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ASCO 2010Best of Breast Cancer

Sunil Verma MD, MSEd, FRCP(C)

Medical Oncologist

Chair, Breast Medical Oncology

Sunnybrook Odette Cancer Centre

Assistant Professor, University of Toronto

www.OncologyEducation.ca

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Please acknowledge OncologyEducation.ca and Dr. Verma when using these slides.

Objectives

• To highlight the key presentations in Breast Cancer

• To provide clinical context for these presentations

• To discuss clinical implications of this data

Key Highlights in Breast Cancer

Adjuvant Therapy

Neo-adjuvant Therapy

Metastatic Therapy

Adjuvant Therapy

• The role of Bisphosphonates in the adjuvant setting

• Should AIs be used in combination with ovarian suppression for pre-menopausal women

• New Molecular signatures to help prognosticate and predict benefit of therapy

• Local/Regional Treatment for ESBC

Pre-Menopausal WomenRole of BPs and AIs

Mature results from ABCSG-12

Abstract No. 533

Session type: Poster Discussion

Faculty Michael Gnant

ABCSG-12 Trial Design

• Accrual 1999-2006• 1,803 premenopausal breast cancer patients• Endocrine-responsive (ER and/or PR positive)• Stage I&II, <10 positive nodes• No chemotherapy except neoadjuvant• Treatment duration: 3 years

7

Randomize1 : 1 : 1: 1

Surgery(+RT)

Tamoxifen 20 mg/d

Goserelin3.6 mg q28d

Anastrozole 1 mg/d+ Zoledronic acid 4 mg q6m

Anastrozole 1 mg/d

Tamoxifen 20 mg/d+ Zoledronic acid 4 mg q6m

Aromatase Inhibitors in Pre-Menopausal setting

M Gnant ASCO 2010M Gnant ASCO 2010

Perspective and Clinical Impact

• Mature f/up – now 62 months• Should AI use in pre-menopausal women be

contraindicated even when combined with GnRH analogs?– Anastrozole signficantly less effective than Tamoxifen

in over-weight/obese women– Is ‘one dose fits all’ strategy the right approach?

• There appears to be continued benefit of adjuvant ZA– One needs to consider this approach for selected

patients• We are still eagerly awaiting the results from the AZURE

trial

AZURE: Adjuvant Zoledronic Acid RedUces REcurrence in Breast Cancer

Primary endpoint: DFS Secondary endpoints: Bone-metastases–free survival (BMFS), SREs, overall

survival (OS), predictive biomarkers Exploratory retrospective analysis: Neoadj chemotherapy + ZOL 4 mg 3-4

weekly x 6 months. Primary endpoint: Residual invasive tumour size at surgery

Primary endpoint: DFS Secondary endpoints: Bone-metastases–free survival (BMFS), SREs, overall

survival (OS), predictive biomarkers Exploratory retrospective analysis: Neoadj chemotherapy + ZOL 4 mg 3-4

weekly x 6 months. Primary endpoint: Residual invasive tumour size at surgery

Standard therapyStandard therapy

Standard therapyZoledronic acid 4 mg 6 doses (q 3-4 weeks) 8 doses (q 3 months) 5 doses (q 6 months)

3,360 patientsBreast cancer Stage II/IIIStratification:

• N+/N–

• T-score• ER status• Adj. Syst. Therapy• Pre- / Postmenopausal• Statins

3,360 patientsBreast cancer Stage II/IIIStratification:

• N+/N–

• T-score• ER status• Adj. Syst. Therapy• Pre- / Postmenopausal• Statins

RR

Follow-up without treatment:5 years for recurrence and survival

Follow-up without treatment:5 years for recurrence and survival

Treatment duration 5 years

SREs = Skeletal-related events; R = Randomization; ER = Estrogen receptor.SREs = Skeletal-related events; R = Randomization; ER = Estrogen receptor.

Coleman et al. Br J Cancer 2010; 102: 1099–1105

17

*Exploratory subset analysis aMultivariate analysis (N=205) CR=Complete response

*Exploratory subset analysis aMultivariate analysis (N=205) CR=Complete response

AZURE Subset Analysis: Synergistic Neoadjuvant Effect of CT + ZOL

Median % Path CRRes

idua

l inv

asiv

e tu

mou

r si

ze,

mm

27.415.5

6.9 11.7

Relative ↓ 43%

18

Coleman et al. Br J Cancer 2010; 102: 1099–1105

p=0.006

p=0.146

Molecular Profiling in Breast CancerTitle:

- PAM 50 Prognostic and Predictive Impact

- Meta-analysis: RS+Pathologic+Clinical

• Abstract No 508; 509

• Session type: Breast Cancer – Oral

• Faculty Stephen Chia

G. Tang and John Forbes

Sotiriou C, Pusztai L. N Engl J Med. 2009;360(8):790-800.

ER, estrogen receptor; EU, Europe; FDA, US Food and Drug Administration; Q-RT-PCR, quantitative reverse-transcriptase–polymerase chain reaction; US, United States

*Driven by proliferation, HER2, ER genes

†Laboratories were certified according to the criteria of the Clinical Laboratory Improvement Amendments or by the International Organization for Standardization.

‡Levels of evidence are measured on a scale ranging from I (strongest) to V (weakest)

Commercially Available Genomic Assays for the Prediction of Clinical Outcome in Patients with Breast Cancer*Variable MammaPrint Oncotype DX Theros MapQuant Dx

Provider Agendia Genomic Health Biotherapeutics Ipsogen

Type of assay 70-gene assay 21-gene recurrence score2-gene ratio of HOXB13

to IL17R (H/I) and molecular-grade index

Genomic grade

Type of tissue sample Fresh or frozen Formalin-fixed, paraffin-embedded

Formalin-fixed, paraffin-embedded Fresh or frozen

Technique DNA microarrays Q-RT-PCR Q-RT-PCR DNA microarrays

Centrally certified laboratory† Yes Yes Yes Yes

Indication

To aid in prognostic prediction in patients

<61 years of age with stage I or II, node-negarive

disease with a tumor size of ≤ 5 cm

To predict the risk of recurrence in patients with ER-positive,

node-negative disease treated with tamoxifen; to identify patients with a low risk for

recurrence who may not need adjuvant chemotherapy

To stratify ER-positive patients into groups with a predicted low risk or high risk of recurrence

and a predicted good or poor response to endocrine therapy

To restratify grade 2 tumors into low-risk grade 1 or high-risk

grade 3 tumors, specifically for invasive,

primary, ER-positive grade 2 tumors

Level of evidence (I-V)‡ III II III III

FDA clearance Yes No No No

Availability EU and US EU and US US EU

Basal-like

HER2 + Luminal A

Luminal B

Clinical Outcome

Sotiriou C et al, PNAS 2003. 100; 10393–10398

Molecular Classification

• The final classifier consists of 50 genes and

5 centroids (provided at https://genome.unc.edu/).

• The CV classification accuracy of the 50 genes versus the 2000 genes was 93%.

• The assay is called the

“PAM50”

Intrinsic Subtype Clinical Assay Development

Parker et al., JCO, February 9, 2009

PAM 50Predictive and Prognostic

• Used samples from MA.12 trial– Tam vs. Placebo

• Specimens available in 59% of patients

• Compared PAM50 by qRT-PCR vs IHC

• PAM 50 superior to IHC Methods:

Luminal subtypes by PAM50 was predictive of tamoxifen benefit

RFS: HR 0.56; 95% CI 0.35-0.90 vs

HR 0.80; 95% CI 0.49-1.30 for non-luminal subtypes

Chia ASCO 2010Chia ASCO 2010

Perspective and Clinical Impact

• PAM 50 appears to be a effective in helping us stratify breast cancer outcomes

• The most beneficial use will be to help stratify Triple Negatives and Basal like patients

• Its prognostic benefit provocotive, however we don’t have any information on its predictive utility to predict benefit from adjuvant chemo

Recurrence Score and Clinical + Pathological Factors

• Meta-analysis of data from B-14 and ATAC. A RSPC risk index was defined a priori

• RSPC prognosis combining clinical and pathology information with RS is more powerful than using RS alone

• Fewer patients were classified as intermediate risk by the RSPC index – 18% (with RSPC) vs 26% with RS alone (p-value

0.001), and – 72% of pts with intermediate RS 18-30 were either

up-staged or down-staged with RSPC Index

Tong ASCO 2010Tong ASCO 2010

Perspective and Clinical Impact

• RS is a useful tool in helping us prognosticate and predict the benefit of therapy for ER positive node negative EBC

• The RSPC index may help further stratify the intermediate risk category making this tool very useful in the clinical setting

• Most important clinical advance will be to see if this tool is a good predictive tool for adjuvant chemotherapy

• The tool will be available soon upon the publication of this manuscript

Local Regional Breast Cancer Therapy

ACOSOG Z0010 Trial – Main Conclusions

• No added clinical benefit of IHC on H&E SLN negative tumors

• Only one in thirty three bone tumors were positive of IHC– No Concordance of SLN IHC status with BM

IHC

Hunt ASCO 2010Hunt ASCO 2010

Local Regional Breast Cancer Therapy

NSABP B32

No benefit of ALND in SLN negative patients

Local Regional Breast Cancer Therapy

ACOSOG Z0011• Provides evidence that ALND does not add benefit to

SLND alone in clinically node negative patients• Caveats – Inclusion criteria:

• < 3+ SLN• T1• No matted l.nodes• Received Breast Radiation treatment• Systemic Adjuvant Therapy as appropriate

• LR rates was not associated with number of positive SN, size of SN mets, number of lymph nodes removed

Giuliano ASCO 2010Giuliano ASCO 2010

Local Regional Breast Cancer Therapy

ACOSOG Z0011Study Limitations:

- Limited f/up

- aggressive use of adjuvant therapy

- study was closed pre-maturely

We do need longer f/up for this trial to be practice changing

Local Regional Breast Cancer Therapy

Intergroup Adjuvant Radiation in ER +

• Patient population:– age >70, negative margins, T1, cN0, ER positive,

hormonal treatment for 5 years

• The use of adjuvant RT was associated with only a 6% reduction in IBR– No difference in DM or Survival

• Adjuvant Radiation is not needed for patients with these characteristics

Hughes ASCO 2010Hughes ASCO 2010

Adjuvant Setting

• Adjuvant Bisphosphonate use appears promising• AI use in pre-menopausal setting should only be offered

in combination with oophorectomy for those patients - Tam is contraindicated or

- who can’t tolerate Tamoxifen treatment• Molecular signatures are increasingly being optimized to

help provide better clinical care• The role of ALND for patients with SLN positive tumors

remains to be defined

Neo-Adjuvant

Neoadjuvant Therapy: Chemo vs. Endocrine

• Title: Chemotherapy vs. hormonal therapy as neo-adjuvant treatment in luminal breast cancer: A multicenter, randomized phase II study

• Abstract No. 500

• Faculty E. Alba

Background

• The general consensus is to offer patients with HR positive LABC neoadjuvant chemotherapy

• Endocrine therapy is offered to a select few– Delay in response– Lower pCR – ? Benefit vs. chemo

Results

• This study investigates the value of CT versus HT in this luminal subgroup (based on IHC) in a neoadjuvant setting.

• Pts were randomized to – CT (epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 x 4

cycles [cy] followed by docetaxel 100 mg/m2 x 4 cy [EC-T])

– or HT (exemestane 25 mg daily x 24 weeks [combined with goserelin in premenopausal pts]).

• Results: 95 pts were randomized (47 CT, 48 HT) from March 07 to December 08. 54% of pts were premenopausal. – Clinical response rate was 66% for CT and 48% for HT p = 0.07

– 3 pts with CT and 0 with HT achieved a pCR (p = NS)

Alba ASCO 2010Alba ASCO 2010

Perspective and Clinical Impact

• A well-attempted look at this important question

• The results are blunted due to inclusion of pre-menopausal women and poorly defined criteria of ‘luminal’ breast cancer

• Further studies should clearly define the patient population

• In the meantime, chemo still is the mainstay for these patients

Metastatic

• Should we biopsy our patient who have relapsed with breast cancer?

• A novel chemotherapy for patients with MBC

• Key Targeted Therapy update for MBC

Discordance Receptor Status

• Title:

- Tissue confirmation of disease recurrence

- Should liver mets of breast cancer be biopsied?- Discordance in HR status during tumor progression

• Abstract No. 1007-1009• Faculty Eitan Amir

M. A. Locatelli

E. Karlsson

Biopsy of Metastatic Disease

• Individual patient data from the UK BRITS and Canadian DESTINY studies were pooled.

• Results: 258 patients underwent biopsy. – Recurrent biopsy specimens were obtained from locoregional

recurrence in 54% and from distant metastases in 46%. – Discordance in ER, PgR, or HER2 between the primary and

recurrent disease were 13%, 28%, and 5% respectively– There was no receptor discordance among triple negative

primary tumors. – Biopsy results altered management in 15.9% of patients p=<0.0001

• The number needed to biopsy to alter immediate patient management was 6.3

Amir ASCO 2010Amir ASCO 2010

Utility of metastatic lesion biopsy

• Treatment Decision

• Prognostic Information– It appears that the overall outcome is

dependent on receptor status of metastatic lesion more than primary

• Diagnostic– Benign lesion– Metastatic lesion– New Primary

How does this change our practice?

The metastatic receptor information changes the management plan in about 15% of patients– Most likely due to loss in ER status

• about 20%

– Her2 • loss in HER 2 – about 12-30%• gain in HER 2 – about 5%

- No change in TN receptor status

Perspective and Clinical Impact

• Is there a selection bias in selecting patients for this study

• Many of the biopsies were performed for patients with loco-regional recurrences– This may also bias the results

• No data to suggest if there is discordance between metastatic sites

• Will we deny patients therapy who have a loss of receptor status?

Novel Chemotherapy

• Title: A Phase III study (EMBRACE) of Eribulin mesylate vs physician treatment choice for MBC (prev tx with A +T)

• Abstract No. 1004

• Session type: Breast – Metastatic

• Faculty C. Twelves

Background

• We have made significant advances in patients with EBC and have integrated many of our effective agents in the adjuvant setting

• We need more effective therapies after a patient with MBC progresses on anthracyclines, taxanes and capecitabine

Study Design

Arms Assigned Interventions

1: Experimental Drug: E7389 1.4 mg/m^2 intravenous (IV) infusion given over 2-5 minutes on Days 1 and 8 every 21 days.

2: Active Comparator Drug: Physician's Choice Treatment of the Physician's Choice defined as any single agent chemotherapy, hormonal treatment or biological therapy approved for the treatment of cancer; or palliative treatment or radiotherapy, administered according to

local practice, if applicable.

Results

N= 762 patients

At least two prior metastatic chemo regimens

75% of patients had prior capecitabine

Eribulin Physician choiceOS 13.1 m 10.6 m HR 0.81 p=0.04

PFS 3.7 m 2.2.m HR0.87 p=0.14

RR 12.2% 4.7%

ToxicityMain toxicity associated with this agent

– FN 3.0%, Grade ¾ Neuropathy – 8.2%

Twelves ASCO 2010Twelves ASCO 2010

Main Conclusions

• First Phase III single-agent study in heavily pre-treated MBC to meet its primary endpoint of prolonged overall survival

• ‘Real world” design– 25-50% of patients had been given treatment

that they had previously

• Statistically and clinically significant results

• New option for women with heavily pre-treated MBC

Perspective and Clinical Impact

• This novel chemotherapy will be a substantial advance for our patients with MBC

• The challenge now will be to have this therapy approved and funded in a timely manner

• We do need to study this drug in earlier lines of therapy and in combination with other targeted agents.

• Are there particular subgroups who are more likely to benefit?

• Do post-progression treatments differ markedly between the two groups?

Targeted Therapy in MBC

Avastin in Breast Cancer

Meta-analysis of OS data from three randomized trials of Bevacizumab and first line chemotherapy as treatment for patients with MBCResults

Pooled PFS difference – 2.5 months (HR 0.64)

6.7 m vs. 9.2 m

Pooled OS – No difference

50% in control arm received Bev post progression

O’Shaughnessy ASCO 2010O’Shaughnessy ASCO 2010

Targeted Therapy in Breast Cancer

Sunitinib doesn’t appear to be effective for Breast CancerSunitinib in combination with docetaxel vs. docetaxel alone for the first line treatment of advanced breast cancer

Phase III trial of Sunitinib in combination with capecitabine versus capecitabine in previously treated

advanced breast cancer

J Berg ASCO 2010J Crown ASCO 2010J Berg ASCO 2010J Crown ASCO 2010

Targeted Therapy in Breast Cancer

Sunitinib doesn’t appear to be effective for Breast Cancer

Why did this drug not work in Breast Ca?– Sunitinib

• Multi-focal targeted -> dose reduction common• Short half-life -> targets may not have been

suppressed continously• Optimal biologic and therapeutic dosing remains to

be defined

Blackwell ASCO 2010Blackwell ASCO 2010

Conclusion

• We always have to cautious when we expand the results beyond the inclusion criteria

Conclusion

• We always have to cautious when we expand the results beyond the inclusion criteria

• We have a number of new exciting drugs to offer to our patients– PARP Inhibitors– Eribulin– T-DM1/Pertuzumab/Neratinib– Adjuvant BPs

Conclusion

• We always have to cautious when we expand the results beyond the inclusion criteria

• We have a number of new exciting drugs to offer to our patients– PARP Inhibitors– Eribulin– T-DM1/Pertuzumab/Neratinib– Adjuvant BPs

• The challenge now is to select the right therapy for our patient…. Individualized approach– Molecular tools are increasingly becoming clinic friendly– Understanding the disease biopsy metastic disease

Discussion