Hormone Independent

Metastatic Breast Cancer

Anne Moore, MD

Attending Physician, New York Presbyterian Hospital

Professor of Clinical Medicine

Weill Cornell Medical College

New York

Hormone Independent MBC Definition

• Metastatic breast cancer

– Triple negative from diagnosis

– Biomarkers changed at time of metastatic disease

– ER+ or Her 2+ that is refractory to targeted therapy

Stage IV disease

• Screening for metastases with markers or annual scans not recommended by ASCO guidelines

• Metastatic disease usually found by patient in between doctor visits-lump, pain, other routine exams (eg, pre-op chest xray)

• 3- 5% of newly diagnosed breast cancer patients present with metastatic disease

Stage IV breast cancer Initial work up when metastatic disease is suspected

• History and physical examination

• Routine labs (markers may help)

• Imaging: Bone scan + CT of c-a-p or FDG PET/CT

• Biopsy first recurrence if possible – To establish cancer vs. benign

– To establish metastasis from breast cancer

– To determine ER/PR/HER2

NCCN guidelines 3.2014

Changes in estrogen receptor (ER), progesterone receptor (PgR), and HER2 between the

original pathology report of the primary tumor and the metastasis.

Amir E et al. JCO 2012;30:587-592

©2012 by American Society of Clinical Oncology

Metastatic breast cancer is an incurable disease

Goals of treatment

ASCO guidelines

• To prolong survival

• To palliate symptoms

• To optimize quality of life

Are these in the same order for every patient?

For every treating physician?

ASCO guidelines 2014

Metastatic breast cancer

• What is the average survival after a diagnosis of stage 4 breast cancer?

ECOG adjuvant chemotherapy trials Survival after recurrence

• Almost 14, 000 women enrolled in adjuvant chemotherapy trials: 1978 to 1999

• 24.4 % developed metastatic disease

• Median survival after recurrence was 20 months

Tevaarwerik 2013 Cancer 119:1140

ECOG adjuvant chemotherapy trials Survival after recurrence

• Survival for the general population of metastatic patients has not improved over time

• Inferior survival associated with: – Shorter disease free interval (< 3 years)

– ER and PR negative disease

– Number of positive nodes at diagnosis

– Black race

Tevaarwerik 2013 Cancer 119:1140

ECOG adjuvant chemotherapy trials Longer disease free interval from primary dx is better

Tevaarwerik 2013 Cancer 119:1140

ECOG adjuvant chemotherapy trials ER negative has worse survival

Tevaarwerik 2013 Cancer 119:1140

ECOG adjuvant chemotherapy trials Longer disease free interval is better

ER/PR negative

Tevaarwerik 2013 Cancer 119:1140

Disease free interval less than 3 years- no improvement whether diagnosed in ‘78 or ‘04

Disease free interval more than 3 years- more recent cases doing better

Possible Trastuzumab effect?

Treatment for triple negative metastatic breast cancer

• Surgery

– Oligometastasis-

• Is there a oligometastatic phenotype? Are these the “extraordinary responders?”

• Should we screen for metastasis?

– Mastectomy with stage IV disease?

• Tata Memorial Hospital study-No effect on survival

Treatment for triple negative metastatic breast cancer

• Surgery

– Oligometastasis-

• Is there a oligometastatic phenotype? Are these the “extraordinary responders?”

• Should we screen for metastasis?

– Mastectomy with stage IV disease?

• Tata Memorial Hospital study-No effect on survival

• Radiation therapy

– Palliation

Treatment for triple negative metastatic breast cancer

• Surgery – Oligometastasis-

• Is there a oligometastatic phenotype? Are these the “extraordinary responders?”

• Should we screen for metastasis?

– Mastectomy with stage IV disease? • Tata Memorial Hospital study-No effect on survival

• Radiation therapy – Palliation

• Supportive care – Treatment of bone metastasis: Pain relief and decrease fractures

• Bisphosphonates • RANK ligand inhibitor-denosumab

What is the best way to treat the disease?

High dose chemotherapy and bone marrow or stem cell transplant does not cure metastatic breast cancer

ASCO Guidelines

ASCO guidelines: For hormone independent metastatic breast cancer

• Sequential single agent chemotherapy is recommended

• Combination chemotherapy may be used for patients who present with rapidly advancing disease where time may allow only one potential chance for treatment

Best evidence: E1193 Trial • Large published randomized trial comparing

single agent to combination therapy in 1st line metastatic patients – Used our most active drugs: doxorubicin and

paclitaxel – alone or in combination

– Cross-over mandated at time of progression

– Phase III, cooperative setting

Sledge, G. et al. JCO 21:588-592 (2003)

Results E1193

Response (CR + PR)

Median TTF (Months)

Median Survival

(Months)

DOX 36 6 18.9

Paclitaxel 34 6 22.2

Dox/Pac 47 8 22

Sledge, G. et al. JCO 21:588-592 (2003)

There are some doublet chemotherapies that have shown

superior survival

Combination taxane chemotherapy

options

Line of

Rx

ORR

(%)

TTP

(mo)

OS

(mo)

X vs. XD (511) 1st – 3rd

Capecitabine (X) 30% 4.2 11.5

Cape/docetaxel (XD) 42%* 6.1* 14.5 *

T vs. GT (529) 1st

Paclitaxel (T) 26.9% 4.0 15.8

Gemcitabine/Paclitaxel

(GT) 43.1%* 6.1* 18.6*

O’Shaughnessy J JCO 2002;20:2812

Albain K JCO 2008;26:3950

Doublet chemotherapies that have shown superiority

ASCO guidelines: Metastatic breast cancer

No single agent is superior –several active agents appropriate for first line chemotherapy

Single vs Combination regimens No compelling evidence that combination regimens

are superior to sequential single-agent regimens

SINGLE AGENT • Anthracyclines Doxorubicin Pegylated liposomal doxorubicin • Taxanes Paclitaxel Albumin bound paclitaxel Docetaxel • Antimetabolites Capecitabine

Gemcitabine • Non-taxane microtubule agents Vinorelbine Ixibepilone Eribulin

News from WebMD: March 2011

Phase III EMBRACE Trial of Eribulin Versus Treatment of

Physician’s Choice for Heavily Pretreated MBC

Twelves et al. J Clin Oncol 2010; 28(suppl):958s (abstract CRA1004).

Eligibility criteria:

•Locally recurrent or

metastatic breast cancer

•2-5 prior chemotherapies:

– ≥ 2 for advanced disease

– Prior anthracycline and

taxane

•Progression ≤ 6 months

since last chemotherapy

•Neuropathy grade ≤ 2

Treatment of Physician’s Choice (TPC) Any monotherapy approved for treatment of cancer or supportive care only

Eribulin mesylate 1.4 mg/m2, days 1, 8

q 3 weeks

R

A

N

D

O

M

I

Z

E

Primary endpoint: OS

Secondary endpoints: PFS, ORR, safety

2 : 1)

Phase III EMBRACE Trial: Overall

Survival

Cortes J Lancet 2011;377:914

OS: 13.1 vs 10.7 mos

PFS: 3.7 vs 2.2 mos

• In this day of “personalized medicine” with next-generation sequencing etc, can we match the chemotherapy to the individual tumor?

ASCO guidelines: Metastatic breast cancer

• “Chemotherapy regimens should not be tailored to specific subtypes such as triple negative or lobular”

• BUT we should look for signals to pursue…

• We are looking for true synergistic interaction that may have the potential to increase survival

ERIBULIN 301 STUDY Eribulin vs Capecitabine for patients previously treated with

anthracyclines and taxanes

Kaufman et al, SABCS 2012 Abstr S6-6

ERIBULIN 301 STUDY Eribulin vs Capecitabine for patients previously treated with

anthracyclines and taxanes

Kaufman et al, SABCS 2012 Abstr S6-6

Is this a signal to listen to?

How long to continue chemotherapy in the responding/stable patient?

ASCO guidelines: Metastatic breast cancer

Chemotherapy should be continued until progression of disease as tolerated because it modestly improves overall survival and substantially improves progression free survival…. Balance against toxicity and quality of life

Optimal Duration of First Line Chemotherapy for MBC

Progression Free Survival

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

11 trials

2,269 pts

ASCO Guidelines

• With regard to targeted agents, the role of bevacizumab is controversial and this therapy should only be considered with single-agent chemotherapy when there is life-threatening disease..

Treatment for triple negative metastatic breast cancer

Targeted therapy

Bevacizumab - Approved in 2008 for first line therapy with paclitaxel in metastatic Her2 negative breast cancer

Treatment for triple negative metastatic breast cancer

On June 29, 2011 the FDA’s Oncologic Drugs Advisory Committee removed the approval based on follow up studies showing a small effect on tumor growth with no benefit to overall survival or QOL

Are we rethinking VEGF inhibition for metastatic breast cancer?

ESMO 2014

2 studies for metastatic disease, her 2 negative, ER/PR negative or positive (most had been treated with hormonal therapy) TANIA (494 pts): After initial response to bevacizumab + first line chemotherapy, pts showed benefit to continuing bevacizumab with second-line chemotherapy as compared to second-line chemotherapy alone

IMELDA (284 pts): After response or stable disease on bevacizumab and docetaxel, there was improved PFS and OS in those pts who received maintenance with bevacizumab and capecitabine as compared to maintenance bevacizumab alone.

Lancet Oncology 15: October 2014

Are we rethinking VEGF inhibition for metastatic breast cancer?

ESMO 2014

2 studies for metastatic disease, her 2 negative, ER/PR negative or positive (most had been treated with hormonal therapy) TANIA (494 pts): After initial response to bevacizumab + first line chemotherapy, pts showed benefit to continuing bevacizumab with second-line chemotherapy as compared to second-line chemotherapy alone

IMELDA (284 pts): After response or stable disease on bevacizumab and docetaxel, there was improved PFS and OS in those pts who received maintenance with bevacizumab and capecitabine as compared to maintenance bevacizumab alone.

These papers were discussed by Dr Hope Rugo who “concluded that at present the role of bevacizumab is unclear in breast cancer.”

Lancet Oncology 15: October 2014

What to do with the “stage 4 ned” patient?

• 52 yo woman has a chest wall recurrence 3 years after mastectomy for stage 2A triple negative breast cancer treated with adjuvant chemorx

• The mass is excised (triple negative) and RT is given

• “Stage 4 ned”—What to recommend

Aebi,S SABCS 2012

Benefit of chemotherapy limited to ER/PR negative

Future Therapies

• Clinical trials.gov: 400 studies currently recruiting and open for MBC

– TN specifically: 41 studies

– Many targeting specific pathways related to molecular profiling and the biology of the disease

PARP inhibitors GPNMB (CDX-011) PIK3CA

HSP 90 Angiogenesis Aurora Kinase

MET FGFR mTOR

ADC (folate) EGFR HER3

ɣ-Secretase estradiol JAK2

LIV-1 AKT Src

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THANK YOU!