Breast Cancer: HER2+ & ER+ Friday August 22, 2014 Sara A. Hurvitz, MD, FACP Associate Professor of Medicine Director, Breast Oncology Program, UCLA Medical Director, Clinical Research Unit, Jonsson Comprehensive Cancer Center/UCLA
Breast Cancer: HER2+ & ER+
Friday August 22, 2014 Sara A. Hurvitz, MD, FACP Associate Professor of Medicine Director, Breast Oncology Program, UCLA Medical Director, Clinical Research Unit, Jonsson Comprehensive Cancer Center/UCLA
Learning Objectives
After reading and reviewing this material, the participant should be able to:
• Define the benefit imparted by adjuvant trastuzumab in small HER2+ tumors
• Describe the efficacy and toxicity data associated with adjuvant lapatinib plus trastuzumab
• Understand the emerging role of ovarian suppression and aromatase inhibitor in premenopausal ER+ breast cancer
• Comprehend current data relating to the prognostic impact of vitamin D levels in patients with early breast cancer
• Explain the impact of the addition of bevacizumab to adjuvant therapy for HER2 negative breast cancer
Outline
• HER2+ disease – Small tumors: benefit of trastuzumab/chemo?
– ALTTO: the verdict re dual blockade with lapatinib?
• ER+ Breast cancer – Adjuvant endocrine therapy in premenopausal (TEXT/SOFT)
• Adjuvant bevacizumab HER2 normal disease
• Vitamin D in adjuvant setting
HER2+ Disease
Do small tumors benefit from trastuzumab?
Trastuzumab for Early Breast Cancer
TRIAL ARMS # Pts
DFS OS HR F/U NOTES
Int N9831
+
NSABP B31
Perez JCO 2011
ACTaxol®(T)
ACTH
ACTH
3351 4-yr
86% AC-TH
74% AC-T
P<0.001
4-yr
93% AC-TH
86% AC-T
P<0.001
OS 0.61
DFS 0.52
4 yr H qwk
HERA
Piccart SABCS 2012
Std chemo then:
Observ vs.
H x 1 yr
(Vs. H x 2 yr)
3401
(5090 incl 2 year)
8-yr DFS events:
471 H 1 yr
570 no H
P<0.0001
8-yr OS events
278 H 1 yr
350 no H
P=0.005
OS 0.76
DFS 0.76
8 yr 1/3 pts LN neg, H q3wk, 1/4 prior taxane, x-over allowed
BCIRG 006
Slamon
NEJM 2011
ACTaxotere® (T)
ACTH
T/Carboplatin/H
3222 5-yr DFS
84% AC-TH
81% TCH
75% AC-T
5-yr OS
92% AC-TH
91% TCH
87% AC-T
OS:
0.63 ACTH
0.77 TCH
65 mo
After chemo, H given q3wk
NCCN Guidelines: Adjuvant Choices
(until 2013)
Preferred adjuvant trastuzumab-containing regimens
– AC followed by paclitaxel + concurrent trastuzumab
– TCH
Alternative trastuzumab regimens
– Docetaxel/trastuzumab followed by FEC
– Trastuzumab after chemotherapy (sequential)
– AC followed by docetaxel/trastuzumab
NCCN. Clinical practice guidelines in oncology: breast cancer. v.3.2012.
Overall Survival Early Breast Cancer
Impact of adjuvant trastuzumab
• 1458 patients with operable, non-metastatic breast cancer from Italy (Registry)
• 1210 (83%) HER2 negative (blue line)
• 219 (15%) HER2+ – 53 received trastuzumab (green line)
– 161 did not receive trastuzumab (red line) Musolino, et al. Cancer 2010
What we (probably) know
• Trastuzumab benefits patients with HER2+ tumors (>2 cm and/or LN+)
• 1 year trastuzumab=2 years trastuzumab (HERA)
• 6 mos trastuzumab might be inferior to 1 year trastuzumab (PHARE)
• Concurrent chemo/trastuzumab seems to be better than sequential (Perez, N9831)
• Patients with T1N0 ER+HER2+ tumors treated with chemo/endocrine tx/trastuzumab have good prognosis (5-year DFS 91%, 5-yr OS 97%) (O’Sullivan, et al. SABCS 2013)
One of the Remaining Questions
• Does trastuzumab benefit patients with small
HER2+ tumors?
– Is there a difference in trastuzumab-related
benefit between hormone receptor negative vs.
hormone receptor positive
Efficacy Of Adjuvant Trastuzumab Compared
With No Trastuzumab for Patients With HER2-
Positive Breast Cancer And Tumors ≤ 2cm: A
Meta-analysis Of The Randomized Trastuzumab
Trials
O'Sullivan CC, Bradbury I, de Azambuja E, Perez EA, Rastogi P, Spielmann M, Joensuu H, Ballman KV, Costantino JP, Delaloge S, Zardavas D, Piccart-Gebhart M, Zujewski JA, Holmes E, Gelber RD.
Long term follow up on behalf of the Trastuzumab Overview Group
Trials Included in This Analysis
Presented by: Ciara C. O’Sullivan email:ciara.o’[email protected]
Trial HER2+
Tumors
Timing
of
Trastuzumab
Duration
of
Trastuzumab
Chemotherapy
regimen
Median
follow up
(years)
HERA 5,102 Sequential 1 or 2 years
Any – 94% A;
26% A and T
8.0
NCCTG
N9831
3,505 Concurrent
or
sequential
1 year ACT
AC w TH
AC w TH
8.7
NSABP
B-31
3,222 Concurrent 1 year ACT
ACTH
9.4
PACS 04 528 Sequential 1 year FECH
DE H
5.0
FinHER 232 Concurrent 9 weeks D+/-HFEC
V+/-HFEC
5.6
A-doxorubicin; T-paclitaxel; w-weekly ; H-trastuzumab; F-5-fluorouracil; E-epirubicin; C-
cyclophosphamide; D-docetaxel; V-vinorelbine
HER2-Positive Tumors ≤ 2cm
Trial HER2+
Tumors
HER2+
Tumors
≤2cm
Received
Trastuzumab
DID NOT
receive
Trastuzumab
HERA 5,102 2,002 1,320 682
NCCTG
N9831
3,505 756 405 351
NSABP
B-31
3,222 1,146 711 435
PACS 04 528 235 106 129
FinHER 232 81 46 35
TOTAL PTS 12,589 4,220 2,588 1,632
Presented by: Ciara C. O’Sullivan email: ciara.o’[email protected]
RESULTS: HR-Positive Disease: Tumor Size
(≤ 2cm) & Nodal Status
Presented by: Ciara C. O’Sullivan email: ciara.o’[email protected]
N-2,263
DFS for HR-Positive Disease Treated With or
Without Trastuzumab: Tumors ≤ 2cm
Time in years
Perc
enta
ge d
isease fre
e
0.00.2
0.40.60.8
Logrank p= 0.052
O355 313 283 265 120T699 635 591 553 295 1
HERA
0 2 4 6 8 10
Logrank p= 0.38
O177 168 152 136 107 41T369 346 325 297 227 93
N9831
Logrank p= 0.02
O252 227 203 183 142 79T224 208 199 190 145 76
NSABP_B31
0 2 4 6 8 10
Logrank p= 0.5
O20 17 13 4T21 19 17 7
FinHer
0.00.2
0.40.6
0.8
Logrank p= 0.082
O84 76 55 15T62 57 44 12
PACS04ObsTras
Study-to-study
heterogeneity is
not statistically
significant
Presented by: Ciara C. O’Sullivan email: ciara.o’[email protected]
Cumulative Incidence of Recurrence or Death:
HR-Positive Disease with Tumors ≤ 2cm and N 0/1
19.4%
12.7%
13.1%
8.1%
8 year gain 6.7% (s.e. 2.9%)
Logrank p=0.005
Hazard ratio 0.64
8 year gain 2.1% (s.e. 2.1%)
Logrank p=0.12
Hazard ratio 0.68
4.5%
2.9%
7.4%
5.3%
Presented by: Ciara C. O’Sullivan email: ciara.o’[email protected]
HR-negative disease : Tumor Size ≤ 2cm & Nodal
Status
Presented by: Ciara C.O’Sullivan email: ciara.o’[email protected]
N= 1,957
DFS for HR-Negative Disease Treated With or Without
Trastuzumab: Tumors ≤ 2cm
Time in years
Perc
enta
ge d
isease fre
e
0.00.2
0.40.60.8
Logrank p= 0.071
O328 246 217 200 93T621 522 462 428 240 1
HERA
0 2 4 6 8 10
Logrank p= 0.048
O174 150 137 122 80 23T342 323 292 264 176 60
N9831
Logrank p= 1.7e-06
O183 150 132 112 84 44T181 175 163 159 129 64
NSABP_B31
0 2 4 6 8 10
Logrank p= 0.7
O15 13 11 4T25 23 22 4
FinHer
0.00.2
0.40.6
0.8
Logrank p= 0.6
O45 38 30 5T44 35 26 4
PACS04ObsTras
Study-to-study
heterogeneity
Is statistically
significant
Presented by: Ciara C. O’Sullivan email: ciara.o’[email protected]
Cumulative Incidence of Recurrence or Death:
HR-Negative Disease with Tumors ≤ 2cm
33.4%
27.6%
24.0%
18.8%
8 year gain 9.4% (s.e. 2.8%)
Logrank p<0.0001
Hazard ratio 0.7
21.2%
14.7%
12.4% 8.3%
8 year gain 8.8% (s.e. 2.1%)
Logrank p=0.0001
Hazard ratio 0.6
Presented by: Ciara C.O’Sullivan email:ciara.o’[email protected]
Presented by: Ciara C.O’Sullivan email:ciara.o’[email protected]
Conclusions • Patients with tumors ≤ 2 cm benefitted substantially in terms of both
DFS and OS from trastuzumab therapy (but almost all T1c, LN+)
• Proportional benefit was similar for HR-positive and HR-negative
cohorts, but the patterns and incidence of relapse appeared to differ
over follow up time (hormone rec negative, higher rates recurrence!)
• Trastuzumab therapy contributed to the very favorable results
previously reported for patients with HR-positive tumors ≤2cm with 0-1 pos nodes
Unanswered questions
• Effects of trastuzumab in LN negative disease
– Data supports use of trastuzumab in tumors >5 mm in size (NCCN guidelines v 3.2014).
– Use of trastuzumab and chemo for T1a tumors not tested clinically yet: risk-benefit analysis and clinical judgment needed.
• Use of non-anthracycline regimen (TCH or paclitaxel/trastuzumab?)
• This analysis excluded BCIRG006 study
Is there a role for dual HER2
blockade in the curative setting?
Review of neoadjuvant data
Combination of Lapatinib and Trastuzumab
has Superior Anti-tumor Activity
• Treatment with lapatinib plus trastuzumab resulted in complete tumor remission
• Effect was durable: no tumor relapse observed after 8 mo post treatment
• Lapatinib induced accumulation of
inactive HER2 at plasma membrane
• Trastuzumab-mediated cytotoxicity was higher with the addition of lapatinib in MCF7/HER2 cells
• In vivo activity was consistent with
in vitro data demonstrating the combination as synergistic
Scaltriti, et al. Oncogene 2009;28(6):803-814
Konecny, et al. Cancer Res 2006;66:1630-1639; Xia, et al. Oncogene 2004;23: 646–653
Study/ neoadjuvant regimen
Total pCR Trastuzumab
Total pCR Lapatinib
Total pCR H+L
NeoALTTO1
N=455 27.6% 20.0% 46.8%
NSABP B-412 N=519
49.4% 47.4% 60.2% (*p NS)
CALGB 406013 N-299
43% 29% 52%
CHER-LOB4 N=121
25% 26.3% 46.7%
TRIO B075
N=130 47% 25% 51%
Pathological CR rates (breast and LN) with trastuzumab (H) and/or lapatinib (L)
1. Baselga J et al. Lancet. 2012;18:633-640. 2. Robidoux et al. Lancet Oncol; published online October 4, 2013
3. Carey, et al. ASCO 2013 4. Guarneri, et al. JCO; 2012;31
5. Hurvitz, et al. SABCS 2013
Why is addition of lapatinib to
trastuzumab not leading to consistent
(statistically significant)
improvements in PCR?
• Lack of power?
• Dose reductions required for HER2-targeted
agents/chemo when lapatinib is added?
Study/
presurgical regimen
Trastuzumab Lapatinib Trastuzumab +
Lapatinib
NeoALTTO1
(6 weeks T and/or L then
weekly paclitaxel (WP) x
12 plus T and/or L
93% 66.2% 61% (L)
90% (T)
NSABP B-412
(AC-WP plus T and/or L)
77% 65% 63%
CHER-LOB3
(WPx12then FEC x 4
plus H and/or L
throughout)
Not reported 31% permanently
off lapatinib early
17% permanently
off lapatinib early
TRIO B074
(TC + H and/or L)
100% 72% 73%
Completion of neoadjuvant therapy
1. Baselga J et al. Lancet. 2012;18:633-640. 2. Robidoux et al. Lancet Oncol; published online October 4, 2013
3. Guarneri, et al. JCO; 2012;31
4. Hurvitz, et al. SABCS 2013
NeoALTTO
Piccart-Gebhart, SABCS 2013, Abstract S1-01
NeoALTTO
Piccart-Gebhart, SABCS 2013, Abstract S1-01
Piccart-Gebhart, SABCS 2013, Abstract S1-01
NeoALTTO
Is there a role for dual HER2
blockade in adjuvant setting?
Adjuvant Lapatinib + Trastuzumab
“ALTTO”
All patients: radiotherapy, if indicated (concomitant with targeted therapy). Hormone receptor-positive patients: endocrine therapy for at least 5 years. *The L alone arm was closed on 18 Aug 2011 following IDMC recommendation
Lapatinib*
34 weeks 6 wks 12 weeks
3-weekly Trastuzumab
All (neo)adjuvant
chemo prior to
anti-HER2 therapy
Lapatinib + 3-weekly Trastuzumab
Lapatinib Weekly
Trastuzumab
wash out
DESIGN 1: SEQUENTIAL ANTI-HER2 THERAPY AFTER ALL CHEMOTHERAPY (N= 4,613)
52 weeks
34 weeks 6 wks 12 weeks
Tras alone: 8 mg/kg 6 mg/Kg iv, q21 days Lap alone: 1500 mg po qd Tras Lap: T 4 mg/kg 2 mg/Kg iv q7 days; L 1500 mg po qd Tras + Lap: T 8 mg/kg 6 mg/Kg iv, q21 days; L 1000 mg po qd
Piccart-Gebhart, ASCO 2014, Abstract LBA-4
Weekly
Trastuzumab
Lapatinib*
34 weeks 6 wks 12 weeks
3-weekly Trastuzumab
Anthracycline-
based chemo first
52 weeks
Lapatinib + 3-weekly Trastuzumab
Lapatinib wash out
DESIGN 2: CONCURRENT ANTI-HER2 THERAPY AFTER ANTHRACYCLINE-BASED CHEMOTHERAPY (N= 3,337)
w-P or 3-w D
w-P or 3-w D
w-P or 3-w D
w-P or 3-w D
w-P: weekly paclitaxel (80 mg/m2); 3-w D: q3 weeks docetaxel (75-100 mg/m2) All patients: radiotherapy, if indicated (concomitant with targeted therapy). Hormone receptor-positive patients: endocrine therapy for at least 5 years. *The L alone arm was closed on 18 Aug 2011 following IDMC recommendation
34 weeks 6 wks 12 weeks
Piccart-Gebhart, ASCO 2014, Abstract LBA-4
Weekly
Trastuzumab
Lapatinib*
28 weeks 6 wks 18 weeks
3-weekly Trastuzumab
Non-anthracycline-
based chemo with
anti-HER2 therapy
52 weeks
Lapatinib + 3-weekly Trastuzumab
Lapatinib wash out
DESIGN 2B: CONCURRENT ANTI-HER2 THERAPY WITH A NON-ANTHRACYCLINE CHEMOTHERAPY (N= 431)
3-w D + carbo
3-w D + carbo
3-w D + carbo
3-w D + carbo
3-w D: q3 weeks docetaxel (75 mg/m2); carbo: carboplatin (AUC 6) All patients: radiotherapy, if indicated (concomitant with targeted therapy). Hormone receptor-positive patients: endocrine therapy for at least 5 years. *The L alone arm was closed on 18 Aug 2011 following IDMC recommendation
28 weeks 6 wks 18 weeks
Piccart-Gebhart, ASCO 2014, Abstract LBA-4
DESIGN CONSIDERATIONS
• Primary endpoint: DFS
• Target enrollment of at least 8,000 patients.
• Timing of primary analysis:
• 850 DFS events are required for the comparison of L + T vs. T (80% power using a 2-sided alpha error = 0.0167); OR
• 4.5 years median follow-up, whichever comes first.
• Event rate lower than anticipated: the current analysis is based on 555 DFS events at a median follow-up of 4.49 years (range: 1 day to 6.40 years).
• First interim efficacy analysis (IDMC on 18th August 2011): comparison of lapatinib alone versus trastuzumab crossed the futility boundary; patients switched to trastuzumab. Lapatinib alone arm is not reported here.
Piccart-Gebhart, ASCO 2014, Abstract LBA-4
DISTRIBUTION OF THE STRATIFICATION
FACTORS BY TREATMENT ARM
L + T
(N = 2,093)
T → L
(N = 2,091)
T
(N = 2,097)
Receptor Status
Positive 1,203 (57%) 1,205 (58%) 1,200 (57%)
Negative 890 (43%) 886 (42%) 897 (43%)
Timing of chemotherapy
Sequential (Design 1) 1,155 (55%) 1,143 (55%) 1,147 (55%)
Concurrent (Design 2 and 2B) 938 (45%) 948 (45%) 950 (45%)
Lymph Node Status
Not applicable (neoadjuvant
chemotherapy) 168 (8%) 170 (8%) 181 (9%)
Node negative 845 (40%) 842 (40%) 844 (40%)
1-3 positive nodes 617 (29%) 617 (30%) 603 (29%)
>=4 positive nodes 463 (22%) 462 (22%) 469 (22%) Piccart-Gebhart, ASCO 2014, Abstract LBA-4
DISTRIBUTION OF PATIENT
CHARACTERISTICS BY TREATMENT
ARM L + T
(N = 2,093)
T → L
(N = 2,091)
T
(N = 2,097)
Menopausal Status
Premenopausal 908 (43%) 929 (44%) 908 (43%)
Postmenopausal or male 1,185 (57%) 1,162 (56%) 1,189 (57%)
Pathological primary tumor size - largest diameter of invasive component
Missing 27 41 38
≤ 2cm 937 (45%) 938 (46%) 942 (46%)
> 2cm to ≤ 5cm 1,002 (49%) 980 (48%) 990 (48%)
> 5cm 127 (6%) 132 (6%) 127 (6%)
Piccart-Gebhart, ASCO 2014, Abstract LBA-4
DISEASE-FREE SURVIVAL (DFS) ANALYSIS
MFU = 4.5 yrs
* * 97.5% CI
**
**p-value ≤ 0.025 required for statistical significance
Piccart-Gebhart, ASCO 2014, Abstract LBA-4
DFS BY HORMONE RECEPTOR STATUS
Interaction tests p = 0.70 L + T p = 0.60 T L
MFU = 4.5 yrs MFU = 4.5 yrs
*
* 95% CI
*
* 95% CI
Piccart-Gebhart, ASCO 2014, Abstract LBA-4
DFS BY CHEMOTHERAPY TIMING
Interaction tests p = 0.41 L + T p = 0.31 T L
MFU = 4.9 yrs MFU = 3.9 yrs
*
* 95% CI
*
* 95% CI
Piccart-Gebhart, ASCO 2014, Abstract LBA-4
OVERALL SURVIVAL (OS) ANALYSIS
MFU = 4.5 yrs
*
* 95% CI
Piccart-Gebhart, ASCO 2014, Abstract LBA-4
PROPORTION OF PATIENTS RECEIVING ≥ 85% OF THE PLANNED DOSE OF ANTI-HER2 DRUGS
% o
f p
atie
nts
Design 1 (N= 4,613) Design 2 & 2B (N= 3,768)
PROPORTION OF PATIENTS RECEIVING ≥ 85% OF THE PLANNED DOSE OF ANTI-HER2 DRUGS
% o
f p
atie
nts
Design 1 (N= 4,613) Design 2 & 2B (N= 3,768)
L + T
MAIN DIFFERENCES IN AEs BY TREATMENT ARM
% o
f A
Es b
y tr
eat
me
nt
arm
AEs T L T p < 0.001 for
incidence for all arms when compared to T
Diarrhoea Hepatobiliary Rash or Erythema
AEs ≥G3
(15) (1)
(5) (5) (1)
(3) (1)
(4) (3)
The Verdict re Lapatinib?
• Increases toxicity (diarrhea is dose limiting)
• Without trastuzumab is inferior in efficacy
• Decreases amount of chemotherapy and HER2-directed tx that can be given
• NeoALTTO update at SABCS 2013 shows no difference in EFS or OS for patients who received trastuzumab plus lapatinib
• Evidence insufficient to support its use in early breast cancer setting
Study/ neoadjuvant regimen
Total pCR Trastuzumab
Total pCR Lapatinib
Total pCR H+pertuzumab
Total pCR H+L
NeoALTTO1
N=455 28% 20.0% n/a 47%
NSABP B-412 N=519
49% 47% n/a 60%
CALGB 406013 N-299
43% 29% n/a 52%
CHER-LOB4 N=121
25% 26% n/a 47%
TRIO B075
N=130 47% 25% n/a 51%
NEOSPHERE6 Docetaxel x 4 N=417
22% n/a 39% n/a
TRYPHAENA7 TCHP x 6 N=225
n/a n/a 52% n/a
Pathological CR rates (breast and LN)
1. Baselga J et al. Lancet. 2012;18:633-640. 2. Robidoux et al. Lancet Oncol; published online October 4, 2013
3. Carey, et al. ASCO 2013 4. Guarneri, et al. JCO; 2012;31
5. Hurvitz, et al. SABCS 2013 6. Gianni, et al. Lancet Oncol 2012;13 7. Schneeweiss, et al.
Sept 30, 2013:
FDA Approval of First Neoadjuvant
Regimen in Breast Cancer
Hormone Receptor Positive
Disease
Adjuvant Use of Ovarian Suppression plus
Tamoxifen or AI in young women
Premenopausal Endocrine Therapy
• Optimal adjuvant endocrine therapy for premenopausal women with
HR+ breast cancer is uncertain
• Tamoxifen for at least 5 years is a standard of care
– 10 years now supported by the ATLAS and ATTOM trials
• Ovarian function suppression (OFS) may be given in addition
• TEXT/SOFT studies ask: Does adjuvant therapy with the aromatase
inhibitor (AI) exemestane improve disease-free survival relative to
tamoxifen in premenopausal women treated with OFS for HR+ breast
cancer?
Presented by: Olivia Pagani, MD
TEXT and SOFT Designs
Presented by: Olivia Pagani, MD
R
A
N
D
O
M
I
Z
E
Tamoxifen+OFS x 5y
Exemestane+OFS x 5y
R
A
N
D
O
M
I
Z
E
Tamoxifen x 5y
Tamoxifen+OFS x 5y
Exemestane+OFS x 5y
Tamoxifen+OFS x 5y
Exemestane+OFS x 5y
Joint Analysis
(N=4690)
• Premenopausal
• ≤12 wks after surgery
• No chemo
OR
• Remain premenopausal
≤ 8 mos after chemo
• Premenopausal
• ≤12 wks after surgery
• Planned OFS
• No planned chemo
OR planned chemo
SUPPRESSION OF OVARIAN FUNCTION TRIAL (N=3066)
TAMOXIFEN AND EXEMESTANE TRIAL (N=2672)
OFS=ovarian function suppression
Enrolled: Nov03-Apr11
Median follow-up 5.7 years
TEXT
SOFT
Treatments Protocol treatment was for 5 years from randomization
• Ovarian Function Suppression
TEXT • All women started with GnRH agonist triptorelin (IM q28d)
• Triptorelin initiated concurrently with chemotherapy, if it was given
• Bilateral oophorectomy or irradiation as alternatives to triptorelin after 6 months
SOFT • Choice of OFS method
• Oral endocrine therapy • Exemestane 25 mg daily, or
• Tamoxifen 20 mg daily
• In TEXT started 6 to 8 weeks after initiation of OFS, or after chemotherapy if given
Presented by: Olivia Pagani, MD
Study Procedures
• Adjuvant trastuzumab allowed, if indicated
• Annual mammography and bone densitometry recommended
• Bisphosphonates not permitted unless T-score ≤ -1.5 or participating in a
randomized adjuvant trial
• Targeted AEs and other grade 3-5 AEs (CTCAE v3.0)
• Quality-of-life self-assessment of global and symptom-specific indicators
• Primary Endpoint: DFS
Presented by: Olivia Pagani, MD
Statistical Considerations • DFS event rate much lower than anticipated (Regan et al., The Breast 2013)
• Protocols amended in 2011 (before efficacy data available): – For the E+OFS v. T+OFS comparison, a planned secondary joint analysis of TEXT &
SOFT was promoted to become the primary analysis
– With data cut-off in late-2013 (>5 years median follow-up), power 84% for HR=0.75
(2-sided α=0.05) in the combined analysis
– No interim analyses
• ITT analysis; stratified by trial, chemotherapy use, nodal status
Presented by: Olivia Pagani, MD
Characteristics
Presented by: Olivia Pagani, MD
No chemo
TEXT
(N=1053)
No
chemo
SOFT
(N=943)
Chemo
TEXT
(N=1607)
Prior
chemo
SOFT
(N=1087)
Overall
(N=4690)
Age <40 yr 16% 9% 30% 49% 27%
LN + 21% 8% 66% 57% 42%
T-size
>2cm 19% 15% 53% 47% 36%
HER2 + 5% 3% 17% 19% 12%
Surgery to
random.
(median) 1.5 mo 1.8 mo 1.2 mo 8.0 mo 1.6 mo
Exemestane+OFS Improved DFS
Presented by: Olivia Pagani, MD
5.7 years median follow-up
Difference 3.8% at 5 years
Sites of First Failure
Presented by: Olivia Pagani, MD
Site of First Failure
(DFS event)
E+OFS
(N=2346)
T+OFS
(N=2344)
Overall
(N=4690)
All DFS events N (%) 216 (9.2) 298 (12.7) 514
Local 23 (1.0) 28 (1.2) 51
Contralateral breast 9 (0.4) 27 (1.2) 36
Regional ± above 9 (0.4) 30 (1.3) 39
Soft tissue / distant LN ± above 4 (0.2) 6 (0.3) 10
Bone ± above 54 (2.3) 65 (2.8) 119
Viscera ± above 75 (3.2) 105 (4.5) 180
Second (non-breast)
malignancy
38 (1.6) 32 (1.4) 70
Death without prior cancer event 2 (0.1) 5 (0.2) 7
Death w/ recurrence suspected 2 (0.1) -- 2
60% of first
failures
involved
distant sites
Exemestane+OFS Reduced Recurrence
Presented by: Olivia Pagani, MD
• 4% absolute improvement in 5-yr freedom from breast cancer for exemestane+OFS
• No significant difference in overall survival
Presented by: Olivia Pagani, MD
Some women have excellent prognosis with highly-effective endocrine therapy alone
>97% breast cancer-free at 5 years when treated with exemestane+OFS
Women Who Did Not Receive Chemotherapy
16% <40 years; 19% T-size >2cm; 21% N+ 9% <40 years; 15% T-size >2cm; 8% N+
N=1996
Women Who Received Chemotherapy
Presented by: Olivia Pagani, MD
BC
Absolute improvement with exemestane+OFS
5-yr freedom from breast cancer: 5.5% in TEXT and 3.9% in SOFT
5-yr freedom from distant recurrence: 2.6% in TEXT and 3.4% in SOFT
66% N+; 53% T-size >2cm; 30% <40 years 57% N+; 47% T-size >2cm; 49% <40 years
Exemestane+OFS
(N=2318)
Tamoxifen+OFS
(N=2325) CTCAE v3.0 Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4
Depression 50% 3.8% 50% 4.4%
Musculoskeletal 89% 11% 76% 5.2%
Osteoporosis (% T< -2.5) 39% (13%) 0.4% 25% (6%) 0.3%
Fracture 6.8% 1.3% 5.2% 0.8%
Hypertension 23% 6.5% 22% 7.3%
Cardiac
ischemia/infarction
0.7% 0.3% 0.3% 0.1%
Thrombosis/embolism 1.0% 0.8% 2.2% 1.9%
CNS ischemia 0.7% 0.3% 0.3% 0.1%
CNS bleeding 0.6% <0.1% 0.9% 0.1%
Hot flushes/flashes 92% 10% 93% 12%
Sweating 55% -- 59% --
Vaginal dryness 52% -- 47% --
Libido decrease 45% -- 41% --
Dyspareunia 31% 2.3% 26% 1.4%
Urinary incontinence 13% 0.3% 18% 0.3%
Selected Adverse Events
Presented by: Olivia Pagani, MD
Conclusions
• Exemestane+OFS, as compared with tamoxifen+OFS, significantly
improves DFS, BCFI and DRFI and is a new treatment option for
premenopausal women with HR+ early breast cancer
• No significant difference in overall survival, conclusions premature at
this early point in follow-up of HR+ breast cancer
• Side effect profile of exemestane+OFS mirrors that seen with AIs in
postmenopausal women
• Some premenopausal women diagnosed with HR+ breast cancer have
an excellent prognosis with highly-effective endocrine therapy alone
• Long-term follow-up needed
Presented by: Olivia Pagani, MD
Additional Info and Remaining
Questions
• Early cessation of all treatments more common in AI
(16% vs 11%)
• Quality of life similar for two arms (Abstract 557)
• Subset analysis of 90 patients in exemestane/OFS
arm showed that up to 25% of women has suboptimal
estradiol suppression at any given timepoint (3, 6, and
12 mos). (Abstract 585 ASCO 2014)
– Are these patients receiving less benefit compared
to tamoxifen?
• How does AI/OFS compare to 10 years of tamoxifen?
Unanswered question:
Is there a benefit to adding ovarian
suppression to tamoxifen in
premenopausal women?
SOFT analysis of tamoxifen vs
tamoxifen/OFS to report end of
2014
PROGNOSTIC ASSOCIATIONS OF 25OH VITAMIN D
IN NCIC CTG MA.21 A PHASE III ADJUVANT RANDOMIZED CLINICAL TRIAL
OF THREE CHEMOTHERAPY REGIMENS
(CEF, EC/T, AC/T) IN HIGH RISK BREAST CANCER
AE Lohmann, JW Chapman, MJ Burnell, MN Levine, E Tsvetkova, KI Pritchard, KA Gelmon, P O'Brien, L Han, HS Rugo, KS Albain, EA Perez, TA Vandenberg, HI Chalchal, RPS Sawhney, LE Shepherd, PJ Goodwin
VITAMIN D AND BREAST CANCER BACKGROUND
Recent research has resulted in concerns that
inadequate Vitamin D may lead to:
• Higher risk of breast cancer
Inconsistent results from observational studies, RCTs.
IOM 2011: Insufficient evidence to conclude association existed.
• Poor breast cancer outcomes
Not seen in two Post-hoc correlative analyses in intervention trials
(NCIC CTG MA.14 and ISPY trial).
Consistently seen in observational studies.
Pritchard KI et al J Clin Oncol 2011 Oct 10;29(29):3869-76 Clark AS et al Cancer Med 2014 Apr 9 [Epub ahead of print]
BLOOD LEVELS OF VITAMIN D - PROGNOSIS META-ANALYSIS OF OBSERVATIONAL STUDIES
Rose A. et al Breast Cancer Res Treat (2013) 141:331–339
1.0 11.1 VitD deficiency
associated with longer DFS
VitD deficiency associated
with shorter DFS
HR [95% CI]
Goodwin, 2009
Kim, 2011
Hatse, 2012
Vrieling, 2011
Coleman, 2012
Clark, 2012
OVERALL
HR [95% CI]
1.71
3.97
4.00
2.09
1.78
1.88
2.13 [1.64 – 2.78]
Goodwin, 2009
Hatse,2012
Tretli, 2012
Vrieling, 2011
OVERALL
VitD deficiency
associated With longer OS
VitD deficiency associated
with shorter OS
1.60
2.04
2.38
1.55
1.76 [1.35 – 2.30 ]
1.0 4.8
DFS OS
CHANGING CLASSIFICATION OF VITAMIN D STATUS
INSTITUTE OF MEDICINE
J Clin Endocrinol Metab 2011, 96: 53–58
25(OH)D ng/ml (nmol/L)
Status
25 (OH)D ng/ml (nmol/L)
Status
<20 (<50) Deficient <16 (<40 ) Deficient
20≥<30 (50-75) Insufficient ≥16 (≥40) Meets needs of 50% of population
≥30<150 (75-375)
Sufficient ≥20 (≥50)
Meets needs of 97.5% of
population
≥ 150 (≥ 375) Toxic >50 (>125) Raises concern of toxicity
Pre-IOM classification 2011 IOM classification
Holick, N Engl J Med. 2007,357(3):266-81
Vitamin D Substudy - HYPOTHESIS
In MA21, low levels of 25(OH)vitamin D would be associated with reduced:
Relapse-free survival
Breast cancer specific survival
Overall Survival
MA21 DESIGN
Surgery
2104 patients:
•Node +ve or
•High risk node –ve BC
•<60 years
From December 2000 to May 2005
MA21 RFS RESULTS
Burnell et all. J Clin Oncol. 2010 Jan 1;28(1):77-82
RFS ( 30.4 m):
CEF= 90.1%
EC/T=89.5%
AC/T=85.0% (worse)
Vitamin D Substudy - METHODS
Fasting plasma was collected from consenting patients before initiation of systemic therapy, frozen and stored at -80C.
25-hydroxyvitamin D was measured in 1 batch using a radioimmunoassay kit (DIASORIN) at Mount Sinai Hospital, Toronto (Dr. Azar Azad lab)
Assay coefficient of variation <12%
Patients
characteristics With Blood
N=934 (%)
Without Blood
N=1170 (%)
Total
N=2104 (%) P-value
Age <50
50
559 (60)
375 (40)
727 (62)
443 (38)
1286 (61)
818 (39)
.29
T status Tx/T1
T2/T3/T4
332 (36)
601 (64)
412 (35)
758 (65)
744 (35)
1360 (65)
.87
Nodal status N0
N1/2
255 (27)
679 (73)
334 (29)
836 (71)
589 (28)
1515 (72)
.53
Race White
Other
856 (92)
78 (8)
1010 (86)
160 (14)
1866 (89)
238 (11)
.0001
Partial mastectomy
Total mastectomy
448 (48)
486 (52)
625 (53)
545 (47)
1073 (51)
1031 (49)
0.01
ER negative
positive
362 (39)
572 (61)
502 (43)
668 (57)
864 (41)
1240 (59)
.05
Her2 negative/missing
positive
836 (90)
98 (10)
1027 (88)
143 (12)
1863 (89)
241 (11)
.22
PS ECOG 0
1,2
752 (81)
182 (19)
1015 (87)
155 (13)
1767 (84)
337 (16)
.0001
Patient Characteristics- With and Without Blood
No imbalance for menopausal status, grade, radiation, T status and chemotherapy.
RESULTS • Median follow-up of 9.2 years.
• Mean vitamin D blood levels: 69.7 nmol/L (27.9 ng/ml).
25(OH)D
ng/ml
(nmol/L)
Status
Results
25 (OH)D
ng/ml
(nmol/L)
Status
Results
<20 (<50) Deficient 19.5% <16 (<40 ) Deficient 10.2%
20≥<30 (50-75)
Insufficient 35% ≥16 (≥40) Meets needs
of 50% of population
88.5%
≥30<150 (75-375)
Sufficient
45.5%
≥20 (≥50)
Meets needs of
97.5% of population
77.1%
≥ 150 (≥ 375)
Toxic 0% >50 (>125) Raises concern of toxicity
3.4%
Pre-IOM classification 2011 IOM classification
RESULTS RELAPSE-FREE SURVIVAL (P = 0.36 Vit D continuous)
Sufficient vs Insufficient/Deficient
HR=0.88 95% CI (0.67-1.16)
Pre-IOM classification
≥40 to 50 vs <40 HR=1.43 95% CI (0.75-2.74)
>50 to125 vs <40 HR=1.14 95% CI (0.65-1.99)
≥125 vs <40 HR=0.65 95% CI (0.21-2.00)
Years Years
IOM classification
p= .39 p= .58
RESULTS BREAST CANCER SPECIFIC SURVIVAL
(P = 0.26 Vit D continuous)
Sufficient/ Deficient or Insufficient
HR=0.89 95% CI (0.64-1.2)
≥40 to 50 vs <40 HR=1.4 95% CI (0.67-2.96)
>50 to 125 vs <40 HR=1.07 95% CI (0.56-2.02)
≥125 vs <40 HR=0.65 95% CI (0.18-2.37)
Pre-IOM classification IOM classification
Years Years
p= .46 p= .50
RESULTS OVERALL SURVIVAL
(P = 0.33 Vit D continuous)
Sufficient/ Deficient or Insufficient
HR=0.96 95% CI (0.71-1.28)
≥40 to 50 vs. <40 HR=1.44 95% CI (0.73-2.83)
>50 to 125 vs. <40 HR=1.03 95% CI (0.58-1.85)
≥125 vs. <40 HR=0.50 95% CI (0.14-1.77)
Pre-IOM classification IOM classification
Years Years
p= .78 p= .27
CONCLUSION
No evidence that 25-OH Vitamin D blood level is associated with RFS, BCSS or OS in MA.21.
In contrast to previous observational studies in the same era, the majority of subjects had adequate vitamin D levels at study entry.
Differences in study populations – potential bias towards selection of healthier subjects who are Vitamin D replete in RCTs MA.21 mean 69.7 nmol/L vs 42.5 -58.1 in
observational studies
MA.21 % deficient 19.5 vs 37.5% -75.6% in observational studies
Post hoc analysis of a subset of patients not fully
representative of the entire study population.
Restrictive study population (white, young and with high
risk BC).
BMI was not available for inclusion in analyses.
Single measure of Vitamin D.
No information about vitamin D supplementation.
LIMITATIONS
DISCUSSION
The role of vitamin D in breast cancer is unproven.
These results do not support a recommendation for vitamin D supplementation as a means of improving breast cancer outcomes.
Randomized trials of Vitamin D supplementation would be desirable but may not be feasible, given recent research showing common use of Vitamin D supplementation, higher Vitamin D levels and unwillingness of BC patients with low levels to be randomized to placebo. (Cescon et al, Breast Cancer Res Treat. 2012 Jul;134(2):759-67).
E5103
A Double-Blind Phase III Trial of Doxorubicin and Cyclophosphamide
followed by Paclitaxel with Bevacizumab or Placebo in Patients with
Lymph Node Positive and High Risk Lymph Node Negative Breast
Cancer
Kathy Miller, Anne O'Neill, Chau Dang, Donald Northfelt, William
Gradishar, Lori Goldstein, Ingrid Mayer, Adam Brufsky, Stuart
Bloom, Joseph Sparano, Amye Tevaarwerk, Kevin Fox, Carolyn
Hendricks, Ernie Balcueva, George Sledge
Rationale
• Tumor growth dependent on angiogenesis
• Bevacizumab improves PFS but not OS in
metastatic breast cancer
• Pro-angiogenic pathways more numerous
and redundant as cancer progresses
– Greater benefit in the adjuvant setting?
Presented by: Kathy D. Miller, MD abstract # 500 79
Study Design
AC q2 or q3 weekly, investigator choice. HRx and radiation per SOC
R
A
N
D
O
M
I
Z
E
1:2:2
All arms
unblinded on
C8D1
Arm B: BAC > BT
Paclitaxel 80 mg/m2/wk x 12
Bevacizumab 15 mg/kg q21d x 4
AC +
Bevacizumab x 4
Arm A: AC > T
AC +
Placebo x 4
Paclitaxel 80 mg/m2/wk x 12 +
Placebo 15 mg/kg q21d x 4
Arm C: BAC > BT > B
AC +
Bevacizumab x 4 Bevacizumab 15
mg/kg q21d x 10
Paclitaxel 80 mg/m2/wk x 12
Bevacizumab/ 15 mg/kg q21d x 4
Study Highlights
81 Presented by: Kathy D. Miller, MD
• LN(+) by H&E staining OR high risk LN(-) – ER(-) tumor > 1 cm
– ER(+) tumor > 5 cm
– ER(+) tumor < 5cm with recurrence score > 11
• HER2 negative
• 1’ Endpoint: IDFS
Patient Characteristics Arm A
(n=1000)
Arm B
(n=1986)
Arm C
(n=2008)
Age 52 (25-78) 52 (21-85) 52 (22-82)
ER+ 62% 62% 62%
Tumor size
< 2.0 cm 37.6% 39% 38.6%
>2 - < 5 cm 52% 50.7% 51%
> 5 cm 10% 10% 10%
LN status
Negative 26% 26% 26%
1-3+ 43% 43% 43%
>4 31% 31% 31%
82 Presented by: Kathy D. Miller, MD
Invasive Disease Free Survival
Presented by: Kathy D. Miller, MD 83
Arm C vs. A
HR 0.87 (0.70-1.08), *p=0.17
*two-sided
Arm A Arm B Arm C
5 yr
IDFS
77% 76% 80%
Invasive Disease Free Survival
Presented by: Kathy D. Miller, MD 84
Group N HR 95% CI
Overall 3008 0.87 (0.71, 1.06)
Age < 40 364 1.09 (0.60, 1.99)
Age 40-64 2359 0.77 (0.61, 0.97)
Age > 65 285 1.04 (0.57, 1.90)
ER negative 1079 0.77 (0.58, 1.03)
ER positive 1925 0.93 (0.71, 1.22)
LN negative 822 1.02 (0.65, 1.59)
1-3 LN 1226 0.71 (0.50, 1.00)
> 4 LN 958 0.94 (0.70, 1.26)
Tumor 0-2 cm 1151 0.88 (0.59, 1.31)
Tumor >2 - < 5 cm 1545 0.83 (0.64, 1.08)
Tumor > 5 cm 309 1.00 (0.59, 1.69)
Grade I 248 0.48 (0.18, 1.27)
Grade II 987 0.73 (0.50, 1.07)
Grade III 1079 1.01 (0.78, 1.30)
Favors bevacizumab Favors placebo
Overall Survival
Presented by: Kathy D. Miller, MD 85
Arm A Arm B Arm C
5 yr
OS
90% 86% 90%
Arm C vs. A
HR 0.89 (0.68-1.17)
*p=0.41
*two-sided
Median Follow-up 47.5 months
Bevacizumab Toxicities Step 1 (concurrent chemotherapy)
86 Presented by: Kathy D. Miller, MD
NCI-CTC Grade
(%)
Arm A
(n=1000)
2 3 4
Arm B
(n=1986)
2 3 4
Arm C
(n=2008)
2 3 4
Hypertension n/a 2 <1 n/a 8 <1 n/a 7 <1
Thrombosis 1 3 1 1 2 1 1 2 1
Proteinuria 1 0 0 1 <1 0 1 <1 0
Hemorrhage
(nose)
<1 0 0 1 <1 0 2 <1 0
GI perforation 0 <1 0 0 0 <1 0 <1 <1
*LV systolic 4 1 0 5 2 <1 4 2 <1
*LV diastolic <1 <1 0 1 <1 0 1 1 0
*Clinical CHF at
15 mos
1.0% 1.9% 3.0%
*Presented in detail, Miller et al SABCS 2012
87 Presented by: Kathy D. Miller, MD
Bevacizumab Toxicities Step 2 (monotherapy)
NCI-CTC Grade
(%)
Arm C
(n=1166)
2 3 4
Hypertension n/a 11 <1
Thrombosis 1 1 <1
Proteinuria 3 2 <1
Hemorrhage
(nose)
1 <1 0
GI perforation 0 0 <1
*LV systolic 5 3 <1
*LV diastolic 1 <1 0
*Presented in detail, Miller et al SABCS 2012
Conclusion
• Bevacizumab does not improve DFS in the
adjuvant setting
– Results similar to the *Beatrice and **Beth trials
• No new toxicities identified
– Small but significant increase in CHF
– Early discontinuation common
88 Presented by: Kathy D. Miller, MD *Cameron et al Lancet Oncology 2013
**Slamon et al SABCS 2013
Summary • HER2-driven cancers
– Small (T1) tumors benefit from trastuzumab regardless of
ER status
• Not clear how much benefit trastuzumab imparts in T1a/LN negative
– Lack of sufficient data to support dual HER2 targeting with
lapatinib/trastuzumab in early breast cancer
• Lack of improved DFS or EFS with combination in
adjuvant/neoadjuvant setting; possibly due to lack of power and/or
dose reductions due to toxicity
• Hormonally driven cancers
– Young women with ER+ disease: use OFS + AI?
• If so, check estradiol levels!
• Unclear how this compares to 10 years tamoxifen
• Awaiting data re tamoxifen/OFS vs. tamoxifen
Summary
• Prognostic value of vitamin D levels
– No clear evidence that vitamin D correlates with clinical outcome
– Primary reason to test in breast cancer patient is to help support bone health in women who have had chemotherapy and/or endocrine therapy that threatens bone density
• Bevacizumab – No survival benefit in HER2- metastatic breast cancer (Ribbon I,
Ribbon II, AVADO, E1103)
– No survival benefit in HER2+ MBC (Averel)
– No survival benefit in TN MBC (Beatrice)
– No DFS or OS benefit in adjuvant HER2+ breast cancer (BETH, Slamon, et al 2013)
– No IDFS or OS benefit in HER2- adjuvant setting (E5103)
Questions & Discussion