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Approaches to Metastatic Disease in Breast Cancer

Anne F. Schott, MD

University of Michigan

The Goals

• Maximizing the quality of life (QoL),• Prevention and palliation of symptoms• Prolongation of survival

• Not cure in the vast majority of patients • How to optimally use the tools we have to

maximize patient quality of life and lengthen survival?

Prognostic Factors in Patients With Metastatic Breast CancerPrognostic factor Favorable Unfavorable

Performance status Good Poor

Sites of disease Bone, soft tissue Viscera, CNS

No. of sites of disease Few Multiple

Hormone receptor status Positive Negative

Her-2/neu status NegativePositive (significance less clear in Her-2/neu inhibitors era)

Disease-free interval >2 years <2 years

Prior adjuvant therapy No Yes

Prior therapy for MBC No Yes

Kaplan–Meier curves illustrating overall survival for patients with de novo stage IV versus relapsed disease.

Dawood S et al. Ann Oncol 2010;21:2169-2174

© The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Survival differences among women with de novo stageIV and relapsed breast cancer

Survival differences among women with de novo stage IV and relapsed breast cancer

Survival differences among women with de novo stage IV and relapsed breast cancer

VariableHazard ratio

Lower 95%

Upper 95%

P value

Relapsed versus de novo 1.75 1.47 2.08 <0.0001

Race (black versus white) 1.38 1.18 1.61 <0.0001

Race (Hispanic and other versus white)

0.88 0.75 1.03 0.112

Age at metastasis 1.01 1.00 1.01 0.0004

Year of metastatic diagnosis 1.01 0.98 1.03 0.606

LVI (positive versus negative) 1.19 1.08 1.32 0.001

HR (positive versus negative) 0.59 0.53 0.66 <0.0001

Grade (III versus I/II) 1.51 1.34 1.71 <0.0001

Visceral or other metastases versus bone only

1.39 1.24 1.56 <0.0001

Multiple or brain metastases versus bone only

2.10 1.80 2.43 <0.0001

Influences on Treatment Choices

• Hormone receptor status of the primary tumor or its metastases

• HER-2/neu status• The duration of the relapse-free interval since primary

diagnosis• The location and extent of metastases (visceral versus

nonvisceral)• Previous treatment (including its effects and tolerance)• Patient symptoms• Patient preferences• Anticipated side-effects of treatment • Availability and access to treatment

Patient Case #1

• 46 year old woman, breast cancer 6 years ago, postmenopausal due to TAH, presents with a supraclavicular lymph node

• Biopsy – ER positive, PR negative, Her-2 negative

• Prior therapy AC x 4 and tamoxifen x 5 years, completed two years ago

• Staging evaluation with CT scan shows pleural metastases, several small lung metastases, and slightly enlarged mediastinal lymph nodes

Options in this case

• Chemotherapy• Chemotherapy combined with hormonal

therapy• Hormonal therapy• Clinical trial

Chemotherapy vs Tamoxifen vs Concurrent Therapy

Tam AC Tam + AC

Response 22.1% 45.1% 51.3%

Clinical Benefit 80% 88% 91%

Median Survival 22.8 mo 22.5 mo 19.04 mo

• Although median survival not improved for chemo over tamoxifen, RR increased: patients did not all cross over

• Led to recommendation of hormonal therapy first – retest in modern day?

ANZ BCTG 7802

Concurrent chemotherapy and hormonal therapy

• No survival benefit seen in metastatic setting with combined tamoxifen with cytotoxic chemotherapy

• Adjuvant setting suggests worse outcome of chemotherapy concurrent with tamoxifen (SWOG 8814)

• Would this hold true for aromatase inhibitors?

Characteristics of Hormone Sensitive MBC• A long disease-free interval (>2 years)• No (or limited) visceral involvement• Limited metastatic sites and disease-

related symptoms and• Slow disease progression

Why Use Hormonal Therapy Alone Metastatic Disease?• ER rich tumors less responsive to chemotherapy

– less likely to have pCR in neoadjuvant setting– less likely to benefit in adjuvant setting

• Hormonal therapy can be used longer than chemotherapy with fewer side effects

• Minimal disease, asymptomatic disease, non-life-threatening disease if ER or PR positive should get hormonal therapy– bone-only metastases, bone/pleura, lymph node

Selection of Hormonal Agents-Postmenopausal

• Aromatase inhibitors superior to tamoxifen first line

• Fulvestrant equal to anastrozole, following tamoxifen failure

Hormonal Therapy for Metastatic DiseasePost-Menopausal

ONLY

Aromatase Inhibitor

Aromatase inhibitor Fulvestrant

Aromatase inhibitor Fulvestrant Megestrol acetate

Androgens2nd aromatase

inhibitorMegestrol acetate

Tamoxifen

Tamoxifen

Fulvestrant

Newer Strategies for Endocrine Responsive Breast Cancer?

• What is the role of combination endocrine therapy in metastatic disease?– S0226: anastrozole +/- fulvestrant– TAMRAD/Bolero2 adding everolimus

• What new agents can be used in hormonal combinations to overcome endocrine resistance?

HR = 0.80 (95% CI 0.68 - 0.94)

Median PFS

Combination 15.0 mos (95% CI 13.2-18.4)

Anastrozole 13.5 mos (95% CI 12.1-15.1)

0.00

0.25

0.50

0.75

1.00

Pro

gres

sion

-free

sur

viva

l

345 193 92 39 11 3 0AN + FV349 199 114 53 21 8 2AN

N at risk

0 12 24 36 48 60 72Months since registration

Anastrozole + Fulvestrant (268 events)

Anastrozole (297 events)Stratified log-rank p = 0.0070

All eligible patients (n=694)Progression-Free Survival in S0226

Overal l

Prior tamNo prior tam

MeasurableNon-measurable

Age 65+Age < 65

De novo0-5 years5-10 years10 years+

Bone onlyVisceralNon-v isceral

HER2-negativeHER2-pos itive

No prior chemoPrior chemo

Combination better Combination worse

.4 .6 .8 1 1.2 1.4 1.6Hazard ratio

Hazard ratio with 95% confidence intervalsUnplanned subset analys is

RTreatment A:

exemestane (EXE) + everolimus (EVE) (n=485)

Treatment B:

exemestane + placebo (n=239)Randomized

2:1

N= 724 ER+, previously non-steroidal aromatase inhibitor treated MBC patients

Primary Outcome: Progression Free Survival

Baseline characteristics were well balanced; median age was 62 years; 56% had visceral involvement and 84% were sensitive to prior hormone therapy. Prior therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%) and chemotherapy for metastatic disease (25%).

BOLERO-2

EVE + EXE PBO + EXE HR p-value

PFS (interim analysis)

(median, months)7.4 3.2 0.44

(95% CI: 0.36-0.53)<1 x 10-16

PFS (central assessment)

(median, months)11.0 4.1  0.36

(95% CI: 0.28-0.45)<1 x 10-16

Overall survivalinterim analysis planned after 182 deaths (December 2011)

23.1% in everolimus arm29.3% in placebo arm

RESULTSMedian follow up of 12.5 months

Patient case #2

• 53 year old diagnosed 2 years ago, Stage II ER-, PR-, Her-2 neu –

• Received AC-Taxol, lumpectomy and RT• CXR incidentally showed lung nodule• Recurrence also detected in liver and

lymph nodes • Biopsy confirmed same receptor profile• Asymptomatic, PS 0

Question

• What would you recommend for this patient?– Single agent chemotherapy– Combination chemotherapy– Observation

The Goals

• Maximizing the quality of life (QoL),• Prevention and palliation of symptoms• Prolongation of survival

Active single agents in breast cancer

• Taxanes– Docetaxel, paclitaxel

• Anthracyclines– Doxorubicin, epirubicin,

liposomal doxorubicin• Alkylating agents• Fluoropyrimidines

– 5-FU, capecitabine• Vinorelbine• Ixabepilone • Eribulin

• Gemcitabine• Platinums• Topo I inhibitors

Additive

Synergistic

Antagonistic

Concept of Additive, Synergistic, and Additive Combination Regimens

+

Commonly Used Combination Therapies: Preclinical Predictions• Doxorubicin + cyclophosphamide• Doxorubicin + Docetaxel• Docetaxel + capecitabine• Platinums + taxanes• Gemcitabine + taxanes• Gemcitabine + cisplatinum• Vinorelbine + docetaxel• Vinorelbine + capecitabine• Cyclophosphamide + capecitabine

• Additive• Antagonistic• Synergistic• Synergistic• Synergistic• Additive• Synergistic• Additive• Synergistic

Table 2 – Main characteristics of randomized controlled trials testing chemotherapy regimens reported 2000-2007

Total number of trials (n < 150 excluded) 63

Median trial size 305

Main research questions

Combination versus combination 20

Combination versus single agent 13

Single agent versus single agent 3

Combination versus sequential single agent 3

Dose questions

High-dose therapy 3

Dose 4

Dose intensity 2

Dose schedule 3

Drug formulation 9

Duration 3

Statistically significant benefit

In response rate 19 (30%)

In PFS 22 (35%)

In OS 8 (13%)

QOL Measured in 19 (30%)

Cochrane Review:

Wilcken, Dear

European Journal Of Cancer 4 4 ( 2 0 0 8 ) 2 2 1 8 –2 2 2 5

Author # patient

s

Arm A Arm B OS A OS B p-Value Toxicity/QOL

Feher, O 410 Epirubicin Gemcitabine 19.1 11.8 0.0004 Toxicity similar

O’Shaughnessy 511 Docetaxel/capecitabine

Docetaxel 14.5 11.5 0.0126 Arm A more toxic but trend to less decrease in QOL. Cost effective

Jassem, J 267 Doxorubicin/paclitaxel

FAC 23.3 18.3 0.013 Arm A neutropaenia. Arm B emesis

Albain, KS 529 Paclitaxel/gemcitabine

Paclitaxel 18.5 15.8 0.018 Arm A more toxic

Bontenbal, M 216 Docetaxel/doxorubicin

FAC 22.6 16.2 0.019 Arm A more FN

Stockler, M 325 Intermittent or continuous capecitabine

CMF 22.0 18.0 0.02 Capecitabine HFS. CMF FN

Jones, S 449 Docetaxel Paclitaxel 15.4 12.7 0.03 Docetaxel more toxic. QOL same

Icli, F 201 Oral etoposide/cisplatin

Paclitaxel 14.0 9.5 0.039 Toxicity similar

8/63 Trials With Survival Benefit

None of these trials included a sequential crossover design

Combination A-Taxol vs. Single Agent Sequential: E1193

Combination Capecitabine + Docetaxel

Crossover in only 25% of patients (non-US population)

Cyclophosphamide (CPA) Effect on Capecitabine Metabolism

CPA

31

S0430RIBBON-1

( NJ Robert, ASCO 2009)

RIBBON-2(Brufsky,

SABCS 2009)

Thomas et al (J Clin Oncol 25:5210-5217

SOLTI(Baselga,

SABCS 2009)

S0430

CAPE Combinator

Placebo/Bevacizumab

Placebo/Bevacizumab

Control/Ixabeplione

Placebo/Sorafenib CPA

# of pts 206/409 47/97 377/375 114/115 96

Prior chemos0123

100%ExcludedExcludedExcluded

Excluded100%

ExcludedExcluded

9%/7%49%/48%37%/41%

6%/5%

54%/43%45%/57%ExcludedExcluded

54%32%14%

Excluded

ER or PR +ER- PR-Her2-Her 2+Unknown

NR NR49%/47%26%/24%14%/16%11%/13%

68%/77%29%/17%Excluded

3%/6%

56%?37%?6%?1%

Response 23.6%/35.4% NR 14%/35% 30.7%/38.3% 36%

PFS (months) 5.7/8.6 4.1/6.9 4.2/5.8 4.1/6.4 5.9

Combination vs. Single Agent Chemotherapy• Consistent increases in response rate with

combination vs. single agent therapy• Consistent increase in toxicity as well• Increase in response rate could be seen with

either synergistic, additive, OR ANTAGONISTIC combinations

• The only true test of a survival benefit (for combination vs use at all) in patients who are not gravely ill includes a “crossover” design

Patient case #2.B

• 53 year old diagnosed 2 years ago, Stage II ER-, PR-, Her-2 neu –

• Received AC-Taxol, lumpectomy and RT• Presented with right upper quadrant pain.

Recurrence detected in bone, liver and lymph nodes

• Biopsy confirmed same receptor profile• Highly symptomatic, PS 2

Question

• In addition to symptom management, what would you recommend for this patient?– Single agent chemotherapy– Combination chemotherapy– Observation

Selection of chemotherapy agents in metastatic disease• Patient characteristics

– Prior therapy exposures (anthracycline, taxane)– Residual toxicity (neuropathy)– GI function (capecitabine)

• Patient preferences– Alopecia– Oral versus IV– Weekly versus q 3 weeks

• Tumor characteristics?– Are there any identifiers for chemotherapy response?

ASCO Clinical Practice Guideline Update on the Use of Chemotherapy Sensitivity and Resistance Assays

Recommendation Category 2004 and 2011 Recommendations

Use of CSRAs

The use of CSRAs to select chemotherapeutic agents for individual patients is not recommended outside of the clinical trial setting.

Chemotherapy treatment decisions

Oncologists should make chemotherapy treatment recommendations on the basis of published reports of clinical trials and a patient's health status and treatment preferences.

Future research:evaluating CSRAs in clinical trials

Because the in vitro analytic strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority.

JCO August 20, 2011 vol. 29 no. 24 3328-3330

Treatment Duration

• Fixed chemotherapy length?• How long?

Results of search strategy.

Gennari A et al. JCO 2011;29:2144-2149

©2011 by American Society of Clinical Oncology

Duration of Chemotherapy for Metastatic Breast Cancer: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Overall survival.

Gennari A et al. JCO 2011;29:2144-2149

©2011 by American Society of Clinical Oncology

Progression-free survival.

Gennari A et al. JCO 2011;29:2144-2149

©2011 by American Society of Clinical Oncology

June 26, 2007 42

New(er) Agents in Metastatic Breast Cancer

• Locally recurrent or MBC• 2-5 prior chemotherapies

• Progression ≤6 months of last chemotherapy

• Neuropathy ≤grade 2• ECOG ≤2

Eribulin mesylate1.4 mg/m2, 2-5 min IV

Day 1, 8 q21 days

Treatment of Physician’s Choice (TPC)

Any monotherapy (chemotherapy, hormonal, biological)* or

supportive care only†

Randomization 2:1

• PFS• ORR• Safety

•Overall survival

Primary endpoint

Secondary endpoints

EMBRACE study design

Stratification:– Geographical region, prior capecitabine, HER2/neu status

Global, randomized, open-label Phase III trial (Study 305)

Patients (N=762)

− ≥2 for advanced disease− Prior anthracycline and

taxane

* Approved for treatment of cancer

†Or palliative treatment or radiotherapy administered according to local practice, if applicable

ECOG, Eastern Cooperative Oncology Group; IV, intravenous; PFS, progression-free survival;HER2/neu, human epidermal growth factor receptor 2

EMBRACE Design Features• Strengths:

– Heavily pre-treated patient population (median 4 prior regimens), a setting of clear unmet need

– Treatment choices reflect real-world options– Large trial with “all comers” design– Powered to look for OS with two-sided log-rank test

• Limitations:– Not a blinded study– Patients in TPC arm could receive treatments they have

been exposed to previously– If many patients elected BSC, then it becomes a trial of

“1 vs 0” additional lines of therapy– Does schema invite investigator bias in considering

subsequent lines of therapy beyond progression?

Overall survival (months)

0.0

0.2

0.4

0.6

0.8

1.0

0 282624222018161412108642

Su

rviv

al p

rob

abili

tyOverall survival

EribulinMedian 13.12 months

TPCMedian 10.65 months

HR* 0.81 (95% CI 0.66, 0.99)p-value†=0.041

2.47 months

TPC (n=254)

Eribulin (n=508) 53.9%

1 year survival

43.7%

ITT population; *HR Cox model including geographic region, HER2/neu status, and prior capecitabine therapy as strata†p value from stratified log-rank test (pre-defined primary analysis); HR, hazard ratio; CI, confidence intervals

Does 3rd Line Chemotherapy Palliate Refractory Breast Cancer?h 3rd line chemotherapy:

h 30% had improvement in emotional status

h 34% had major improvement in HRQL scores

h 6% had objective clinical response

h Tumor response correlated with more energy, diminished distress, and functional improvement

h Not all “benefit” was seen in responders, and not all “responders” benefit

McLachlan SA, Pintilie M, Tannock IF. Breast Cancer Res Treatment 1999;54:213

Clinical Trials are Often Appropriate

• PARP inhibitors• Stem cell targeted agents

– Notch pathway– Hedgehog pathway– CXCR1/2

• MEK• AKT/PI3K• Other anti-angiogenic

Measuring treatment benefit – clinical trial methodologies focus on tumor “response”

• Plain films• CT scan• Bone scan• MRI• PET scan• MUC-1 based tumor antigens• CEA, CA 125• Circulating Tumor Cells• Other biological markers of response

%P

rob

abil

ity

of

Pro

gre

ssio

n F

ree

Su

rviv

al

0 5 10 15 20 25 30 35 40 45 55 60 65 70 75 80

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

50

~7 mos~2.1 mos

CTC at 1st Follow-up predict PFS

1st Follow-up (3 - 4 wk)N = 163Log rank p < 0.0001

Time from Baseline (Weeks)

<5 CTC (n=114)

≥5 CTC (n=49)~7-8 mos

~5-6 WEEKS

First F

ollowup

S0500 Trial SchemaMetastatic Breast Cancer

Starting 1st Line ChemotherapyN = 350

Metastatic Breast CancerStarting 1st Line Chemotherapy

N = 350

End 1st cycle / blood draw 5-7 days prior to next cycleEnd 1st cycle / blood draw 5-7 days prior to next cycle

Group B - RandomizedN = 104

Group B - RandomizedN = 104

End Therapy / Final Blood drawEnd Therapy / Final Blood draw

Analysis & Report1º End Points = PFS (Progression / RECIST) & OS (12 month follow-up)2º End point = QOL (SWOG Method)

Analysis & Report1º End Points = PFS (Progression / RECIST) & OS (12 month follow-up)2º End point = QOL (SWOG Method)

Arm 2 – Δ TherapyN = 52

Arm 2 – Δ TherapyN = 52

Arm 1- same therapyN = 52

Arm 1- same therapyN = 52

Group A – Same Therapy N = 246

Group A – Same Therapy N = 246

<5CTC ≥5CTC

*2 x 8ml CellSave tubes 1 x 10mL EDTA Processed at:

• Immunicon• Impath Labs

*2 x 8ml CellSave tubes 1 x 10mL EDTA Processed at:

• Immunicon• Impath Labs*Baseline blood draw / begin new therapy*Baseline blood draw / begin new therapy

The Goals of “Active Therapy”

• Prolonged survival• Relief of symptoms primarily by

decreasing disease bulk• Not cure in the vast majority of patients

• “To cure sometimes, to relieve often, to comfort always” - Anonymous

Palliative Care

• At some point, “active treatment” goals are unrealistic

• Drop the goal “prolongation of survival”• Focus only on “relief” and “comfort”

– Pain and symptom management– Family involvement/planning– Spiritual needs– May be best served by hospice

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In memory of….You can shed tears that she is gone,

or you can smile because she has lived.

You can close your eyes and pray that she'll come back,

or you can open your eyes and see all she's left.

Your heart can be empty because you can't see her,

or you can be full of the love you shared.

You can turn your back on tomorrow and live yesterday,

or you can be happy for tomorrow because of yesterday.

You can remember her only that she is gone,

or you can cherish her memory and let it live on.

You can cry and close your mind, be empty and turn your back.

or you can do what she'd want:

smile, open your eyes, love and go on.

---David Harkins

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