab

57 Immune Checkpoint Inhibition Anti PD-1 Pembrolizumab Anti PD-L1 Durvalumab A Phase 1b Study of Abemaciclib in Combination With Pembrolizumab for Patients With Stage IV Non Small Cell Lung Cancer or Hormone Receptor Positive, HER2 Negative Breast Cancer. (NCT ) n=25 Primary Outcome Measures: Number of Participants with One or More Serious Adverse Event(s) Number of Participants with NonSerious Adverse Event(s).

58 Immune Checkpoint Inhibition Anti PD-1 Pembrolizumab Anti PD-L1 Durvalumab Pembrolizumab, Letrozole, and Palbociclib in Treating Patients With Stage IV Estrogen Receptor Positive Breast Cancer With Stable Disease That Has Not Responded to Letrozole and Palbociclib. (NCT )

59 Immune Checkpoint Inhibition Anti PD-1 Pembrolizumab Anti PD-L1 Durvalumab ULTIMATE: Durvalumab and Endocrine Therapy in ER+/Her2- Breast Cancer After CD8+ Infiltration Effective Immune Attractant Exposure. (NCT ) The first cohort patients will receive tremelimumab (3 mg/kg, single infusion) as immune attractant Primary Outcome Measures: pathological Complete Response

60 Take home messages (1) Endocrine resistance in patients with HR-positive breast carcinoma continues to represent an oncological challenge. Efforts at elucidating the molecular mechanisms of endocrine resistance have revealed a number of targets that act downstream or upstream the ER or that crosstalk with it. Alterations in the PI3K signaling pathway are among the most frequent somatic mutations in ER-positive breast carcinomas, which are associated with endocrine resistance. Numerous PI3K inhibitors are currently undergoing preclinical and clinical development. Notable successes include agents targeting mtor and CDK4/6 in combination with endocrine therapy, whereas failures include the disappointing performance of pan-pi3k inhibition. Increasing target selectivity may improve efficacy while decreasing off-target toxicity, as has been seen with newer CDK4/6 inhibitors compared with earlier pan-cdk inhibitors. It is hoped that similar enhanced clinical utility will be seen with isoform-selective PI3K inhibitors.

61 Take home messages (2) Similarly, efforts to develop next-generation SERDs combining improved oral bioavaliability with enhanced ER targeting, HDAC Inhibitors and Immune Checkpoint Inhibition, appears promising. We need to better identify which patients are most likely to derive the most benefit from combination therapy, and design efficient clinical trials that take into account ER-positive disease biology and timing of additional intervention to modulate endocrine response. Equally important is to identify those patients with ER-positive disease that will be adequately controlled by endocrine therapy alone, in order to avoid the risk of overtreatment and unnecessary toxicity, and so that we continue to promote the core value of endocrine therapy as a simple treatment that preserves quality of life.

62 Take home messages (3) Defining populations with a specific alteration in a given signalling pathway could improve the likelihood of benefit from a targeted agent, limit unnecessary exposure to toxicity and allow the sustainability of these newer treatments. The ultimate goal is to apply developments to patients with early-stage breast cancer who may remain at risk of relapse because of failure of their adjuvant endocrine therapy. As such, the clinical benefit of the targeted combination strategies with proven efficacy in HR+ advanced breast cancer is being evaluated in double-blind, randomized, controlled clinical studies in the adjuvant setting.

63 Treatment landscape and research questions in postmenopausal women with metastatic ER+HER2 breast cancers Turner NC, et al. Lancet 2016

64