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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


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


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%


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


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


3. Guarneri, et al. JCO; 2012;31

4. Hurvitz, et al. SABCS 2013

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


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*



Anthracycline-

based chemo first

52 weeks


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



Weekly

Trastuzumab

Lapatinib*



Non-anthracycline-

based chemo with

anti-HER2 therapy

52 weeks


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



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.


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%)


DISEASE-FREE SURVIVAL (DFS) ANALYSIS

MFU = 4.5 yrs

* * 97.5% CI

**

**p-value ≤ 0.025 required for statistical significance


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


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


OVERALL SURVIVAL (OS) ANALYSIS

MFU = 4.5 yrs

*

* 95% CI


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)


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


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


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


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


Characteristics


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


5.7 years median follow-up

Difference 3.8% at 5 years

Sites of First Failure


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


• 4% absolute improvement in 5-yr freedom from breast cancer for exemestane+OFS

• No significant difference in overall survival


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


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


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


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%


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


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


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)


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


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

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