1. New Insights in the Hormone Therapy for Breast Cancer
11/11/16
James Waisman, MD
Clinical Professor
Medical Oncology
City of Hope

2. I do not have anything to disclose.
Disclosures
I do not have anything to disclose.

3. Breast Cancer Subtypes and Prognosis
Heterogeneity of outcome reproducibly identified across multiple datasets.
© 2016 National Comprehensive Cancer Network, Inc. All rights reserved.

4. Estrogen Receptor Signaling
Pietras & Marquez, 2008

5. PI3-Kinase Targeting

6. Comparison of First Line AI ± Fulvestrant Trials
FACT1
SWOG 02262
No. Patients
514
707
De Novo Metastatic Disease
13%
39%
Prior Adjuvant Chemotherapy
45%
33%
Prior Adjuvant Endocrine Therapy (TAM)
68%
40%
Prior Adjuvant AI
1.5%
excluded
Median TTP/PFS Range (mo)
10-11
13-15
PFS Benefit No
Yes
Median OS Benefit (mo)
No, 37.8 vs mos
Yes, 41.3 vs 47.7
mos
1. Bergh J, et al. J Clin Oncol. 2012;30:
2. Mehta RS, et al. N Engl J Med. 2012;367:435-44

7. Need for improved hormone therapy with minimal toxicity
FACT1: TTP
SWOG 02262: PFS
Bergh J, et al. J Clin Oncol. 2012;30:
Mehta RS, et al. N Engl J Med. 2012;367:435-44

8. FERGI Study Design – Part I
ER+, HER2-, postmenopausal women with advanced or MBC
Prior aromatase inhibitor in adjuvant (PD<6mo) or metastatic setting
ECOG PS 0, 1
No diabetic patients
0-1 chemotherapy or ≤2 prior endocrine therapies
Fulvestrant 500mg1 +
pictilisib (GDC-0941)
340 mg QD
Treat to PD2 R
1:1
Cross
Over
pictilisib + fulvestrant
Fulvestrant 500 mg1 +
placebo QD
Treat to PD2
N = 168
Stratification factors
1° objective
2° objectives
PIK3CA-MT and PTEN loss3
Measurable disease
1o vs. 2o resistance4
PFS in the ITT
PFS in PIK3CA-MT pts
Safety
Objective response rate
Duration of objective response PK
1 Administered on D1 of each 28 day cycle and C1D15; 2 Tumor assessments performed every 8 weeks; 3Exons 9 and 20 in the codons encoding amino acids E542, E545, and H1047 were detected by RT-PCR; 4 Disease relapse during or within 6 months of completing AI treatment in the adjuvant setting, or disease progression within 6 months of starting AI treatment in the metastatic setting. 5 Data presented is with an additional year of follow up per-protocol primary analysis.
Median duration of follow up 17.5 months
Finn et al. ASCO 2016

9. Progression-Free Survival in the ITT Population
Finn et al. ASCO 2016

10. Progression-Free Survival Based on Tumor PIK3CA Mutation Status
PIK3CA-Mutant Population
PIK3CA “Wild-Type” Population
PIK3CA mutation status does not predict benefit of the addition of pictilisib to fulvestrant
Finn et al. ASCO 2016

11. ctDNA PIK3CA Non-mutant n=387
Clinically Meaningful PFS Improvement in Patients With ctDNA PIK3CA Mutations
ctDNA PIK3CA Mutant n=200
Buparlisib +
Fulvestrant
n=87
Placebo
n=113
Median PFS, months (95% CI)
7.0 (5.0–10.0)
3.2 (2.0–5.1)
HR (95% CI)
0.56 (0.39–0.80)
One-sided nominal P value
<0.001
ctDNA PIK3CA Non-mutant n=387
Buparlisib +
Fulvestrant
n=199
Placebo
n=188
Median PFS, months (95% CI)
6.8 (4.7–8.5)
6.8 (4.7–8.6)
HR (95% CI)
1.05 (0.82–1.34)
One-sided nominal P value
0.642
Probability of Progression-free Survival, %
Time (Months)
100 60 80 40 20 4 8 14 18 2 6 10 12 16 22
Buparlisib + fulvestrant (n/N=48/87)
Placebo + fulvestrant (n/N=90/113)
Probability of Progression-free Survival, %
Time (Months)
100 60 80 40 20 4 8 14 18 2 6 10 12 16 26 28 22 24
Buparlisib + fulvestrant (n/N=124/199)
Placebo + fulvestrant (n/N=126/188)
Finn et al. ASCO 2016

12. Clinical Studies on ESR1 mutations lacking - detection
Primary breast cancer – activating, somatic ESR1 mutation < 1%
TCGA, Nature 2012
Advanced breast cancer somatic ESR1 mutation – metastatic series (19%)
Toy et al., AACR 2016
Presented by Sarat Chandarlapaty at 2016 ASCO Annual Meeting

13. What Is the Prevalence of Mutation?
D538G, Y537S/N/C
Circulating mutation frequency
44/144 patients mutated
63 mutations
(30.6%)
Augusto et al. ASCO 2016
Agreement with other studies of cfDNA in large populations of AI treated patients:
Spoerke et al. Nat Comm (37%)
Chandarlapaty et al. SABCS 2015 (29.8%
Turner et al. ASCO 2016
Presented by Sarat Chandarlapaty at 2016 ASCO Annual Meeting

14. Patients At Risk for Mutation?
Treatments
Wild type (n=100)
Mutant
(n=44) P
AI exposure before progression (mo.)
<3
3-6
>6
Median duration of exposure
4 (4)
25 (25)
71 (71)
10.5
2 (5)
42 (95) 15
0.002
0.02
Patients with ESR1 Mutation (%)
Augusto et al. ASCO 2016
Turner et al. ASCO 2016

15. PFS by ESR1 Mutation Status
ESR1 positive
ESR1 negative
PFS=progression-free survival.
March 2015 final PFS data cut, Cristofanilli et al. Lancet Oncol, 2016.

16. ESR1 Mutation Analysis by Digital PCR in the Randomized Phase III SoFEA Study
Johnston et al. Lancet Oncol, 2013; O’Leary et al. AACR, Fribbens et al. J Clin Oncol, 2016 (in press).

17. PALOMA-1/TRIO-18 Study Design (NCT00721409)
Cohort 1
Cohort 2
Palbociclib 125 mg/d† +
Letrozole
2.5 mg/d
Palbociclib 125 mg/d† +
Letrozole
2.5 mg/d
RANDOMIZATION*
RANDOMIZATION*
ER+/HER2− advanced breast cancer with CCND1 amplification and/or loss of p16
ER+/HER2− advanced breast cancer
1:1
1:1
Letrozole
2.5 mg/d
Letrozole
2.5 mg/d
n=66
n=99
Randomized phase II open-label trial involving 50 centers in 12 countries
Key eligibility criteria: inoperable ER+/HER2– locally recurrent disease, postmenopausal status, no prior therapy for advanced breast cancer, no prior CDK inhibitors, no letrozole within 12 months, no prior/current brain metastases, measurable disease (RECIST 1.0) or bone-only disease, ECOG performance status ≤1, adequate bone marrow and renal function
*Randomization stratified by disease site and disease-free interval.
† Palbociclib schedule 3/1 (28-day cycles).
Finn RS, et al. Lancet Oncol. 2015;16(1):25-35.

18. PALOMA-1/TRIO-18: PFS (ITT Population)
100
Palbociclib plus letrozole 90
Letrozole 80 70 60
Progression-free survival, % 50 40 30 20 10
HR (95% CI 0.319–0.748; one-sided P = .0004) 4 8 12 16 20 24 28 32 36 40
Time, months
Number at risk
Palbociclib plus letrozole 84 67 60 47 36 28 21 13 8 5 1
Letrozole 81 48 36 28 19 14 6 3 3 1
Finn RS, et al. Lancet Oncol. 2015;16(1):25-35.

19. Overall Survival (intention-to-treat population)
HR=hazard ratio
Finn RS et al. Lancet Oncol. 2015;16:25-35

20. PALOMA-1/TRIO-18: Forest Plot for PFS
PAL + LET
LET
Hazard ratio
(95% CI)
Interaction
P value*
Patients
Events
Patients
Events
All patients (intention-to-treat population) 84 41 81 59
0.488 (0.319–0.748)
Cohort 1 34 15 32 25
0.299 (0.156–0.572)
0.14 2 50 26 49 34
0.508 (0.303–0.853)
Age group (years)
<65 years 47 24 42 35
0.315 (0.184–0.539)
0.34
≥65 years 37 17 39 24
0.505 (0.269–0.948)
Baseline ECOG performance status 46 21 45 31
0.434 (0.246–0.766)
0.78 1 38 20 36 28
0.398 (0.220–0.721)
Disease site
Visceral 37 21 43 34
0.547 (0.317–0.944)
Bone Only 17 5 12 7
0.294 (0.092–0.945)
0.44
Other 30 15 26 18
0.402 (0.200–0.808)
Previous chemotherapy
Yes 34 17 37 24
0.479 (0.255–0.898)
0.75 No 50 24 44 35
0.397 (0.234–0.671)
Previous antihormonal therapy
Yes 27 12 28 19
0.460 (0.222–0.956)
0.88 No 57 29 53 40
0.397 (0.244–0.646)
Previous systemic therapy
Yes 40 20 44 28
0.539 (0.302–0.962)
0.36 No 44 21 37 31
0.341 (0.194–0.599)
Time from end of adjuvant treatment to disease recurrence
≤12 months (including de-novo presentation) 59 31 51 39
0.418 (0.259–0.674)
0.95
>12 months 25 10 30 20
0.399 (0.185–0.858)
0.34
≤12 months (excluding de-novo presentation) 15 7 14 5
0.765 (0.232–2.523)
0.062
0.125
0.250
0.500
1.000
2.000
4.000
*Two-sided P value.
Finn RS, et al. Lancet Oncol. 2015;16(1):25-35.
Favors palbociclib plus letrozole
Favors letrozole

21. PALOMA-1/TRIO-18: Best Overall Response
Combined
Characteristic
PAL + LET
LET
All randomized patients, n 84 81
Objective response rate, % (95% CI)
Complete response, n (%)
Partial response, n (%)
43 (32−54)
1 (1)
35 (42)
33 (23−45)
26 (32)
Stable disease, n (%)
37 (44)
30 (37)
Stable disease ≥24 weeks, n (%)
32 (38)
20 (25)
Stable disease <24 weeks, n (%)
5 (6)
10 (12)
Progressive disease, n (%)
3 (4)
18 (22)
Indeterminate, n (%)
8 (10)
6 (7)
Patients with measurable disease, n 65 66
55 (43−68)
1 (2)
35 (54)
39 (28−52)
26 (39)
20 (31)
22 (33)
2 (3)
15 (23)
7 (11)
3 (5)
Finn RS, et al. Lancet Oncol. 2015;16(1):25-35.

22. PALOMA-1/TRIO-18: All-Causality AEs Occurring in ≥10% of Patients (Safety Population) (1/2)
Adverse event, %
PAL + LET (n=83)
LET (n=77)
All grades
Grade 3/4
Any adverse event 99 76 84 21
Neutropenia 75 54 5 1
Leukopenia 43 19 3
Fatigue 41 23
Anemia 35 6
Nausea 25 2 13
Arthralgia 16
Alopecia 22
n/a
Diarrhea 20 4 10
Hot flush 12
Thrombocytopenia 17
Decreased appetite 7
Dyspnea 8
Nasopharyngitis
Back pain 11
No cases of febrile neutropenia were reported
One (1%) grade 5 event occurred in the PAL + LET group (from disease progression); none occurred in the LET group.
Finn RS, et al. Lancet Oncol. 2015;16(1):25-35.

23. Hematologic AEs ─All Causality
Palbociclib + Letrozole (N=444)
Placebo + Letrozole (N=222)
 Any Grade
Grade 3
Grade 4
Any Grade
Any AE, % 99 62 14 95 22 2
Neutropeniaa 80 56 10 6 1
<1
Leukopeniaa 39 24
Anemiaa 5 9
Thrombocytopeniaa 16
AE=adverse event. aIncludes clustered Medical Dictionary for Regulatory Activity (MedDRA) preferred terms.
Finn et al. ASCO 2016

24. Non-hematologic AEs Occurring in ≥15% of Pts - All Causality
Palbociclib + Letrozole (N=444)
Placebo + Letrozole (N=222)
Any Grade
Grade 3
Grade 4
Any AE, % 99 62 14 95 22 2
Fatigue 37 28
<1
Nausea 35 26
Arthralgia 33 1 34
Alopecia 16
Diarrhea 19
Cough 25
Back pain
Headache 21
Hot flush 31
Constipation 15
Rash 18 12
Asthenia 17
Vomiting
Extremity pain
Stomatitis 6
Decreased appetite 9
Dyspnea
Insomnia
Finn et al. ASCO 2016

25. Consistent Clinical Benefit Seen Across PALOMA Studies
Design
Phase 2
Open label
Phase 3
Placebo control
Endocrine partner
Letrozole
Patients on study, N
n=165
n=666
Efficacy (palbociclib vs control arm)
Primary endpoint: PFS HR
0.49
0.58
Median PFS, mo
20.2 vs 10.2( 10.0mos)
24.8 vs 14.5 ( 10.3mos)
Secondary endpoints, %
ORR (ITT, measurable disease)
43 vs 33,
55 vs 39
42 vs 35,
55 vs 44
CBR (ITT)
81 vs 58
85 vs 70
CBR=clinical benefit response; ITT=intent-to-treat; ORR=objective response rate.
Finn et al. Lancet Oncol
Finn et al. ASCO

26. Design of Phase III Study in Recurrent MBC (1023)- PALOMA-3
Palbociclib
(125 mg QD; 3 wks on/1 wk off)
+ Fulvestrant† (500 mg IM q4w)
HR+, HER2– ABC
Pre-/peri-* or post-menopausal
Progressed on prior endocrine therapy:
On or within 12 mo adjuvant
On therapy for ABC
≤1 prior chemotherapy regimen for advanced cancer
*All received goserelin.
n=347
2:1 Randomization
N=521
Stratification:
Placebo (3 wks on/ 1wk off)
+ Fulvestrant† (500 mg IM q4w)
Visceral metastases
Sensitivity to prior hormonal therapy
Pre-/peri- vs Post-menopausal
n=174
Post-menopausal patients must have progressed on prior aromatase inhibitor therapy.
†administered on Days 1 and 15 of Cycle 1.
Clinicaltrials.gov NCT

27. Primary Endpoint: PFS (ITT Population)2 4 6 8 10 12
Time (Month) 20 30 40 50 60 70 80 90
100
PFS Probability (%)
347
279
132 59 16
PAL+FUL
174
109 42 1
PCB+FUL
Number of patients at risk
Primary Endpoint: PFS (ITT Population)
Palbociclib + Fulvestrant
n=347
Placebo + Fulvestrant
n=174
Median PFS, months
(95% CI)
9.2
(7.5, NE)
3.8
(3.5, 5.5)
HR (95% CI)
0.422 (0.318, 0.560)
2-sided P value
<
CI=confidence interval; HR=hazard ratio; ITT=intent-to-treat; NE=not estimable; PFS=progression-free survival.
Turner N et al. NEJM 2015

28. PFS: Patient Subgroup Analysis
Turner N et al. NEJM 2015

29. Possibly Related Treatment-emergent Adverse Events in ≥15% of Breast Cancer Patients
Adverse Event (n=47)
Grade 1
n (%)
Grade 2
Grade 3
Grade 4
All Grades
Diarrhea
20 (42.6)
8 (17.0)
3 (6.4)
0 (0.0)
31 (66.0)
Nausea
17 (36.2)
2 (4.3)
27 (57.4)
Fatigue
11 (23.4)
1 (2.1)
Neutrophil count decreased
6 (12.8)
9 (19.1)
19 (40.4)
Vomiting
14 (29.8)
4 (8.5)
Platelet count decreased
5 (10.6)
15 (31.9)
White blood cell decreased
7 (14.9)
13 (27.7)
One patient experienced Grade 3 febrile neutropenia; no discontinuations due to neutropenia; No grade 5 adverse events
Finn et al. ASCO 2016

30. Landscape: CDK Inhibitors
Agent
Targets
Phase of Development
Alvocidib (flavopiridol)
CDK 1/2/4/6/7/9
Phase I/II
Seliciclib (R-roscovitine)
CDK 2/7/9
Phase I
Dinaciclib (SCH )
CDK 1/2/5/9
Phase III
BAY
CDK 1/2/4/9
Palbociclib (PD )
CDK 4/6
Phase III- FDA Approved
Abemaciclib(LY )
LEE 011 Ribociclib
© 2016 National Comprehensive Cancer Network, Inc. All rights reserved.

31. N = 724 BOLERO-2: Study Design Endpoints EVE 10 mg daily +
Postmenopausal women
ER+, HER2– unresectable locally advanced or metastatic BC
Recurrence or progression after letrozole or anastrozole
EVE 10 mg daily +
EXE 25 mg daily (n=485)
Randomize 2:1
Placebo +
EXE 25 mg daily (n=239)
Stratification:
Sensitivity to prior hormone therapy
Presence of visceral metastases
Endpoints
Primary: PFS (local assessment)
Secondary: OS, ORR, CBR, QOL, safety, PK
Exploratory: Biomarkers
Abbreviations: BC, breast cancer; CBR, clinical benefit rate; ER+, estrogen receptor-positive; EVE, everolimus; EXE, exemestane; HER2–, human epidermal growth factor receptor-2–negative; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PK, pharmacokinetics; QOL, quality of life.
Baselga J, et al. N Engl J Med. 2012;366(6):

32. BOLERO-2 (18-mo): Final PFS Analysis Based on Local Assessment—Met Primary Endpoint (4.6-mo Prolongation of PFS)
1.0
HR = 0.45 (95% CI, )
Log-rank P < .0001
0.8
Kaplan-Meier medians
EVE+EXE: 7.8 months
0.6
PBO+EXE: 3.2 months
Probability of
Progression-Free Survival
0.4
0.2
Censoring times
EVE+EXE (n/N = 310/485)
PBO+EXE (n/N = 200/239) 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Time, months
No. at risk
EVE+EXE
485
394
318
236
194
147 99 57 42 23 13 10 4 1
PBO+EXE
239
146
103 61 42 27 17 9 6 2 1 1
Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo; PFS, progression-free survival.
Yardley DA, et al. Adv Ther. 2013;30(10):

33. BOLERO-2 (39-mo): Final OS Analysis
HR = 0.89 (95% CI, )
Log-rank P = .14
Kaplan-Meier medians
EVE+EXE: months
PBO+EXE: months
Censoring times
232
109
248
113
266
120
279
130
292
145
311
153
330
162
347
170
373
182
399
194
414
201
429
211
448
220
471
485
239
EVE+EXE
PBO+EXE
No. at risk 11 5 23 8 39 18 58 28 91 41
118 56
154 77
196 98
216
102 1
At 39 months’ median follow-up, 410 deaths had occurred (data cutoff date: 03 October 2013)
- 267 deaths (55%) in the EVE+EXE arm vs 143 deaths (60%) in the PBO+EXE arm
One-sided P value was obtained from the log-rank test stratified by sensitivity to prior hormonal therapy and presence of visceral metastasis from IXRS®.
Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; IXRS®, Interactive Voice and Web Response System; PBO, placebo.
Piccart et al. presented at EBCC-9; 19–21 March 2014; Glasgow, Scotland. Abstract 1LBA.

34. PI3K ER+ Studies Treatment Disease conditions Trial status
Trial number
Phase I
BYL719 + letrozole
Postmenopausal women hormone receptor-positive stage IV breast cancer
Ongoing
NCT
BKM120 + fulvestrant
Postmenopausal women estrogen receptor-positive stage IV breast cancer
NCT
BKM120 or BEZ235 + letrozole
Ongoing, not recruiting
NCT
XL147 or XL765 + letrozole
Completed
NCT
Phase II
PF exemestane vs exemestane alone
Estrogen receptor-positive stage IV breast cancer
Withdrawn prior to enrollment
NCT
PF letrozole vs letrozole alone
Postmenopausal women estrogen receptor-positive early (phase II) and advanced (phase I b) breast cancer
Terminated
NCT
GDC-0941 or GDC-0980/placebo + fulvestrant
Postmenopausal women estrogen receptor-positive, AI treated, stage III B-IV breast cancer
NCT
Phase III
BKM120/placebo + fulvestrant
Postmenopausal women hormone receptor-positive, AI treated, stage III B-IV breast cancer progressed on or after mTOR inhibitor-based treatment
NCT
Postmenopausal women hormone receptor-positive, stage III B-IV breast cancer refractory to AIs
NCT
National Comprehensive Cancer Network, Inc.

35. Placebo + Fulvestrant until PD
Phase 3 Study: MONARCH 2
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Fulvestrant with or without LY , a CDK4/6 Inhibitor, for Women with Hormone Receptor Positive, HER2 Negative Locally Advanced or Metastatic Breast Cancer
Women with HR+, HER2- Locally Advanced or Metastatic Breast Cancer (N=550) R
LY Fulvestrant
until PD
Placebo + Fulvestrant until PD
2:1
Primary endpoint: Progression-Free Survival (PFS)
August 10: Pre-planned analysis, continue as planned
Finn et al. ASCO NCT

36. Phase 3 Study: MONARCH 3
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Nonsteroidal Aromatase Inhibitors (Anastrozole or Letrozole) plus LY , a CDK4/6 Inhibitor, or Placebo in Postmenopausal Women with Hormone Receptor-Positive, HER2-Negative Locoregionally Recurrent or Metastatic Breast Cancer with No Prior Systemic Therapy in this Disease Setting
Women with HR+, HER2- Locoregionally Recurrent or Metastatic Breast Cancer with DFI>12 mos following (neo)adjuvant ET or presenting de novo with metastatic disease (N=450) R
LY NSAI
until PD
Placebo + NSAI until PD
2:1
Primary endpoint: Progression-Free Survival (PFS)
Finn et al. ASCO NCT

37. Phase III Studies in ER+/HER2- MBC
Palbociclib
(PD ; Pfizer)
Ribociclib
(LEE-011; Novartis)
Abemaciclib
(LY ; Eli Lilly)
Fulvestrant
(AZ)
Study
PALOMA-2
PALOMA-3
PEARL
MONALEESA-2
MONALEESA-3
MONALEESA-7
MONARCH-2
MONARCH-3
FALCON
Setting
1st line
1st or later line
Later line
1st or 2nd line
Menopausal status
Post
Pre and Post
Pre
Target No. Patients
650
521
348
667
660
630
450
524
Endocrine Partner
Letrozole
Exemestane or
Anastrozole or letrozole, or tamoxifen
Anastrozole or
letrozole
Fulvestrant + placebo vs. anastrozole + placebo
Primary Endpoint
PFS
© 2016 National Comprehensive Cancer Network, Inc. All rights reserved.

38. Endocrine Therapy for Recurrent or Stage IV Disease
Premenopausal patients with hormone-receptor positive disease should have ovarian ablation/suppression and follow postmenopausal guidelines.
Postmenopausal Patients
Non-steroidal aromatase inhibitor (anastrozole, letrozole)
Steroidal aromatase inactivator (exemestane)
Exemestane + everolimus
Palbociclib + letrozole
Palbociclib + fulvestrant (category 1)
Fulvestrant
Tamoxifen or toremifene
Megestrol acetate
Fluoxymesterone
Ethinyl estradiol
© 2016 National Comprehensive Cancer Network, Inc. All rights reserved.

39. First-Line Therapy Second-Line Therapy
Hormone therapy should be offered to patients whose tumors express any level of estrogen and/or progesterone receptors.
Treatment recommendations should be offered on the basis of type of adjuvant treatment, disease-free interval, and extent of disease at the time of recurrence. A specific hormonal agent may be used again if recurrence occurs > 12 months from last treatment.
Endocrine therapy should be recommended as initial treatment for patients with HR-positive MBC, except for patients with immediately life-threatening disease or for those experiencing rapid visceral recurrence during adjuvant endocrine therapy.
Treatment should be administered until there is unequivocal evidence of disease progression as documented by imaging, clinical examination, or disease- related symptoms.
The use of combined endocrine therapy and chemotherapy is not recommended.
Patients should be encouraged to consider enrolling in clinical trials, including those receiving treatment in the first-line setting.
Sequential hormone therapy should be offered to patients with endocrine- responsive disease, except in the case of rapid progression with organ dysfunction; no specific order of agents is recommended.
When fulvestrant is administered, it should be administered using the 500-mg dose and with a loading schedule (treatment start, day 15, day 28, then once per month).
Rugo HS et al. ASCO, 2016;

40. Targeted Therapy
A nonsteroidal AI and palbociclib may be offered to postmenopausal women with treatment-naïve HR- positive MBC, because progression-free survival (PFS) but not overall survival (OS) was improved compared with letrozole alone.
Exemestane and everolimus may be offered to postmenopausal women with HR-positive MBC who experienced during prior treatment with nonsteroidal AIs with or without one line of prior chemotherapy, either before or after treatment with fulvestrant, because PFS but not OS was improved compared with exemestane alone.
Fulvestrant and palbociclib may be offered to patients who experienced progression during prior treatment with AIs with or without one line of prior chemotherapy, because PFS was improved compared with fulvestrant alone. Treatment should be limited to those without prior exposure to cyclin- dependent kinase 4/6 inhibitors.
The addition of HER2-targeted therapy to first-line AIs should be offered to patients with HR-positive, HER2-positive MBC in whom chemotherapy is not immediately indicated.
Genomic or expression profiling should not be used at this time to select treatment for HR-positive MBC.
Rugo HS et al. ASCO, 2016;

41. Qualifying Statements
Tumor markers or circulating tumor cells should not be used as the sole criteria for determining disease progression.
Providers should recognize and acknowledge special issues faced by premenopausal women with MBC, including loss of fertility.
Treatment should take into account the biology of the tumor and the menopausal status of the patient, with careful attention paid to ovarian production of estrogen.
There is more toxicity associated with the combination of exemestane and everolimus compared with other single-agent endocrine options.
There is more toxicity associated with the combination of palbociclib and endocrine therapy compared with other single-agent endocrine options.
Palbociclib should be administered once per day for 21 days every 28 days; the primary toxicity is neutropenia. Blood counts should be monitored every 14 days for the first two 28-day cycles, then at the start of each subsequent cycle, with neutropenia managed by dose delays and reductions. Although no data exist at present, any AI could be substituted depending on individual tolerance. On the basis of the data from PALOMA-3, palbociclib can also be combined with fulvestrant in the second-line setting or greater, including after one line of chemotherapy.
Chemotherapy in combination with HER2-targeted therapy is indicated in de novo and visceral dominant disease, because this treatment offers a survival benefit compared with chemotherapy alone.
There is no routine clinical role for genomic or expression profiling in the selection of treatment for HR- positive MBC.
Rugo HS et al. ASCO, 2016;

42. Thank you for your attention.