advanced&metastatic breast cancer

BREAST CANCERLOCALLY ADVANCED AND METASTATIC DISEASE

Prepared by Mahran Alnahmi Supervisor Prof.Dr. Abbas Omar

INTRODUCTION

Breast cancer, the second-leading cause of cancer deaths in women, is the disease women fear most.

Breast cancer can also occur in men, but it's far less common.

Yet there's more reason for optimism than ever before.

Most common Cancer in women in developed countries. The lifetime risk (upto age 85)

1940 - 5% ---- ----one in 20.

2000- 12.6% -------- one in 8

Incidence worldwide incidence 1.2 million(WHO) Death – 2nd leading cause of cancer death. 40,000 in US per

year, worldwide much higher

STATISTICS

Hereditary (10% of pts have 1st deg relatives)Genetic mutations- BRCA 1, 2Radiation- esp. during childhood- mantle RT upto 20%

incidence by 50 y.Benign disease- proliferative, with atypiaPrevious h/o breast caDiet- obesity; dietary fat, anti-ox.- inconclusive. Hormonal factors- increased risk with excess exposure to

estrogens; Progesterone containing OCPs

ETIOLOGY

RISK FACTOR MODELS

Gail model: ( www.nci.nih.gov )Uses the following criteria:-current age-age at menarche-age at first child birth-no. of first degree relatives with breast ca-no. of previous benign biopsies-atypical hyperplasia in a prev. biopsy-race

PATHOLOGY

In-situ Carcinomas- DCIS, LCIS; Paget’s disease of nipple

Invasive Cas-Invasive Ductal Ca (80%)Invasive lobular Ca (10%)

Other invasive Cas- Medullary, papillary, tubular, cribriform, metaplastic, squamous, adenoid cystic, mucinous, secretory, undifferentiated.

“Intrinsic” breast cancer subtypes

Basal-like ER- PR- HER2- ck5/6+ and /or HER1+

Luminal A ER+ and/or PR+ HER2-

Luminal B ER+ and/or PR+ HER2+

HER2+ / ER – ER- PR- HER2+

“Unclassified” Negative for all five markers

SPREAD OF BREAST CANCER

Direct invasion- into chest muscles, wall, skin/nipple-areola.

Lymphatic- Locoregional - axilla, supraclavicular, infraclavicular and Internal mammary

Blood- Bones, lungs, liver, brain– Distant metastasis- stage IV

MODES OF SPREAD

Local- Lump, discharge, skin/nipple changes, axillary, arm swelling, ulcer ,Pain, tenderness- Inflammatory Ca

Distant- back ache, cough, breathlessness, headache, vomiting, anorexia, etc.

O/E – lump-hard, irregular , nipple retraction, peau de orange/puckering.

Nipple discharge, axillary nodes

CLINICAL SYMPTOMS-

History and physical Examination.Mammography.FNAC/biopsy of the lump/gland- histology and

receptor status studiesHer 2 /neu, prognostic indicator studiesEvaluation- CBC, RFT, LFT, ALP, S. Ca++, Cardiac

evaluation, Metastatic work up- CXR, USG A+P, Bone scan, ?

PET. CT thorax, brain- only if symptoms suggestive.

DIAGNOSIS

American Joint Committee on Cancer Staging System for Breast Cancer(p)T (Primary Tumor) Tis Carcinoma in situ (lobular or ductal) T1 Tumor ≤2 cm T1a Tumor ≥0.1 cm, ≤0.5 cm T1b Tumor >0.5 cm, ≤1 cm T1c Tumor >1 cm, ≤2 cm T2 Tumor >2 cm, ≤5 cm T3 Tumor >5 cm T4 Tumor any size with extension to the chest wall or skin T4a Tumor extending to the chest wall (excluding the pectoralis) T4b Tumor extending to the skin with ulceration, edema,nodules T4c Both T4a and T4b T4d Inflammatory carcinoma

N0 No regional node involvement, no special studies N0 (i-) No regional node involvement, negative IHC N0 (i+) Node(s) with isolated tumor cells spanning <0.2 mm

N0 (mol-) Negative node(s) histologically, negative PCR N0 (mol+) Negative node(s) histologically, positive PCR N1 Metastasis to 1-3 axillary nodes and/or int.

mammary positive by biopsy N1(mic) Micrometastasis (>0.2 mm, none >2.0 mm) N1a Metastasis to 1-3 axillary nodes N1b Metastasis in int. mammary by sentinel biopsy N1c Metastasis to 1-3 axillary nodes and int. mammary

by biopsy

(P)N (NODES)

N2 Metastasis to 4-9 axillary nodes or int. mammary clinically positive, without axillary metastasis

N2a Metastasis to 4-9 axillary nodes, at least 1 >2.0 mm N2b Int. mammary clinically apparent, negative axillary nodes N3 Metastasis to ≥10 axillary nodes or combination of axillary and int. mammary metastasis N3a ≥10 axillary nodes (>2.0 mm), or infraclavicular nodes N3b Positive int. mammary clinically with ≥1 axillary nodes or

>3 positive axillary nodes with int. mammary positive by biopsy N3c Metastasis to ipsilateral supraclavicular nodes

M (Metastasis)

M0 No distant metastasis M1 Distant metastasis

Tumor size less than 2 cm

STAGE 1

2-5 cm with N1 or N0More than 5cm but N0Less than 2 cm or T0 but no more than N2

STAGE 2

Larger than 5 cm with any NLess than 5 cm with nodal mattingLess than 5 cm with supraclavicular LN involvement

Stage 3

Inflammatory breast

STAGE 3

Metastatic breast cancer

STAGE 4

BREAST CANCER

Locally Advanced And Metastatic Disease

Locally Advanced and Metastatic Breast Cancer

Overview:Principles of neoadjuvant chemotherapy for locally

advanced and inflammatory breast cancerSystemic therapy of metastatic breast cancer

ChemotherapyHormonal agentsBiologic agentsBisphosphonates

Rationale for selection of treatment in metastatic diseasechemotherapy vs. hormonal agentsIdeal first line agents?

Locally Advanced Breast Cancer

Definition: breast cancer, without distant metastatic spread, which is unresectable due to

Satellite skin nodulesExtensive regional lymph node involvementFixation to skin or chest wall Inflammatory breast cancer


Combined modality treatment is the standard of care for locally advanced breast cancer.Neoadjuvant chemotherapy

Goals are to improve resectability of the tumour and to increase rates of breast conserving treatment and establish tumor sensitivity

Locoregional therapySurgery, or radiotherapy, or both.


Response rates to neoadjuvant chemotherapy:

Major responders: 47-100%Clinical complete responders: 8-63%Pathologic complete responders: 3-30%

A major response to chemotherapy is associated with improved disease-free and overall survival.


Survival is related to axillary lymph node status after neoadjuvant chemotherapy.

Positive nodes 5-year overall survival0 75%

1-4 40-50%

5-10 30%

>10 20%


Survival is related to response of primary tumour to neoadjuvant chemotherapy.

Author Median follow-up, years

Survival, patients with complete response

Survival, patients with partial response

Method of response assessment

Eltahir, 1998

5 74% overall survival

36% overall survival

Clinical response

Kuerer, 1999

5 89% overall survival

64% overall survival

Pathologic response

Bonnadonna,1998

8 86% disease-free survival

56% disease-free survival

Clinical response


Duration of neoadjuvant chemotherapy

Optimal duration of treatment is not known.Rule of thumb: “treat until maximal response.”May require from 2-8 treatments, depending on

rapidity of response.Patients should be assessed by multidisciplinary

team after every 2 cycles of chemotherapy to determine optimal timing of surgery.

DEFINITIONS FOR RESPONSE EVALUATION OF PRIMARY SYSTEMIC THERAPY

CLINICAL DEFINITION

Complete: no palpable mass detectable (cCR)

Partial: reduction of tumour area to < 50% (cPR)

IMAGING DEFINITION

No tumour visible by mammogram and/or ultrasound and/or MRI

PATHOLOGICAL DEFINITION

Only focal invasive tumour residuals in the removed breast tissue

Only in situ tumour residuals in the removed breast tissue (pCR inv)

No invasive or in situ tumour cells (pCR)

No malignant tumour cells in breast and lymph nodes (pCR breast and nodes).


Ideal neoadjuvant chemotherapy regimen has not been identified.

Anthracycline based (epirubicin or adriamycin) chemotherapy is often used at start (AC, CAF, FEC).

Taxanes (taxol, taxotere) are also extremely effective and have been shown to increase the rate of pathologic complete responses.


Impact of Taxanes in NeoadjuvantChemotherapy.TAX-301 trial

162 patients, randomly assigned to pre-operative CAVP X 8 cycles vs CAVP x 4 then Taxotere X4

5 year overall survival:CAVP X 8: 78%CAVP X 4 + Taxotere X 4: 97%

Role Of Docetaxel In Neo-adjuvant Therapy For Breast Cancer

Neoadjuvant Taxotere

The Aberdeen TrialNSABP B27GEPARDUO

4 cycles of Taxotere

4 cycles of CVAP

No Response

Response

Ra nd om

i se

All Patients

4 cycles of CVAP

First Phase

Tax301 StudyConducted by the Aberdeen Breast Group

Second phase

4 cycles of Taxotere

Final A

s sessment / S

u rgery

Aberdeen Tax 301Objective clinical response rates

1st phase: 4 cycles CVAP

Response % of patients

Complete 15

Partial 52

Stasis 33

Progression 1

ORR - 67%

N=162 patients; 4 cycles of CVAP given to all patients

Aberdeen Tax301Objective clinical response rates2nd phase: responding patients

CVAP n=52

Taxotere n=52

Response % %

Complete 33 56

Additional partial 31 29

Maintained partial 29 6

Progression 4 0

ORR 64 85*

* p=0.03

Aberdeen Tax 301Objective clinical response rates

2nd phase: non-responding patients

Response % of patients

Complete 11

Partial 36

Stasis 31

Progression 9

ORR - 47%N=55 patients; additional 4 cycles of Taxotere given

Aberdeen Tax301 Aberdeen Tax301

Type of surgeryType of surgery undertaken

Breast conservation surgeryTaxotere 67%

CVAP 48%

Conservation Mastectomy0

20

40

60

80

100 Taxotere

CVAP

Type of surgery

% o

f pat

ient

s

(p<0.01)

Tax 301 Overall Survival

Time (months)

Median Follow - up: 60 months

Surv

ival

pro

babi

lity

1.0

0.9

0.8

0.720 40 60 80 100

Log rank p=0.04

TaxotereCVAP

97%

78%

Neoadjuvant Taxotere

The Aberdeen TrialNSABP B27

GEPAR-DUO

NSABP B-27

Operable Breast CancerOperable Breast Cancer

RandomizationRandomization

AC x 4 AC x 4 Tam X 5 YrsTam X 5 Yrs



SurgerySurgery Taxotere x 4Taxotere x 4 SurgerySurgery

SurgerySurgery Taxotere x 4Taxotere x 4

( 2411 pts )

40%

45%

100100

8080

6060

4040

2020

00

%%

p < 0.001p < 0.001

ACACN=1502N=1502

AC Taxotere AC Taxotere N=687N=687

65%

26%

NSABP B-27 Clinical ResponseNSABP B-27 Clinical Response

cCRcCRcPRcPRcNRcNR

14% 9%

NSABP B-27 Pathological Response (pCR) in Breast

p < 0.001

AC TaxotereN=786

ACN=1567

3.9%

9.8%

7.2%

18.9%20

10

0

30 No TumourNon-Invasive

26.1%13.7%

NSABP B-27:Proportion of Patients with negative axillary lymph

nodes

58.2

p < 0.001p < 0.001

ACACN=1534N=1534

AC TaxotereAC TaxotereN=752N=752

8080

6060

4040

2020

00

%%

50.8

NSABP B-27: Breast Conservation: Breast Conservation

p = 0.7061 63

8080

6060

4040

2020

00

%%

ACAC(N=1492)(N=1492)

AC TaxotereAC TaxotereN=718N=718

LOCALLY ADVANCED BREAST CANCER

Role of Herceptin (trastuzumab):Initial reports are encouraging, but use of herceptin cannot be

recommended outside of a clinical trial.

Role of High-dose chemotherapy with stem cell support:No improvement in DFS or OS, with significant increase in

toxicity and worsening of quality of life, therefore not recommended.


Hormonal Management Acceptable in Estrogen Receptor and/or

Progesterone Receptor positive cancers.Best used in patients where chemotherapy is

relatively contraindicatedElderly

Poor performance status

Comorbid illness

Patient reluctance to accept chemotherapy


Hormonal Management, continued:Rate of pathologic complete response is greatly

diminished.Rate of breast-conserving treatment is greatly

diminished.Response to treatment is much slower, e.g. 3-9

months.

Multidisciplinary Cancer Breast Management


Trials of Neoadjuvant Trastuzumab:Summary of Efficacy

•Preoperative clinical responses observed

– Overall response rate, 70% to 90%– Clinical complete response, 15% to 30%– Pathologic complete response, approximately 18%

•Responses higher for patients with 3+ expression of HER2

The relative efficacy of neoadjuvant endocrine therapy versus chemotherapy in postmenopausal

women with ER positive breast cancer

Methods: 121 postmenopausal women with ER(+) and/or PgR(+) breast cancer T2N1–2, T3N0–1, T4N0M0 assigned to NAT with either CT Dox 60 mg/m2 + Pac 200 mg/m2, every 3 weeks, 4 cycles, n=62 patients (pts), or HT with aromatase inhibitors, anastrazole 1 mg, n = 30 pts, 3 months).

In CT arm the most frequent grade III/IV toxicity was alopecia ( 79.3 % ), neutropenia ( 43.1 %), cardiotoxicity (6.8 %), diarrhea (1.7%). HT was well tolerated. The most commonly adverse events were hot flushes (23.3%), vaginal discharge (6.6%), musculosskeletal disorders (1.7%).

Note this does not give the pathologic CR rate.

Letrozole Is More Effective Neoadjuvant Endocrine Therapy Than Tamoxifen for ErbB-1– and/orErbB-2–Positive, Estrogen Receptor–Positive Primary Breast Cancer: Evidence From a Phase III


Summary:Standard of care is multimodality treatment.

Chemotherapy: should contain anthracyclines and/or taxanes and should begin before surgery.

Locoregional therapy: should be performed when a maximal tumour response has been obtained.

Post-operative chemotherapy: should be performed if less than 8 cycles were given pre-operatively, until a total of 8 cycles of chemotherapy have been given.

Hormonal management: is a slower option, and is restricted to ER and/or PR positive tumours.

METASTATIC BREAST CANCER

Goals of treatment of metastatic breast cancer:Cure: not a realistic goal

Few patients have complete responses, and disease free intervals are short.

Prolongation of survival:5-10% of patients will survive 5 years or more.

2-5% of patients are long-term survivors (>10 years).

Improvement of Quality of Life:Most patients experience fewer disease symptoms, with

manageable treatment side effects.


Numerous treatment options exist:

Chemotherapy: anthracyclines, taxanes, vinorelbine, capecitabine

Hormonal therapies: tamoxifen (Nolvadex), anastrozole (Arimidex), letrozole (Femara), exemestane (Aromasin), megestrol acetate (Megace)

Biologic agents: trastuzumab (herceptin)

Bisphosphonates: pamidronate, zolendronate


Different options can be combined.

Herceptin and chemotherapy.

Hormonal agents and bisphosphonates.

Herceptin, chemotherapy and bisphosphonates.


How is initial therapy selected?

Patient factors: age, comorbid conditions, willingness to accept side effects.

Tumour factors: ER, PR, her-2/neu status.Course of illness: extent and location of metastases,

disease-free interval, pace of spread of metastases.Treatment factors: adjuvant chemotherapy, adjuvant

hormonal agents, adjuvant radiotherapy.


The use of hormonal agents is favoured if:

Tumour is ER and/or PR positive.Disease-free interval is long.Few sites of metastases.Metastases do not involve visceral organs. Pace of disease progression is slow.Patient has responded to previous hormonal agents.


Use of hormonal agents, continued

Hormonal agents require 8-12 weeks to determine their efficacy, thus they are not recommended for patients with extensive visceral metastases.

Initial response to hormonal agents is 50-60% in ER/PR positive patients.


The use of chemotherapy is favoured if:Tumour is negative for ER and PR.Disease-free interval is short.Extensive metastases are present, especially visceral

disease (liver, lung).Disease is progressing rapidly.Patient has not responded to previous hormonal

agents.

Initial response to chemotherapy is 50-75%.No clear advantage of combination regimens over

use of sequential single agents.


Hormonal agents:Tamoxifen:

Mixed estrogen receptor agonist-antagonist.Can be used in premenopausal and postmenopausal

women.Response rates are 50-60%.Duration of response may be years.Toxicities: hot flashes, increased risks of DVT/

pulmonary embolism, endometrial cancerMay be associated with tumour reluctance in up to

13% of patients.


Hormonal agents, continued:Aromatase inhibitors:

Anastrozole (Arimidex), non-steroidal

Letrozole (Femara), non-steroidal

Exemestane (Aromasin), steroidal

Method of action: block conversion of adrenal androgens to estrogen in adipose tissue and in the breast.

Use is restricted to postmenopausal women.

Side effects: hot flashes, myalgias/arthralgias, increased risk of osteoporosis, altered lipid profiles.


Hormonal agents, continued:

Aromatase inhibitors: Anastrozole and Letrozole:

are non-steroidal aromatase inhibitors.

are both superior to Megace in tamoxifen refractory patients.

Have similar efficacy to tamoxifen, with fewer side effects.


Hormonal agents, continued:

Aromatase inhibitors:Exemestane:

is a steroidal aromatase inhibitor.

is superior to Megace, and at least as effective as Tamoxifen.

can be effective in patients who have failed non-steroidal aromatase inhibitors.


Hormonal agents, continued:Megace (megestrol acetate)

Is a progestinBefore aromatase inhibitors, was considered

second-line therapy, after tamoxifen.May still have activity in some patients who have

failed tamoxifen and/or aromatase inhibitors.Side effects: increased appetite, weight gain,

increased risk of DVT/pulmonary embolism.

Sequencing of Hormonal agents in metastatic breast cancer:Postmenopausal patients:

Anastrozole or Letrozole as first lineExemestane as second lineTamoxifen and Megace remain options for third line

OR for patients who do not tolerate aromatase inhibitors.

Premenopausal patients:Tamoxifen as first lineMegace OR aromatase inhibitor with ovarian

ablation as second line.


Chemotherapy:Numerous agents have activity in metastatic

breast cancer:AnthracyclinesTaxanesFluoropyrimidinesVinca alkaloidsOther drugs: cyclophosphamide, methotrexate,

gemcitabine


Anthracyclines doxorubicin (Adriamycin),epirubicin, mitoxantrone

liposomal-PEGylated doxorubicin (Doxil-Caelyx)

Are among the most active agents in breast cancer (response rate at least 50%)


Taxanes Paclitaxel (Taxol) Docetaxel (Taxotere)

Nanoparticle albumin-bound paclitaxel (Abraxane)Are the single most active drugs in breast cancer

and the most active in adriamycin-refractory patients. (RR = 60%)

Common toxicities include peripheral neuropathy, myalgias, arthralgias and alopecia.


Paclitaxel (taxol) can induce anaphylactoid reactions, requiring

premedication with steroids and antihistamines.Efficacy and toxicity profile can be improved by

weekly administration (as opposed to q3weeks).Docetaxel (taxotere)

Can induce responses in 25% of patients who are resistant to paclitaxel.

Cumulative toxicities include fluid retention, sclerosis of tear ducts, loss of fingernails/toenails.


Nanoparticle albumin-bound paclitaxel (Abraxane)Novel formulation, does not require Cremophor.No risk of anaphylactoid reaction, thus no need for

steroids.Better tissue penetration.Less toxic and more effective than paclitaxel.Approved in the USA, not yet approved in Canada.


Fluoropyrimidines:5-fluorouracil:

is commonly used in combinations, such as CMF, CAF, FEC.

Has activity as a single agent, esp. in prolonged infusions, but these regimens are not convenient.

Toxicities: mucositis (stomatitis, enteritis, colitis), hand-foot syndrome, some myelosuppression


Fluoropyrimidines, cont’dCapecitabine (Xeloda)

Oral 5-FU derivative, given BID X14 days q21days.

Prodrug is activated to 5-FU in tumour cells, mimics a prolonged 5-FU infusion.

Has activity even in patients who are refractory to anthracyclines and taxanes!! (RR=25%)

Dose limiting toxicity is usually hand-foot syndrome.

NOT HEPATICALLY METABOLIZED, thus ideal agent in patients with severe liver dysfunction!


Vinca alkaloids:Vinorelbine (Navelbine)

Semi-synthetic vinca alkaloid, related to VCR/VBLLess neurotoxicity, due to diminished binding to

axonal microtubules.Active even in heavily pretreated patients (response

rates = 25-50%).Excellent toxicity profile: no nausea, no alopecia,

no mucositisWell tolerated by elderly, frail patients


Other drugs:CyclophosphamideMethotrexateGemcitabine

All have limited activity as single agents, but are useful in combinations with other active drugs

e.g. CMF, CAF, Gemcitabine-Taxol


Biologic agentsHerceptin (trastuzumab)

Humanized mouse monoclonal antibody directed against the her-2/neu protein.

Has activity against breast cancers that strongly overexpress her-2/neu (score= 3+/3).

Has activity as a single agent, even in heavily pre-treated patients.


Herceptin, cont’d

Can be safely administered with taxanes and vinorelbine, with increased response rates (compared to chemotherapy alone).

Cannot be given with adriamycin; response rates increase BUT rate of cardiomyopathy rises to 27%!!!

Patients on herceptin who have received anthracyclines in the past need monitoring for cardiac toxicity.


Bisphosphonates:Pamidronate (Aredia)Zolendronate (Zometa)

Given monthly to patients with bone metastases.Leads to decreased risk of skeletal complications

(pain, fractures, need for radiotherapy)Few toxicities: fever and chills post-infusion,

muscle spasms (transient hypocalcemia)Rare cumulative toxicity: osteonecrosis of the

mandible (!)


A rational approach to selecting therapy for patients with metastatic breast cancer:

For patients with bone metastases: monthly administration of Pamidronate or

Zolendronate (regardless of ER/PR/her-2 status)

For patients with ER and/or PR positive breast cancer, with low burden of metastases and slow pace of disease: start with hormonal agents.If patient was on a hormonal agent at time of relapse,

try to select a non cross-resistant agent.


A rational approach to selecting therapy for patients with metastatic breast cancer:For patients with ER-negative/PR-negative disease

OR for patients with high tumour burden OR with rapid disease progression:

Start with chemotherapyIn anthracycline-naïve patients, use anthracyclines.In patients who had adjuvant anthracyclines, use

taxanes.


A rational approach to selecting therapy for patients with metastatic breast cancer:For patients with ER-negative/PR-negative disease OR

for patients with high tumour burden OR with rapid

disease progression:2nd, 3rd, 4th lines of treatment depend on patient’s

previous side effects and current symptoms.

e.g. navelbine contraindicated in patient with abnormal liver function tests; capecitabine would be a safer choice.


A rational approach to selecting therapy for patients with metastatic breast cancer:For patients with her-2/neu 3+ disease:

Herceptin should be given with taxane or vinorelbine chemotherapy.

Herceptin can be given as a single agent even in heavily pre-treated patients.

Herceptin as a single agent can be given as “maintenance” therapy after “inducing” a major reduction in tumour burden with herceptin-chemo combination.


Hormone receptorpositive

Triple-negative

HER2-Positive

*Note, these are just examples. Each patient is different and treatment is tailored accordingly.

Treatment

HER2+ disease: a paradigm for advances in

targeted therapy

Lapatinib

Oral dual tyrosine kinase inhibitor of HER2 and EGFR

FDA approved in combination with capecitabine for trastuzumab-resistant disease

May have CNS penetration

Well tolerated; common toxicities include rash and diarrhea

Pertuzumab with trastuzumab

HER2 receptor

Trastuzumab

Pertuzumab

Dimerisation domain of HER2

• Inhibitor of HER dimerization: binds HER2 and prevents formation of homo- or heterodimers• Suppresses activation of several intracellular signaling cascades driving cancer cell growth• Synergistic with trastuzumab• Approved for first-line treatment of metastatic Her2+ breast cancer in combination with trastuzumab

and taxane chemotherapy

CLEOPATRA: phase 3 study of pertuzumab in untreated metastatic disease

1:1 HER2-positive

MBC

Docetaxel + trastuzumab + placebo

Docetaxel + trastuzumab + pertuzumab

N=808

Pertuzumab prolongs time until progression by six months (from 12.5 to 18.5 months)

Trastuzumab Emtansine (T-DM1)

T-DM1 is an antibody drug-conjugate

Trastuzumab linked to a potent chemotherapy (DM1)

Average of 3.5 DM1 per antibody

T-DM1 selectively delivers DM1 to HER2+ cells

Receptor-T-DM1 complex is internalized into HER2-positive cancer cell

Potent antimicrotubule agent is released once inside the HER2-positivetumor cell

T-DM1 binds to the HER2 protein on cancer cells

HER2

EMILIA: randomized trial comparing T-DM1 to capecitabine and lapatinib in

previously treated patients

1:1 HER2+ MBC (N=980)

•Prior taxane and trastuzumab

PDT-DM1 3.6 mg/kg q3w IV

Capecitabine 1000 mg/m2 orally bid, days 1–14, q3w

+ Lapatinib

1250 mg/day orally qd

PD

T-DM1 prolongs time until progression by three months (from 6.4 to 9.6 months)

RESULTE

Th3RESA: randomized trial comparing T-DM1 to physician’s choice

Study treatment continues until disease

progression or unmanageable toxicity

HER2 positive

Metastatic breast cancer

Prior trastuzumab, lapatinib and chemotherapy

T-DM1 q3w

Treatment of physician’s choice

N = 7952:1 randomization

2

1

T-DM1 prolongs time until progression by three months (from 3.3 to 6.2 months)

T-DM1 is well-tolerated

Common side effects:Decreased platelet countElevated liver tests

Does not cause typical chemotherapy side effectsNo hair loss

Significant nausea or diarrhea are not common

Does not cause immune suppression or significant neuropathy

ER+ disease: improving on already very effective

treatments

Endocrine therapy for metastatic disease

PremenopausalTamoxifenOvarian

suppression/ablationOvarian suppression +

aromatase inhibitionMegace

PostmenopausalTamoxifenAromatase Inhibitor +/-

everolimusFulvestrantMegace

New drug approval: everolimus

Approved by the FDA in 2012 for patients with metastatic, hormone-receptor positive, HER2-negative breast cancer

*Median time from study entry until worsening of cancer

What’s next for everolimus?

Multiple studies underwayIn HER2+ cancersIn triple negative cancersStudying this drug in combination with other

therapies

Testing the addition of an HSP90 inhibitor to hormonal therapy

Other agents of interest in ER+ disease

Endoxifen CDK 4/6 inhibitorsPI3Kinase inhibitorsAnti-IGF-1R AbSRC/Abl tyrosine kinase inhibitorsCombination therapy with targeted agents that may

overcome endocrine resistance

Triple negative breast cancer:still searching for a target

There are many chemotherapies that are active against metastatic disease

Mitotic inhibitors

vinorelbine

paclitaxel

docetaxel

Antifolatesmethotrexate

Topoisomerase inhibitorsdoxorubicin

Platinums

Sledge reported 47% response rate in first line metastatic disease

Abandoned for many years because of concerns about toxicity—largely replaced by taxanes

Recent interest in patients with triple negative breast cancer

DNA crosslinking mechanism of action

New data from a series of neoadjuvant studies supports activity in TNBC

New chemotherapy: eribulin

Halichondria okadai•Metastatic breast cancer•At least 2 prior chemotherapies

PARP inhibitors

PARP1 is a protein that is important for repairing single-strand DNA breaks

PARP inhibitors prevent DNA repair, leading to cell death

Fast-dividing tumors and tumors containing BRCA mutations, which also impair DNA repair, may be most sensitive to PARP inhibitors

Ongoing trials are investigating the efficacy of PARP inhibitors in breast cancer, particularly triple negative breast cancer and BRCA-associated breast cancer

Inhibit binding to receptor (AR)

T

AR

T

Cell nucleus AR

Cell cytoplasm

Inhibit nuclear translocation of AR

Inhibit AR-mediated DNA binding

Targeting the androgen receptor intriple negative breast cancer

Other agents of interest in triple negative disease

PI3Kinase inhibitorsSRC/Abl tyrosine kinase inhibitorsHSP90 inhibitorsMore to come…

advanced&metastatic breast cancer

Health & Medicine

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t4 tumor

t1a tumor

t3 tumor

t1b tumor

t1c tumor

t2 tumor

skin t4a tumor