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Oncology Grand Rounds
Breast Cancer
Nurse and Physician Investigators
Discuss New Agents, Novel Therapies
and Actual Cases from Practice
Friday, April 29, 2016
6:00 AM – 7:30 AM
Faculty
Kimberly L Blackwell, MD
Emily Olson, APRN, CNP, MSN
Joyce O’Shaughnessy, MD
Jennie Petruney, BSN, MSN, ANP
Moderator
Neil Love, MD
Oncology Grand Rounds Series
Oncology Grand Rounds: Themes
• New agents and treatment strategies: Benefits and risks
• Counseling patients about side effects
– Practical implementation
• End-of-life care
• Psychosocial issues in patient care
• Supporting the supporters
• Job satisfaction and burnout in oncology professionals
• The oncology professional just entering practice
• The bond that heals
Courtesy of Christiana Care Health System
Initial Presentation of ATAC
San Antonio Marriott Rivercenter, December 2001
Baum M, on behalf of the ATAC Trialists' Group.
The ATAC (Arimidex, Tamoxifen, Alone or in
Combination) adjuvant breast cancer trial in postmenopausal women. 24th Annual San Antonio
Breast Cancer Symposium 2001;Abstract 8.
Module 1:
Neoadjuvant and Adjuvant
Therapy for Patients with
Localized HER2-Positive
Breast Cancer
Discussion Topics
• Mechanisms of action of anti-HER2 agents
• Side effects and toxicities of chemotherapy/antiHER2 agents and regimens
• Neoadjuvant versus adjuvant treatment of HER2positive breast cancer
• Patient education issues in the early HER2-positive
setting
• Ongoing and planned clinical trials incorporating
novel HER2-directed therapies in the adjuvant and
neoadjuvant settings
Overview of Breast Cancer
• Estimated number of new cases and deaths in 2016:
– New cases = 249,260
– Deaths = 40,890
• Stage at diagnosis (Percent of patients who present
with):
– Localized disease = 60%
– Regional disease = 33%
– Metastatic disease = 5%
– Unstaged disease = 2%
• Five-year survival estimates (2006-2012) = 89.7%
Cancer Facts and Figures 2016; American Cancer Society Surveillance Research 2011; SEER
Stat Fact Sheet.
Breast Cancer Stage Distribution at Diagnosis
Metastatic
5%
Regional
26%
Locally Advanced
5%
Local
64%
DeSantis CE et al. CA Cancer J Clin 2016;66(1):31-42. Note: Distribution varies by race/ethnicity
Distribution of Breast Cancer Subtypes
HER2+
14%
TNBC
12%
HR+/HER274%
DeSantis CE et al. CA Cancer J Clin 2016;66(1):31-42.
35-Year-Old Woman with a ER/PR-Negative,
HER2-Positive Breast Cancer (Ms Petruney)
• Presented with a 7-cm, ER/PR-negative, HER2-positive breast
mass
• Enrolled in a trial of neoadjuvant trastuzumab/pertuzumab
– Tumor progressed during treatment
– Carboplatin/docetaxel added with excellent clinical
response
• Lumpectomy revealed a small focus of residual disease
• Postoperative radiation therapy and adjuvant
trastuzumab/pertuzumab
• She has 3 young children
• Experienced an episode of acute depression during the
neoadjuvant therapy, which resolved
Case discussion points (Ms Petruney)
• What were some of the key patient education
points that you addressed when the patient was
started on neoadjuvant trastuzumab/pertuzumab?
• What are the most common toxicity/tolerability
issues with trastuzumab/pertuzumab?
• How did the patient tolerate treatment with
trastuzumab/pertuzumab?
HER signaling:
The network begins with the 4 HER receptors
HER1/EGFR
HER2
HER3
HER4
Rowinsky. Oncologist 2003;8(suppl 3):5-17; Yarden et al. Nat Rev Mol Cell Biol 2001;2:127-137.
Pertuzumab and Trastuzumab:
Mechanisms of Action
Pertuzumab
HER2
Trastuzumab
Subdomain IV
HER1/3/4
Dimerization
domain
Trastuzumab:
• Inhibits ligand-independent HER2 signaling
• Activates ADCC
• Prevents HER2 ECD shedding
Pertuzumab:
• Inhibits ligand-dependent HER2
dimerization and signaling
• Activates ADCC
ADCC = antibody-dependent cell-mediated cytotoxicity; ECD = extracellular domain
Adapted from Harbeck N et al. Breast Care (Basel) 2013;8(1):49-55.
Commonly Used Adjuvant and Neoadjuvant
Regimens for HER2-Positive Breast Cancer
Preferred Regimens
• AC  taxane-trastuzumab ± pertuzumab
• TCH ± pertuzumab
Other Regimens
• Docetaxel-cyclophosphamide + trastuzumab
• Paclitaxel + trastuzumab
• FEC  taxane + trastuzumab-pertuzumab
• Trastuzumab-pertuzumab-taxane  FEC
NCCN Breast Cancer Guidelines v1.2016
Trastuzumab Emtansine (T-DM1):
Mechanisms of Action
Immune
effector cell
HER2
T-DM1
HER2
T-DM1
Inhibition of
HER2
shedding
Fcγ receptor
Emtansine
release
Internalization
Antibody-dependent
cellular cytotoxicity
(ADCC)
P
P
P
Inhibition of
HER2
signaling
Lysosome
PI3K
MAPK
Nucleus
Adapted from LoRusso PM et al. Clin Cancer Res 2011.
Inhibition of
microtubule
polymerization
Lapatinib: Mechanism of Action
Ligands
ErbB2
ErbB1/EGFR
IGF-IR
p95 ErbB2
Trastuzumab
X
X
Cell proliferation
Adapted from Vogel C et al. Jap J Clin Oncol 2010;40(11):999-1013.
Would You Recommend Neoadjuvant
Chemotherapy? (2.1-3.0 cm tumor)
Love N et al. SABCS 2015;Abstract P1-14-20.
Module 2:
Management of Metastatic
HER2-Positive Breast
Cancer
Discussion Topics
• Common systemic regimens used in metastatic
HER2-positive breast cancer:
– Treatment schedules
– Efficacy
– Side effects and toxicities
– Patient education issues
• Integration of endocrine treatment into the
management of “triple-positive” breast cancer
Discussion Topics
• Indications for rebiopsy, variations in HER2 and ER
assay results
• Diagnosis and management of CNS metastases in
HER2-positive breast cancer
• New agents and treatment strategies in metastatic
HER2-positive breast cancer
75-Year-Old Woman with a ER/PR-Negative, HER2Positive Metastatic Breast Cancer (Ms Olson)
• 4/2014: Diagnosed with ER/PR-negative, HER2-positive
breast cancer and metastases in the lung and adrenal glands
• Docetaxel/pertuzumab/trastuzumab
– Hospitalized twice with colitis
– Continued dual anti-HER2 therapy
• 12/2015: Brain metastases, progressive lung lesions
• Lives independently with a supportive husband, 2 grown
children
• Continues to travel countrywide
Response to Docetaxel-TrastuzumabPertuzumab (THP) in the Lung
Prior to THP
PR after 4 cycles of THP
CLEOPATRA Study
• Centrally confirmed HER2+ locally
recurrent, unresectable or
metastatic BC (MBC)
• ≤1 hormonal regimen for MBC
• Prior (neo)adjuvant systemic rx,
incl chemotherapy ± trastuzumab
allowed if followed by DFS ≥ 12 mo
• Baseline LVEF ≥ 50%; no CHF or
LVEF < 50% during or after prior
trastuzumab
N = 406
R
1:1
N = 402
Docetaxel +
trastuzumab +
placebo
Docetaxel +
trastuzumab +
pertuzumab
Trastuzumab: 8 mg/kg loading dose  6 mg/kg every 3 weeks until disease progression
Docetaxel: 75 mg/m2 every 3 weeks (increased to 100 mg/m2 at investigator discretion)
Pertuzumab: 840 mg loading dose  420 mg every 3 weeks until disease progression
Baselga J et al. N Engl J Med 2012;366(2):109-19; Swain S et al. SABCS 2012;Abstract P5-1826.
CLEOPATRA: Response and Survival Analyses
Endpoint
Pertuzumab + T + D
Placebo + T + D
Median OS
56.5 mo
40.8 mo
Median PFS
18.5 mo
12.4 mo
80.2%
69.3%
ORR
Baselga J et al. N Engl J Med 2012;366(2):109-19; Swain SM et al. Lancet Oncol 2013;14(6):46171.
Overall Survival (%)
CLEOPATRA: Overall Survival
Pertuzumab, 168 events
Median OS
Pertuzumab
(n = 402)
56.5 mo
Control
(n = 406)
40.8 mo
Hazard ratio: 0.68, p < 0.001
Months
Swain SM et al. N Engl J Med 2015;372(8):724-34.
Control, 221 events
Progressive Pulmonary Mass
CNS and Pulmonary Metastases
MRI of CNS mets
After completion of WBRT
Phase III EMILIA Study
HER2-positive LABC
or MBC (N = 991)
• Prior taxane and
trastuzumab
• Progression on
metastatic treatment
or within 6 months of
adjuvant treatment
T-DM1
PD
3.6 mg/kg q3w IV
1:1
Capecitabine
1,000 mg/m2 PO BID, days 1–14, q3w
+
PD
Lapatinib
1,250 mg/day PO qd
T-DM1
(n = 495)
Cape-lapatinib
(n = 496)
Median OS
30.9 mo
25.1 mo
Median PFS
9.6 mo
6.4 mo
Verma S et al. N Engl J Med 2012;367(19):1783-91.
EMILIA: Overall Survival
Median No.
of Months
Lapatinib-capecitabine (n = 496)
25.1
T-DM1 (n = 495)
30.9
Overall Survival (%)
85.2%
Stratified hazard ratio, 0.68
p < 0.001
64.7%
78.4%
T-DM1
51.8%
Lapatinib-capecitabine
Months
Verma S et al. N Engl J Med 2012;367(19):1783-91.
Case discussion points (Ms Olson)
• What type of end-of-life planning, if any, have you
discussed with the patient?
• How did you respond when she inquired about
physician-assisted death?
Module 3:
Management of ER-Positive,
HER2-Negative
Breast Cancer
Discussion Topics
• Use of genomic assays to determine the need for
chemotherapy and duration of adjuvant endocrine therapy
• Delayed recurrence in this disease subtype; use of
pseudoadjuvant therapy for patients with local recurrence
• Mechanisms of action, efficacy and tolerability issues:
– Endocrine agents
– mTOR inhibitors
– CDK4/6 inhibitors
• Key factors in selecting first-line systemic treatment for
metastatic disease: Chemotherapy versus endocrine
therapy
• Clinical factors affecting the sequencing of therapies in the
metastatic setting
45-Year-Old Woman with a ER/PR-Positive,
HER2-Negative Metastatic Breast Cancer (Ms
Olson)
• 2005: Diagnosed with ER/PR-positive, HER2-negative breast
cancer (premenopausal)
– Adjuvant tamoxifen x 5 years
• 2015: Pelvic bone pain
– Bone scan: Diffuse uptake suggesting metastatic disease
– Biopsy: ER/PR-positive, HER2-negative recurrence
• Bilateral oophorectomy
• Letrozole/palbociclib/zoledronic acid
– Clinical complete response within 3 months, which
continues currently
• Mother of 3 teenagers, continues to work and is experiencing
a high level of anxiety about her life situation
PET/CT of Bone Metastases
Baseline PET/CT: New mets
3 months after letrozole-palbociclib
Annual Hazard Rates of Recurrence for Breast
Cancer by ER Status
Recurrence Hazard Rate
0.3
ER-negative
ER-positive
0.2
0.1
0
0
2
4
6
Years
Saphner T et al. J Clin Oncol 1996;14(10):2738-46.
8
10
12
Progression-Free Survival (Investigator Assessed):
Palbociclib-Fulvestrant versus Placebo-Fulvestrant
Hazard ratio, 0.42
P < 0.001
Palbociclib-fulvestrant (N = 347)
Median progression-free survival,
9.2 mo
Placebo-fulvestrant (N = 174)
Median progression-free survival,
3.8 mo
Turner NC et al. Proc ASCO 2015;Abstract LBA502. NEJM 2015;373(3):209.
Key Toxicities Associated with PalbociclibFulvestrant
Palbociclib + Fulvestrant
(n = 345)
AE
Any
Grade
Grade 3 Grade 4
Placebo + Fulvestrant
(n = 172)
Any
Grade
Grade 3 Grade 4
Neutropenia
79%
53%
9%
4%
0%
<1%
Leukopenia
46%
25%
<1%
4%
0%
<1%
Turner NC et al. Proc ASCO 2015;Abstract LBA502. NEJM 2015;373(3):209-19.
Abemaciclib Monotherapy in Advanced or
Metastatic Breast Cancer
100
Change in tumor size at best response
% Change from Baseline
80
60
40
*
ORR (all): 12/47 (25.5%)
ORR (HR+): 12/36 (33.3%)
ORR (HR-): 0/9 (0%)
*
20
*
0
*
*
*
*
†
-20
*
†
* *
†
*
*
†
-40
-60
-80
HR status
Negative
-100
Positive
Unknown
*
†
* *
*
†
††
†
3 nonevaluable patients are not shown. All patients were required to have measurable disease.
† Patient progressing on endocrine therapy before study entry and continued on that specific therapy
* Indicates HER2+
Tolaney SM et al. SABCS 2014;Abstract 763.
†
Best Change in Tumor Size from Baseline with
Abemaciclib Combined with Other Therapies
Part A
letrozole
Part B
anastrozole
Part C
tamoxifen
Change from baseline (%)
*
Part D
exemestane
Part E
exemestane
+ everolimus
20% increase
30% decrease
Patients
* For this patient, change in tumor size is greater than 100%.
Tolaney SM et al. Proc ASCO 2015;Abstract 522.
MONARCH 3: Phase III Study of First-Line
Abemaciclib with a Nonsteroidal Aromatase
Inhibitor (NSAI)
Postmenopausal women with
HR+, HER2- locoregionally
recurrent or metastatic breast
cancer with disease-free
interval >12 mo following
(neo)adjuvant ET or
presenting de novo with
metastatic disease (N = 450)
Abemaciclib + NSAI
until PD
R
2:1
Placebo + NSAI
until PD
Primary endpoint: Progression-free survival (PFS)
Stratification Factors:
• Nature of disease (visceral metastases versus bone-only metastases
versus other)
• Prior (neo)adjuvant endocrine therapy (AI therapy versus other versus
no prior endocrine therapy)
Goetz MP et al. Proc ASCO 2015;Abstract TPS624. Clinicaltrials.gov; NCT02246621
72-Year-Old Woman with HR-Positive,
HER2-Negative Metastatic Breast Cancer
(Ms Petruney)
• 1981: Mastectomy for early breast cancer
• 2009: HR-positive, HER2-negative recurrence, primarily in
bone
– Exemestane/zoledronic acid (ZDA) x 2 years
– Fulvestrant/ZDA x 15 months
– Tamoxifen/everolimus/ZDA x 3+ years  disease
progression
– Letrozole x 3 months  disease progression
– Nab paclitaxel every 3 weeks with very poor tolerance
• PET scan showed significant improvement
• Continued at 50% dose reduction — just completed
5th cycle with very good tolerance
• Now able to participate fully in activities of daily living
Package inserts for ipilimumab, nivolumab, pembrolizumab (4/2016)
Case discussion points (Ms Olson)
• In general, what are some of the key patient
education points that you address when a patient
with ER-positive metastatic breast cancer is
starting on everolimus?
• What are the most common toxicity/tolerability
issues with everolimus?
• In general, what is your approach to prevention and
management of mucositis associated with
everolimus?
Crosstalk between ER and PI3K/AKT/mTOR
Signaling: Rationale for Dual Inhibition
EGFR
HER2
E
P
P
E
RAS
PI3K
PTEN
RAF
E
AKT
ER
MEK
MAPK
mTOR
E E
ER ER
• mTOR activates ER in a
ligand-independent manner
• Estradiol suppresses apoptosis
induced by mTOR blockade
• Hyperactivation of the mTOR
pathway is observed in endocrine
therapy–resistant breast cancer
cells
• mTOR is a rational target to
enhance the efficacy of hormonal
therapy
ER target gene
transcription
Adapted from: Di Cosimo S, Baselga J. Nat Rev Clin Oncol 2010;7:139-47.
BOLERO-2: PFS with Exemestane-Everolimus
in HR-Positive Advanced Breast Cancer
Probability of Event (%)
Hazard ratio, 0.36
p < 0.001
Everolimus plus exemestane
median PFS, 10.6 mo
Placebo plus exemestane
median PFS, 4.1 mo
Weeks
Baselga J et al. N Engl J Med 2012;366(6):520-9.
Case discussion points (Ms Petruney)
• In general, what are some of the key patient
education points that you address when a patient
with breast cancer is starting on docetaxel or nab
paclitaxel?
• What are the most common toxicity/tolerability
issues with these agents?
• In general, how do you explain the difference
between nab paclitaxel and the other taxanes?
Module 4:
Management of
Triple-Negative Breast
Cancer (TNBC)
Discussion Topics
• Global rationale for neoadjuvant treatment of breast
cancer: Potential advantages in local tumor control
• Role of platinum-based neoadjuvant treatment in TNBC
• Common treatment sequences in metastatic TNBC
• New approaches to TNBC:
– Androgen receptor assays and antiandrogens
– BRCA, BRCAness and the rationale for PARP
inhibitors
– Anti-PD-1/PD-L1 checkpoint inhibitors in TNBC
– Genomic assays for patients who have received all
approved therapies
54-Year-Old Oncology Infusion Nurse with TripleNegative Early Breast Cancer (Ms Petruney)
• Presented with a large breast mass and positive axillary nodes
– Biopsy: ER/PR-negative, HER2-negative infiltrating ductal
carcinoma
• Clinical trial: Neoadjuvant paclitaxel/carboplatin followed by
AC
• Mastectomy: Small focus of DCIS, no evidence of invasive
cancer
• Axillary node dissection and postoperative radiation therapy
• Currently 3 years out and faring well
• Greatly affected by her experience as an oncology nurse
• Quit work and is travelling the country with her husband
• Places a high value on experiencing life
Novel Treatment Approaches to TNBC
• Androgen receptor assays and antiandrogens
• BRCA, BRCAness and the rationale for PARP
inhibitors
• Anti-PD-1/PD-L1 checkpoint inhibitors in TNBC
• Genomic assays for patients who have received all
approved therapies
MDV3100-11: Clinical Benefit According to PREDICT AR
PREDICT AR-
PREDICT AR+
PREDICT
AR-
PREDICT
AR+
Total, n (%)
62 (53%)
56 (47%)
CBR16, %
n
11%
n=7
39%
n = 22
CBR24, %
n
6%
n=4
36%
n = 20
CR or PR, %
n
3%
n=2
9%
n=5
Median PFS
(ITT)
8.1 wks
16.1 wks
n
n = 62
n = 56
Time (weeks)
0-1 prior lines
2+ prior lines
Active
Confirmed CR or PR
Time (weeks)
CR, complete response; PR, partial response; PFS, progression-free survival; CBR,
clinical benefit rate
Traina TA et al. Proc ASCO 2015;Abstract 1003.
OLYMPIA Study Design
Tutt NJ et al. Proc ASCO 2015;Abstract TPS1109.
Change form Baseline in Sum of
Longest Diameter of Target Lesion, %
Pembrolizumab in TNBC: ORR (N = 27) and
Maximum Percentage Change from Baseline
in Target Lesions (N = 23)
Confirmed complete response (nodal disease)
Confirmed partial response
Stable disease
Progressive disease
ORR = 18.5%
Nanda R et al. SABCS 2014;Abstract S1-09.