moderator neil love, md

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ModeratorNeil Love, MD

Faculty

Challenging Cases in Breast Cancer

Oncologist and Nurse Investigators Consult on Actual Patients from the

Practices of the Invited Faculty

Thursday, May 1, 20146:00 AM – 7:30 AM

Joan M Armstrong, MSN, APRN-BCEmily Olson, RN, CNP

Adam M Brufsky, MDDenise A Yardley, MD

Oncology 6-Part Case Series: Key Themes

• Mechanisms of action of novel agents and tissue assays to predict response

• Side effects and toxicities of novel agents; dose adjustments

• Assessment and management of adherence

• Specific goals of therapy and likely outcomes; sequencing of agents in advanced disease

• Local and systemic complications of cancer: Fatigue, pain, CNS involvement

• Care of older, frail patients and those with comorbidities

Oncology 6-Part Case Series: Key Themes

• Clinical trials as a means to access new treatments earlier

• Management of anxiety and depression

• Key determinants of patient satisfaction: What do people with cancer want and need?

• Quality, value and cost: Investing resources optimally

• End-of-life care and planning

• Impact of the cancer experience on family and loved ones, including minor children

• Impact of the oncology experience on oncology health professionals

Agenda

A Patient with a Recent Myocardial Infarction and Locally Advanced ER/PR-Negative, HER2-Positive Breast Cancer•53 yo unemployed single mother of 4 children with inflammatory breast cancer and a complicated history (Ms Olson)

A Patient with Widespread Triple-Negative Metastatic Breast Cancer (mBC) and Bone Marrow Involvement•67 yo with mBC and persistent low blood counts (Ms Olson)

Agenda

Two Patients with HER2-Positive mBC•62 yo with bone and liver metastases who subsequently develops brain metastases (Ms Armstrong)•55 yo with bilateral pulmonary metastases (Ms Olson)

Two patients with ER/PR-positive, HER2-negative mBC•84 yo with bilateral pleural effusions requiring several thoracenteses (Ms Armstrong)•61 yo with mBC who speaks no English (Ms Armstrong)

Case 1 (from the practice of Ms Olson)

• A 53-year-old unemployed single mother of 4 children experienced a myocardial infarction 4 months before presenting with a 6.7-cm, inflammatory, ER/PR-negative, HER2-positive breast cancer

• After a cardiology consultation she received TCH (docetaxel, carboplatin and trastuzumab) and experienced a complete clinical response

• Mastectomy revealed a pathologic complete response in the breast, but 1 lymph node contained residual disease

• She received trastuzumab to complete 1 year of treatment (February 2014)

• Her history includes treatment for depression and extensive alcohol and tobacco use for which she is seeking treatment

Pretreatment

Post-docetaxel/carboplatin/trastuzumab

Long-term outcomes for patients with inflammatory breast cancer

Discussion Point

First-ever FDA approval of a neoadjuvant therapy of breast cancer (pertuzumab/trastuzumab/chemotherapy)

Discussion Point

HER1/3/4

PertuzumabHER2

Trastuzumab

Subdomain IV

Dimerization domain

Trastuzumab:• Inhibits ligand-independent HER2 signaling• Activates ADCC• Prevents HER2 ECD shedding

Pertuzumab:• Inhibits ligand-dependent HER2

dimerization and signaling• Activates ADCC

Pertuzumab and Trastuzumab: Mechanisms of Action

ADCC = antibody-dependent cell-mediated cytotoxicity; ECD = extracellular domain

FDA News ReleaseSeptember 30, 2013

• The US Food and Drug Administration today granted accelerated approval to pertuzumab as part of a complete treatment regimen for patients with early stage breast cancer before surgery (neoadjuvant setting). Pertuzumab is the first FDA-approved drug for the neoadjuvant treatment of breast cancer.

www.fda.gov/newsevents/newsroom/pressannouncements/ucm370393.htm

NeoSphere: Study Design

Patients withoperable orlocally advanced/inflammatoryHER2-positivebreast cancer

Chemonaive andprimary tumors>2 cm (N = 417)

TH (n = 107)Docetaxel +

Trastuzumab

THP (n = 107)Docetaxel +

Trastuzumab +Pertuzumab

HP (n = 107)Trastuzumab +

Pertuzumab

TP (n = 96)Docetaxel +Pertuzumab

FEC q3wk x 3Trastuzumab q3wk, cycles 5-17


Docetaxel q3wk x 4 → FEC q3wk x 3Trastuzumab q3wk, cycles 5-17


SURGERY

Study dosing q3wk x 3

FEC = 5-fluorouracil, epirubicin and cyclophosphamideLocally advanced = T2-3, N2-3, M0 or T4a-C, any N, M0; operable = T2-3, N0-1, M0; inflammatory = T4d, any N, M0

Gianni L et al. Lancet Oncol 2012;13(1):25-32.

NeoSphere: pCR and Hormone Receptor Status

pC

R (

% ±

95

% C

I)

pCR = pathologic complete response; H = trastuzumab; P = pertuzumab; T = docetaxel

Gianni L et al. Lancet Oncol 2012;13(1):25-32.

Resected HER2+ BC

Node+ (except T0)

Baseline LVEG ≥55%

ChemotherapyTrastuzumab x 1 yrPertuzumab x 1 yr

ChemotherapyTrastuzumab x 1 yr

Placebo x 1 yr

R

Primary endpoint: Invasive disease-free survival

Target accrual: 4,806

APHINITY: A Phase III Adjuvant Study Design

www.clinicaltrials.govwww.ibcsg.org ClinicalTrials.gov Identifer: NCT01358877

NCCN Breast Cancer Clinical Practice Guidelines – v3.2014

“A pertuzumab-containing regimen can be administered to patients with ≥T2 or ≥N1, HER2-positive, early-stage breast cancer.”

“Patients who have not received a neoadjuvant pertuzumab-containing regimen can receive adjuvant pertuzumab.”

Adjuvant therapy for node-negative, HER2-positive disease: Clinical trial findings with trastuzumab/paclitaxel

Discussion Point

Adjuvant Paclitaxel and Trastuzumab for Node-Negative HER2+ Breast Cancer

SABCS 2013;Abstract S1-04.

Tolaney SM, Barry WT, Dang CT, Yardley DA, Moy B, Marcom PK, Albain KS, Rugo H, Ellis M, Shapira I, Wolff AC, Carey LA, Overmoyer BA, Partridge AH, Guo H, Hudis CA, Krop IE, Burstein HJ, Winer EP

Phase II Study Design(APT Trial)

HER2+ER+ or ER-Node negative<3 cm

P

T

PACLITAXEL 80 mg/m2 + TRASTUZUMAB 2 mg/kg x 12

P

T

P

T

P

T

P

T

P

T

P

T

P

T

P

T

P

T

P

T

P

T

T

FOLLOWED BY 13 EVERY 3-WEEK DOSES OF TRASTUZUMAB (6 mg/kg)*

T T T T T T T T T T T

Enroll

Planned N = 400

T

* Dosing could alternatively be 2 mg/kg IV weekly for 40 weeksRadiation and hormonal therapy were initiated after completion of paclitaxel

Tolaney SM et al. SABCS 2013;Abstract S1-04.

APT Results (N = 406)

3-year DFS: 98.7%Adverse Events

Type of AE ≥Grade 3 Total

Fatigue 2% 22%

Diarrhea 1% 13%

Neuropathy 3% 13%

Neutropenia 5% 11%

Hyperglycemia 2% 10%

Leukopenia 2% 9%

Allergic reaction 2% 9%

Elevated ALT 2% 7%

Anemia <1% 7%

Tolaney SM et al. SABCS 2013;Abstract S1-04.

Stage I

HER2+*

ER+ or ER-

PS 0-1

Adequate organ fx

Trastuzumab emtansine (T-DM1)every 3 weeks for 17 weeks

Paclitaxel + trastuzumab once weekly for 12 weeks trastuzumab every 3 weeks

beginning from week 13

R

* HER2-positive defined as IHC 3+ or FISH ≥2.0; will be confirmed by central HER2 testing prior to study enrollment

N = 500

ATEMPT Trial Schema

1

3

N = 375

N = 125

Adjuvant endocrine therapy can be initiated after completion of 12 weeks of therapy

Adjuvant radiation therapy can be administered concurrently with study treatment

www.clinicaltrials.govClinicalTrials.gov Identifier: NCT01853748 PI: Sara Tolaney, MD, MPH

Impact of clinical depression and extensive alcohol and tobacco use on patients who are undergoing treatment for cancer

Discussion Point


• A 67-year-old physical therapist was diagnosed in 2011 with locally advanced ER/PR/HER2-negative breast cancer

• She received neoadjuvant dose-dense AC T followed by mastectomy and radiation therapy

• Eleven months later she developed a biopsy-proven supraclavicular lymph node recurrence

– Workup revealed liver metastases

• She received capecitabine as first-line treatment and eribulin in the second line

• She experienced persistent problems with low blood counts, and a bone marrow biopsy revealed tumor infiltration

Liver metastasis

Liver metastasis after 9 months of capecitabine

Liver metastasis after 6 cycles of eribulin

Leptomeningeal disease – April 2014

Neoadjuvant treatment for triple-negative breast cancer (TNBC): Available data with platinum agents

Discussion Point

Paclitaxel 80 mg/m2 wkly x 12 ddAC x 4

Bevacizumab 10 mg/kg q2wk x 9

Bevacizumab 10 mg/kg q2wk x 9

Carboplatin AUC 6 q3wk x 4

Carboplatin AUC 6 q3wk x 4

Paclitaxel 80mg/m2 weekly x 12

Surgery&*

XRT*

No Adjuvant Systemic Treatment Planned*

Paclitaxel 80 mg/m2 wkly x 12



Research biopsies- frozen and fixed

2 X 2 Randomization

ddAC x 4

ddAC x 4

ddAC x 4&Research biopsies if

residual tumor *MD discretion

CALGB-40603 Randomized Phase II Study Schema

Sikov WM et al. SABCS 2013;Abstract S5-01.

Odds ratio: 1.76p = 0.0018

pCR Breast (ypT0/is N any) ± Carboplatin

60% (54-66%)46% (40-53%)

N = 212 N = 221

Sikov WM et al. SABCS 2013;Abstract S5-01.

Mechanism of Action of Eribulin

EribulinEribulin suppresses microtubule growth

Eribulin sequesters tubulin into nonfunctional

aggregates

Eribulin doesn't affect microtubule shortening

Growing microtubule

Eribulin

Eribulin

Eribulin, which is derived from a sea sponge, works by inhibiting microtubules – the scaffolding of cancer cells.

Shortening microtubule

Nonfunctional

tubulin aggregate

Spindle Pole

Adapted from Jordan MA et al. Mol Cancer Ther 2005;4:1086-95.

Neoadjuvant Phase II trial with carboplatin and eribulin in triple negative breast cancer patients

SABCS 2013;Abstract P3-14-14.

Giordano SB, Jeruss JS, Bethke KP, Hansen NM, Khan S, Von Roenn J, Rosen S, Gradishar WL, Siziopikou KP, Meservey C, Kaklamani V. Northwestern University, Chicago, IL

Clinical response rate (PR + CR): 82.8%

A Phase III Study of Eribulin Mesylate versus Capecitabine in Patients with Locally Advanced or MBC Previously Treated with Anthracyclines and Taxanes

Population

Median overall survival

Hazard ratioEribulin Capecitabine

HER2-positive 14.3 mo 17.1 mo 0.965

ER-positive 18.2 mo 16.8 mo 0.897

Triple-negative 14.4 mo 9.4 mo 0.702

Kaufman PA et al. SABCS 2012;Abstract S6-6.

Consider the last patient in your practice who died of triple-negative metastatic breast cancer

How long did the patient live?

<12 months<12 months 55

1919

22

12-24 months 12-24 months

>24 months >24 months

Median = 17 monthsMedian = 17 months

Research To Practice Survey of Clinical Investigators (N = 26) December 2013.

Most common systemic agents administered

Eribulin Eribulin 2121

2121

1919

1818

1717

Platinum Platinum

Capecitabine Capecitabine

Gemcitabine Gemcitabine

Taxane Taxane

Consideration of toxicity profiles and methods of administration in the selection and sequencing of systemic therapies

Discussion Point

Two Patients with HER2-Positive mBC

• 62 yo with bone and liver metastases who subsequently develops brain metastases (Ms Armstrong)

• 55 yo with bilateral pulmonary metastases (Ms Olson)

Case 3 (from the practice of Ms Armstrong)

• A 62-year-old woman presented with ER/PR-negative, HER2-positive breast cancer

– Workup revealed metastatic disease to liver and bone

• Paclitaxel, trastuzumab and pertuzumab were administered, resulting in a partial response, but paclitaxel was stopped after 6 months because of fatigue

• She continued on dual-antibody therapy until disease progression, at which time she was switched to trastuzumab emtansine (T-DM1)

• After 6 months she developed brain metastases and received whole brain radiation therapy followed by capecitabine and lapatinib

Rationale for and available data with the addition of pertuzumab to trastuzumab/taxane

Discussion Point

• Centrally confirmed HER2+ locally recurrent, unresectable or metastatic BC (MBC)

• ≤1 hormonal regimen for MBC

• Prior (neo)adjuvant systemic rx, incl trastuzumab and/or taxane allowed if followed by DFS ≥ 12 mo

• Baseline LVEF ≥ 50%; no CHF or LVEF < 50% during or after prior trastuzumab

Docetaxel + Trastuzumab +

Placebo

Docetaxel + Trastuzumab +

Pertuzumab

1:1

N = 406

N = 402

R

CLEOPATRA Study

Baselga J et al. N Engl J Med 2012;366(2):109-19. Swain S et al. SABCS 2012;Abstract P5-18-26.

CLEOPATRA: Response and Survival Analyses

Endpoint Ptz + T + D Pla + T + D

3-yrs OS 66% 50%

Median PFS 19 mo 12 mo

ORR 80% 69%

Baselga J et al. N Engl J Med 2012;366(2):109-19.Swain SM et al. Lancet Oncol 2013;14(6):461-71.

CLEOPATRA Safety Analysis

• Safety profile similar between groups

• No increase in left ventricular systolic dysfunction with the addition of pertuzumab

• Increased incidence of ≥Grade 3 AEs with pertuzumab

– Diarrhea: 8% vs 5%

– Febrile neutropenia: 14% vs 8%

• All grade rash: 34% vs 24%

Baselga J et al. N Engl J Med 2012;366(2):109-19.

Trastuzumab Emtansine (T-DM1): Mechanisms of Action

Adapted from LoRusso PM et al. Clin Cancer Res 2011.

Emtansine release

Inhibition of microtubule

polymerization

Internalization

Lysosome

Nucleus

HER2

T-DM1

PP

P

HER2T-DM1

Immuneeffector cell

Fcγ receptor

Antibody-dependentcellular cytotoxicity

(ADCC)

Inhibition of HER2

signaling

Inhibition of HER2

shedding

P P

P

PI3K MAPK

PD

PD

Median OS: 30.9 vs 25.1 moMedian PFS: 9.6 vs 6.4 mo

Phase III EMILIA Study

1:1

HER2-positive LABC or MBC (N = 991)

•Prior taxane and trastuzumab

•Progression on metastatic treatment or within 6 months of adjuvant treatment

T-DM1 3.6 mg/kg q3w IV

Capecitabine 1,000 mg/m2 PO BID, days 1–14, q3w

+

Lapatinib 1,250 mg/day PO qd

Verma S et al. N Engl J Med 2012;367(19):1783-91.

Lapatinib + Capecitabine(N = 488)

T-DM1(N = 490)

Adverse Event Any Grade Grade 3 or 4 Any

Grade Grade 3 or 4

Thrombocytopenia 2.5% 0.2% 28.0% 12.9%

• 1st occurrence of Grade 3 or 4 thrombocytopenia typically occurs during the first 2 cycles of T-DM1 treatment

- Majority able to continue treatment with dose modifications

- 2% of patients discontinued T-DM1 due to thrombocytopenia

• 7.2% of patients experienced ≥Grade 3 liver function abnormalities

T-DM1-Associated Side Effects

Verma S et al. N Engl J Med 2012;367(19):1783-91.

ClinicalTrials.gov Identifier: NCT01120184

Phase III MARIANNE Study Design

T-DM1

T-DM1 + pertuzumab

Target Accrual: 1,095 (Active, not recruiting)

• HER2+, locally recurrent or metastatic BC

• No prior treatment for metastatic BC

R

Taxane + trastuzumab

www.clinicaltrials.gov, April 2013


• A 55-year-old secretary received treatment for breast cancer in 2000 and fared well until 2012, when a routine chest x-ray revealed multiple bilateral pulmonary nodules that on biopsy proved to be ER-positive, HER2-positive mBC

• She received docetaxel/pertuzumab/trastuzumab x 6 cycles followed by pertuzumab/trastuzumab

• While receiving chemotherapy, she developed peripheral neuropathy and alopecia, both of which resolved on the double-antibody treatment.

Pulmonary metastases at diagnosis

After 6 cycles of docetaxel/pertuzumab/trastuzumab

ER+, HER2+ mBCAge 45, premenopausalMinimally symptomatic, liver mets

Trastuzumab + pertuzumab +

taxane

Trastuzumab + pertuzumab +

taxane

2424

22Other* Other*

* ET + trastuzumab; trastuzumab + pertuzumab + ET* ET + trastuzumab; trastuzumab + pertuzumab + ET


ER+, HER2+ mBCAge 45, premenopausalAsymptomaticLow disease burden bone mets

ET + TrasET + Tras 1010

55

77

44

ET ET

Tras/Pert/Taxane

Tras/Pert/Taxane

Other* Other*

* Trastuzumab/pertuzumab/ET x 2; trastuzumab + taxane;ET + lapatinib + trastuzumab* Trastuzumab/pertuzumab/ET x 2; trastuzumab + taxane;ET + lapatinib + trastuzumab


Two patients with ER/PR-positive, HER2-negative mBC

• 84 yo with bilateral pleural effusions requiring several thoracenteses (Ms Armstrong)

• 61 yo with mBC who speaks no English (Ms Armstrong)

Case 5 (from the practice of Ms Armstrong)

• An 84-year-old woman initially presented with Stage II ER/PR-positive, HER2-negative breast cancer and received an adjuvant aromatase inhibitor (AI), which she discontinued due to extensive myalgia and arthralgia

• Two years later she was diagnosed with metastatic disease and was noted to have bilateral pleural effusions requiring several thoracenteses

Key Endocrine Therapy Options for Breast Cancer

Treatment Administration and Dose

Ovarian ablation Oophorectomy

Ovarian suppression IM injection

Tamoxifen 20-mg tablet/day

Aromatase inhibitors (AIs)AnastrozoleLetrozoleExemestane

1-mg tablet/day2.5-mg tablet/day25-mg tablet/day

Fulvestrant IM injection 250 mg or 500 mg

AI + fulvestrant Variable doses of AI + 250 or 500-mg fulvestrant (IM injection)

Everolimus + exemestane 10-mg tablet/day + 25-mg tablet/day

Everolimus-Associated Stomatitis

Grade 1 Grade 2 Grade 3 Grade 4

Clinical Exam

Erythema of the mucosa

Patchy ulcerations or pseudomembranes

Confluent ulcerations or pseudomembranes, bleeding with minor trauma

Tissue necrosis, significant spontaneous bleeding

Functional Symptoms

Minimal symptoms, normal diet

Symptomatic but can eat and swallow modified diet

Symptomatic and unable to adequately aliment or hydrate orally

Symptoms associated with life-threatening consequences

De Oliveira et al. Oral Oncol 2011; Ferte C et al. Eur J Cancer 2011; Cawley M et al. Clin J Oncol Nurs 2005

STOPP: Phase II Trial of Alcohol-Free, Steroid-Based Mouthwash for Prevention of Mucositis

• Primary outcome: Incidence of Grade ≥2 stomatitis at 2 months

Rugo HS et al. SABCS 2013;Abstract OT2-6-14.

• Postmenopausal women

• Locally advanced or metastatic HR-positive, HER2-negative BC

• Everolimus + exemestane treatment begun on day 1 of trial

Dexamethasone-basedmouthwash

10 ml (0.5 mg/5 ml dex oral solution)

4x per day

ER+, HER2-neg mBCAge 65, postmenopausalAsymptomaticLow disease burden bone metsAfter 4 years adjuvant anastrozole

Fulvestrant Fulvestrant 1414

88

44

Exemestane/everolimus

Exemestane/everolimus

Other*Other*

* Tamoxifen x 3; fulvestrant + AI* Tamoxifen x 3; fulvestrant + AI


Use of fulvestrant in patients receiving anticoagulation

Discussion Point

Use of Fulvestrant in Patients Receiving Warfarin

“Because fulvestrant is administered intramuscularly,

it should be used with caution in patients with

bleeding diatheses, thrombocytopenia, or in patients

receiving anticoagulants”

Fulvestrant package insert

“In patients with locally advanced or metastatic estrogen receptor-positive breast cancer, fulvestrant 500 mg is associated

with a 19% reduction in risk of death and a 4.1-month difference in median OS compared with fulvestrant 250 mg.”

Final Overall Survival: Fulvestrant 500mg vs 250 mg in the Randomized CONFIRM Trial

J Natl Cancer Inst 2014;1006(1):djt337.

Di Leo A, Jerusalem G, Lubos P, Torres R, Bondarenko IN, Khasanov R, Verhoeven D, Pedrini JL, Smirnova I, Lichinitser, MR, Pendergrass K, Malorni L, Garnett S, Rukazenkov Y, Martin M

Extending adjuvant endocrine therapy beyond 5 years

Use of bisphosphonates as adjuvant treatment

Discussion Points

moderator neil love, md

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