Sesiones interhospitalarias de cáncer de mama

Revisión bibliográfica 4º trimestre 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

• OS for fulvestrant 500 mg versus anastrozole as first-line endocrine therapy for advanced breast cancer.

FIRST study. JCO 2015

• Prospective Validation of a 21-Gene Expression Assay in Breast Cancer TAILORx. NEJM 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

• Impact of intrinsic subtype in pCR rate to trastuzumab, lapatinib or combination of trastuzumab plus lapatinib

CALGB 40601. JCO 2015

Selected papers

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.

TAILORx: Design

Oncotype DX assay

TAILORx: Design

Oncotype DX assay

Primary study group RS 11-25

Randomly assigned

ARM B Hormonal therapy alone

ARM C Chemotherapy +

Hormonal Therapy

TAILORx: Design

Oncotype DX assay

Secondary study group 1 RS < 11

Primary study group RS 11-25

ARM A Hormonal therapy alone

Randomly assigned

ARM B Hormonal therapy alone

ARM C Chemotherapy +

Hormonal Therapy

TAILORx: Design

Oncotype DX assay

Secondary study group 1 RS < 11

Primary study group RS 11-25

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

Key Eligibility Criteria • Node-negative

• ER-pos, HER2-neg • T1c-T2 (high-risk T1b)

• Age 18-75 years • No PBI planned

TAILORx: Inclusion Criteria & Rational for RS

Cutpoints

To minimize the potential for undertreatment the RS ranges used differed from those that were originally defined.

Recurrence Score = 11 • 7.3% distant recurrence rate

at 10 years • 95% CI 5%, 10%

• Low (≤10 vs. <18), • Intermediate (11 to 25 vs. 18 to 30) • High (≥26 vs. ≥31)

Recurrence Score = 25 • 16.1% distant recurrence rate

at 10 years • 95% CI 13%, 20%

Primary end point: 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.

TAILORx: Objectives

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

RS < 11 RS 11-25 P Value

No. eligible patients 1626 6897

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

TAILORx: Patient Characteristics and Treatment

RS < 11 RS 11-25 P Value

No. eligible patients 1626 6897

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)

TAILORx: Patient Characteristics and Treatment

Results: Kaplan Meier Plots and 5 Year Event Rates

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

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

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

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

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. 11-25

•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 11-25

•RxPONDER, OPTIMA - node-positive disease with a RS 25 or lower

•MINDACT – test other gene expression assays

Fulvestrant HD (n=102) 500 mg fulvestrant (i.m., two 250 mg injections) days 0, 14±3, and 28 ±3, then q28 ±3 days

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

Anastrozole (n=103) 1 mg/day po

FIRST: A Phase II, Open-Label Multicenter Trial of Fulvestrant HD Versus Anastrozole

• 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)

FIRST: Overall Survival Follow-up

FIRST: Overall Survival

FIRST: Overall Survival Subgroups Analysis

FIRST: SAEs and Deaths

OS advantage consistent with OS benefit in the second-line setting in CONFIRM trial.S

Strengths and limitations

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

Small sample size.

Strengths and limitations

OS analysis was not specified in the original protocol.

35 patients didn`t contribute to the OS follow-up

(patient or participating center decision).

Fulvestrant 500 mg +

Placebo

Randomization 1:1 (n=450)

Postmenopausal women presenting with ER+ and PgR+ LA/MBC not previously treated with any hormonal therapy.

R

Anastrozole 1 mg +

Placebo

Ongoing phase III study: FALCON

FALCON: Fulvestrant and AnastrozLe Compared in hormonal therapy Naive advanced breast cancer ClinicalTrials.gov identifier: NCT01602380

The first time an endocrine monotherapy has demonstrated improved efficacy compared with a third-generation AI.

Conclusions

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

• 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

Background

Surgery

Clinical Stage II-III HER 2 +

wT + H x 16 w

wT + L x 16 w

wT + H + Lx 16 w

Recommended: Dose-dense AC H x 34 w

Research tissue

Research tissue

CALGB 40601: Design

• 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

CALGB 40601: Objectives

CALGB 40601: pCR Rate

P= 0.13

P= 0.01

CALGB 40601: Pretreatment Intrinsic subtype

CALGB 40601: pCR Rate by intrinsic subpype

Classification of Samples Post-Treatment

Classification of Samples Post-Treatment

Classification of Samples Post-Treatment

• 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.

Conclusions

• 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.

Background

• Prospectively assess the effect of removal of primary tumor on overall survival in women presenting with metastatic breast cancer

MBC n=691

Anthracyclines +/- Taxanes (CR or PR)

(n=415)

R

Loco-Regional Treatment (n=173)

No Loco-Regional Treatment (n=177)

Site of Metastasis Visceral Bone Visceral + bone

nº of Metastasis 2-3 >3

ER/PR Positive Negative

Stratification

Design

n=350

Systemic treatment before progression

Kaplan-Meier Plot of OS

19.2 months [95% CI 15.98–22.46] vs 20.5 months [16.96–23.98]; HR 1.04, 95% CI 0.81–1.34; p=0.79;

OS Subgroup Analyses

Locoregional PFS Distant PFS

NR vs 18.2 months [95% CI 15.1–21.3]; HR 0.16, 95% CI 0.10–0.26; p<0.0001

11.3 vs 19.8 months; HR 1.42, 95% CI 1.08–1.85; p=0.012;

• 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.

Limitations

• 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

Conclusions

• 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.

Hypotheses Emerging From Previous Trials

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

Data Received and Included in Analyses

Recurrence Rate (All patients)

Distant Recurrence Rate (All patients)

Bone Recurrence Rate (All patients)

Breast Cancer Mortality (All patients)

Subgroup analysis of effects on Bone Recurrence Rate

Bone Recurrence Rate

Premenopausal Postmenopausal

Recurrence outside bone rate

Premenopausal Postmenopausal

Breast cancer mortality

Premenopausal Postmenopausal

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

• Adjuvant bisphosphonates reduce bone metastases and

improve survival in post-menopausal women

• 34% reduction in risk of bone recurrence (p=0.00001)

• 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 pre-

menopausal women.

• No significant effects on non-breast cancer deaths,

contralateral breast cancer or loco-regional recurrence.

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.

Conclusions

• 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.

• 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

• pCR after neoadjuvant antiHER2 therapy is markedly higher among HER2-enriched tumors than among HER2-positive tumors of any other subtype. CALGB 40601

CALGB 40601: pCR Rate by intrinsic subpype

Fulvestrant 500 mg (n=102)

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

Anastrozole 1 mg (n=103)

FIRST: A Phase II, Open-Label Multicenter Trial of Fulvestrant HD Versus Anastrozole