Sesiones interhospitalarias de cáncer de mama. Revisión bibliográfica 4º trimestre 2015

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1 Sesiones interhospitalarias de cáncer de mama Revisión bibliográfica 4º trimestre 2015

2 Selected papers Prospective Validation of a 21-Gene Expression Assay in Breast Cancer TAILORx. NEJM 2015 OS for fulvestrant 500 mg versus anastrozole as first-line endocrine therapy for advanced breast cancer. FIRST study. JCO 2015 Impact of intrinsic subtype in pcr rate to trastuzumab, lapatinib or combination of trastuzumab plus lapatinib CALGB JCO 2015 Prospectively assess the effect of removal of primary tumor on overall survival in women presenting with metastatic breast cancer. Gupta et al. Lancet Oncol 2015 To clarify the risks and benefi ts of adjuvant bisphosphonate treatment in breast cancer. Meta-analyses Early Breast Cancer Trialists Collaborative Group (EBCTCG). Lancet Oncol 2015

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4 TAILORx: Background The magnitude of chemotherapy benefit appeared to increase continuously as the RS increased. A clear cutoff point for RS, below which there is no demonstrable benefit from chemotherapy, cannot be accurately defined. Validation in prospectively conducted studies will support the clinical validity and usefulnes of Oncotype DX.

5 TAILORx: Design Oncotype DX assay

6 TAILORx: Design Oncotype DX assay Primary study group RS Randomly assigned ARM B Hormonal therapy alone ARM C Chemotherapy + Hormonal Therapy

7 TAILORx: Design Oncotype DX assay Secondary study group 1 RS < 11 Primary study group RS ARM A Hormonal therapy alone Randomly assigned ARM B Hormonal therapy alone ARM C Chemotherapy + Hormonal Therapy

8 TAILORx: Design Oncotype DX assay Secondary study group 1 RS < 11 Primary study group RS Secondary study group 2 RS > 25 ARM A Hormonal therapy alone Randomly assigned ARM D Chemotherapy + Hormonal Therapy ARM B Hormonal therapy alone ARM C Chemotherapy + Hormonal Therapy

9 TAILORx: Inclusion Criteria & Rational for RS Cutpoints Key Eligibility Criteria Node-negative ER-pos, HER2-neg T1c-T2 (high-risk T1b) Age years No PBI planned To minimize the potential for undertreatment the RS ranges used differed from those that were originally defined. Recurrence Score = % distant recurrence rate at 10 years 95% CI 5%, 10% Recurrence Score = % distant recurrence rate at 10 years 95% CI 13%, 20% Low ( 10 vs. <18), Intermediate (11 to 25 vs. 18 to 30) High ( 26 vs. 31)

10 Primary end point: TAILORx: Objectives Invasive disease-free survival Invasive cancer event defined as the first event of recurrence of ipsilateral breast tumor, local recurrence, regional recurrence, distant recurrence, contralateral second primary invasive cancer, second primary nonbreast invasive cancer (excluding nonmelanoma skin cancer), or death without evidence of recurrence. Secondary end points: Time-to-event analyses of Freedom from the recurrence of breast cancer at a distant site. Freedom from any recurrence. Overall survival rate

11 TAILORx: Patient Characteristics and Treatment RS < 11 RS P Value No. eligible patients Median age 58 years 55 years P<0.001 Post-menopausal 70% 64% P<0.001 Median tumor size 1.5 cm 1.5 cm N.S Histologic grade Low Intermediate High 34% 59% 7% 29% 57% 14% P<0.001 ER Expression > 99% > 99% N.S. PgR Expression 98% 92% P<0.001 Surgery Lumpectomy Mastectomy 68% 32% 72% 28% P<0.001

12 TAILORx: Patient Characteristics and Treatment RS < 11 RS P Value No. eligible patients Median age 58 years 55 years P<0.001 Post-menopausal 70% 64% P<0.001 Median tumor size 1.5 cm 1.5 cm N.S Histologic grade Low Intermediate High 34% 59% 7% 29% 57% 14% P<0.001 ER Expression > 99% > 99% N.S. PgR Expression 98% 92% P<0.001 Surgery Lumpectomy Mastectomy 68% 32% 72% 28% P<0.001 Endocrine therapy in low RS group: AI in 59%, tamoxifen in 34%, sequential tamoxifen- AI in 1%, OFS plus other therapy (3%), or other/unknown (3%) Chemotherapy given to 6 patients in low RS group: (1 of whom recurred)

13 Results: Kaplan Meier Plots and 5 Year Event Rates

14 Results: Kaplan Meier Plots and 5 Year Event Rates No. of events: 88 idfs events and 30 deaths within 5 years of registration, including 18 recurrences (10 distant as first event), 15 second primary breast cancers, 43 other second primary cancers, 12 deaths without another event

15 Results: Kaplan Meier Plots and 5 Year Event Rates No. of events: 88 idfs events and 30 deaths within 5 years of registration, including 18 recurrences (10 distant as first event), 15 second primary breast cancers, 43 other second primary cancers, 12 deaths without another event

16 Results: Kaplan Meier Plots and 5 Year Event Rates No. of events: 88 idfs events and 30 deaths within 5 years of registration, including 18 recurrences (10 distant as first event), 15 second primary breast cancers, 43 other second primary cancers, 12 deaths without another event

17 Results: Kaplan Meier Plots and 5 Year Event Rates No. of events: 88 idfs events and 30 deaths within 5 years of registration, including 18 recurrences (10 distant as first event), 15 second primary breast cancers, 43 other second primary cancers, 12 deaths without another event

18 Conclusions Women with axillary node-negative, ER-positive, HER2-negative breast cancer and RS < 11 have a 1% risk of distant recurrence at 5 years with endocrine therapy alone Clinical characteristics could not reliably distinguish patients with a RS <11 vs Since adjuvant chemotherapy prevents mostly early recurrences within 5 years, chemotherapy may be spared in this population. Additional work needed to determine whether more may be spared chemo TAILORx - node-negative disease with a RS RxPONDER, OPTIMA - node-positive disease with a RS 25 or lower MINDACT test other gene expression assays

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20 FIRST: A Phase II, Open-Label Multicenter Trial of Fulvestrant HD Versus Anastrozole Eligibility (n=205) Postmenopausal, ER+ and/or PgR+ advanced BC No prior endocrine therapy for advanced disease Prior endocrine therapy for early disease allowed provided completion occurred > 12 months before R Fulvestrant HD (n=102) 500 mg fulvestrant (i.m., two 250 mg injections) days 0, 14±3, and 28 ±3, then q28 ±3 days Anastrozole (n=103) 1 mg/day po

21 FIRST: Overall Survival Follow-up Primary endpoint: Clinical Benefit Rate (CBR) Secondary endpoints: ORR, TTP, DoCB, DoR Overall (OS) analysis OS was not definied as endpoint in original protocol Following protocolol amendment in Feb 2011 Analysis planned for at least 65% maturity (after 133 patients had died) Median follow-up Fulvestrant 49.6 moths Anastrozole: 42.5 months Analysis conducted at 66.8% maturity (137 patients had died)

22 FIRST: Overall Survival

23 FIRST: Overall Survival Subgroups Analysis

24 FIRST: SAEs and Deaths

25 Strengths and limitations OS advantage consistent with OS benefit in the second-line setting in CONFIRM trial.s Median OS for anastrozole group higher than previously reported. Limits to overestimate the margin of improvement if the control arm had underperformed. Only 3 patients previously exposed to adjuvant AI AI resistance resulting from previous AI exposure cannot account for the observed OS difference. Similar response to subsequent therapies between the treament groups. Differential second-line response is an unlikely explanation for the observed OS effect

26 Strengths and limitations Small sample size. OS analysis was not specified in the original protocol. 35 patients didn`t contribute to the OS follow-up (patient or participating center decision).

27 Ongoing phase III study: FALCON Randomization 1:1 (n=450) Postmenopausal women presenting with ER+ and PgR+ LA/MBC not previously treated with any hormonal therapy. R Fulvestrant 500 mg + Placebo Anastrozole 1 mg + Placebo FALCON: Fulvestrant and AnastrozLe Compared in hormonal therapy Naive advanced breast cancer ClinicalTrials.gov identifier: NCT

28 Conclusions The first time an endocrine monotherapy has demonstrated improved efficacy compared with a third-generation AI. Alternative in first line to AI the standard of care would be an IA, but individual physicians would have discussions about that with their patients. Justifies the election of fulvestrant as control arm in first-line clinical trials in combination with targeted therapy (CDKs Inhibitors) 1-Robertson et al. SABCS 2014

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30 Background In patients with metastatic HER2 + BC disease, the use of two HER2-targeted drugs (pertuzumab + trastuzumab or lapatinib + trastuzumab has improved survival. In randomized neoadjuvant trials, dual HER2 targeting generally results in higher pcr rates, but the magnitude of this effect has varied. In addition to treatment, several biologic features are implicated in response heterogeneity to HER2 targeting, including tumor intrinsic subtype, hormone receptor status, alterations in signaling pathways such as PI3K, ER and HER family members, and host factors such as antitumor immune response

31 CALGB 40601: Design Research tissue Research tissue wt + H x 16 w Clinical Stage II-III HER 2 + wt + L x 16 w Surgery Recommended: Dose-dense AC H x 34 w wt + H + Lx 16 w

32 CALGB 40601: Objectives Primary end point: pcr in the breast Secondary end point: pcr in breast and ipsilateral axillary lymph nodes Primary Correlative objective: pcr rate by intrinsic subtype Secondary Correlative objectives: Association of pcr with 15 established signatures reflecting cell cycle, pathway signaling and microenvironment Relative changes in gene expression pre- to posttreatment

33 CALGB 40601: pcr Rate P= 0.01 P= 0.13

34 CALGB 40601: Pretreatment Intrinsic subtype

35 CALGB 40601: pcr Rate by intrinsic subpype

36 Classification of Samples Post-Treatment

37 Classification of Samples Post-Treatment

38 Classification of Samples Post-Treatment

39 Conclusions In CALGB 40601, the addition of lapatinib to 16 weeks of treatment with trastuzumab and paclitaxel increases pcr rate in HR - HER2 + tumors. Biologic heterogeneity within HER2 + BC plays an important role in determining response to treatment. pcr was markedly higher among HER2-enriched tumors than among HER2- positive tumors of any other subtype. The distribution of molecular subtypes of residual disease differed from that of untreated tumors. Under the selective pressure of combined HER2 targeting and chemotherapy, a high proportion of residual tumors demonstrated the luminal A subtype Optimizing the selection of HER2-targeted regimens by identifying subpopulations of patients with HER2-positive disease who need more or less therapy could be cost effective and would spare some patients unnecessary exposure to ineffective treatments.

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41 Background Data from experiments in animal models of different cancers have suggested that surgical removal of the primary tumour could potentially increase metastatic spread. Removal of the primary tumour could potentially improve the outcome in breast cancer by removing drug resistant clones of cancer cells. Meta-analysis of retrospective trials suggest improved OS with surgical resection of the primary tumour. Results were probably affected by selection bias and a limited ability to control for potential confounding factors. Prospectively assess the effect of removal of primary tumor on overall survival in women presenting with metastatic breast cancer

42 Design MBC n=691 Anthracyclines +/- Taxanes (CR or PR) (n=415) n=350 R Loco-Regional Treatment (n=173) No Loco-Regional Treatment (n=177) Stratification Site of Metastasis Visceral Bone Visceral + bone nº of Metastasis 2-3 >3 ER/PR Positive Negative

43 Systemic treatment before progression

44 Kaplan-Meier Plot of OS 19.2 months [95% CI ] vs 20.5 months [ ]; HR 1.04, 95% CI ; p=0.79;

45 OS Subgroup Analyses

46 Locoregional PFS Distant PFS NR vs 18.2 months [95% CI ]; HR 0.16, 95% CI ; p< vs 19.8 months; HR 1.42, 95% CI ; p=0.012;

47 Limitations Absence of tailored treatment according to subtype. Near absence of HER2-targeted therapy and use very limited of taxanes and hormonal therapy. The adverse effect of locoregional treatment on distant progression-free survival is probably an artefact of the censoring strategy. About 40% of patients in the no locoregional teatment group who had locoregional progression were censored for future distant events. Follow up by physical examination, except the first TC at 12 weeks.

48 Conclusions PSLT should not be offered to patients with asymptomatic tumors unless in the setting of a clinical trial. The use of primary site local therapy may provide a local control advantage Only 18 (10%) of 177 women in the no locoregional treatment group required palliative surgery during follow-up Detriment in distant progression-free survival? More data are needed. Ongoing trials need to be completed A large benefit of primary site local therapy is unlikely

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50 Hypotheses Emerging From Previous Trials Bisphosphonates predominantly reduce distant metastasis rather than either local recurrence or contralateral disease Effects likely to be largest on bone recurrence Bisphosphonates only improve disease outcome in women who have low levels of reproductive hormones Established natural menopause Induced menopause at start of treatment Possible adverse effects on non-bone recurrence in premenopausal women. Individual patient meta-analysis or verified data on outcomes from all randomised trials that compared use of a bisphosphonate in the adjuvant setting (any type and schedule) vs no biphosphonate or placebo.

51 Primary Outcome & Subgroup Analysis Co- Primary outcomes Time to recurrence: includes distant recurrence, local recurrence and new second primary breast cancer (ipsilateral or contralateral). Time to first distant recurrence. Breast cancer mortality. Planned subgroup analysis Menopausal status: pre, peri, postmenopausal Type of bisphosphonate: aminobisphosphoate, clodronate Schedule of bisphosphonate: advanced cancer, bone protection

52 Data Received and Included in Analyses

53 Recurrence Rate (All patients)

54 Distant Recurrence Rate (All patients)

55 Bone Recurrence Rate (All patients)

56 Breast Cancer Mortality (All patients)

57 Subgroup analysis of effects on Bone Recurrence Rate

58 Bone Recurrence Rate Premenopausal Postmenopausal

59 Recurrence outside bone rate Premenopausal Postmenopausal

60 Breast cancer mortality Premenopausal Postmenopausal

61 Subgroup analysis of type and schedule of Bisphosphonate on Bone Recurrence Rate

62 Conclusions Adjuvant bisphosphonates reduce bone metastases and improve survival in post-menopausal women 34% reduction in risk of bone recurrence (p= ) 17% reduction in risk of breast cancer death (p=0.004) No significant reduction in first distant recurrence outside bone Risk reductions irrespective of ER, node status, use/non use of chemotherapy Benefits similar to aminobisphosphonates and clodronate No effects apparent on disease outcomes in premenopausal women. No significant effects on non-breast cancer deaths, contralateral breast cancer or loco-regional recurrence.

63 Conclusions ABCSG-18 trial has shown that adjuvant denosumab 60 mg/q6m sc reduces risk of disease recurrence or death in postmenopausal breast cancer women. The observed DFS is similar to the EBCTCG biphosphonate meta-analysis.

64 Women with axillary N0, ER +, HER2 - breast cancer and RS < 11 have excellent prognosis with endocrine therapy alone and don`t need adjuvant chemotherapy. TAILORx Fulvestrant 500 mg extends OS versus anastrozole in first line postmenopausal women with ER + locally advanced/metastatic breast cancer. FIRST study. pcr after neoadjuvant antiher2 therapy is markedly higher among HER2- enriched tumors than among HER2-positive tumors of any other subtype. CALGB Surgery should not be offered to patients with asymptomatic tumors unless in the setting of a clinical trial. Gupta et al. Adjuvant bisphosphonates reduce bone metastases and improve survival in post-menopausal women. EBCTCG meta-analysis

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66 CALGB 40601: pcr Rate by intrinsic subpype

67 FIRST: A Phase II, Open-Label Multicenter Trial of Fulvestrant HD Versus Anastrozole Eligibility (n=205) Postmenopausal, ER+ and/or PgR+ advanced BC No prior endocrine therapy for advanced disease Prior endocrine therapy for early disease allowed provided completion occurred > 12 months before R Fulvestrant 500 mg (n=102) Anastrozole 1 mg (n=103)