Metastatic Breast Cancer Flashcards
What are the side-effects of Oestrogens?
Breast tenderness Vaginal discharge Nausea/vomiting Heart failure Venous thrombosis
Use of bisphosphonates should be accompanied by what?
Calcium 1200 to 1500 mg daily
Vitamin D3 400 to 800IU daily
Current clinical trial results support use of bisphosphonates for how long?
2 years
Longer durations of therapy may provide additional benefit, but not yet been tested in clinical trials
Tell me about Denosumab vs Zoledronic Acid
Single RCT
Denosumab 120 mg SC Q4w + IV placebo
Vs
IV Zoledronic acid 4 mg + SC placebo dose
Endpoint = non-inferiority study
Denosumab shown to significantly delay time to first SRE by 20% cf to Zoledronic acid. HR 0.82
And
Delay time to first and subsequent SRE HR 0.77
No diff in TTP or OS
Adverse event profiles similar, including incidence of ONJ
What is Palbociclib
Brand name: Ibrance
CDK4/6 inhibitor
Intended for use in post-menopausal women with ER+, Her2 negative met breast ca who are endocrine-based therapy naive.
Used in combination with letrozole
What is Her2 receptor?
Define Her 2 positivity?
HER2 is a transmembrane glycoproteins epidermal growth factor receptor (EGFR) with Tyrosine kinase activity.
IHC 3+ for HER2 protein
Or
Evidence of HER2 Gene amplification by FISH (FISH >2.0)
What is trastuzumab?
Monoclonal Ab that binds the extra cellular domain of HER2
What is Pertuzumab?
Monoclonal Ab that binds the extra cellular dimerization domain of HER2 and prevents it from binding to itself or to other members of the EGFR family.
Administered in combination with Trastuzumab in tx of HER2+ breast cancer
What is Ado-Trastuzumab Emtansine
= TDM1
Antibody-drug conjugate
Composed of:
- Trastuzumab
- Thioether linker
- antimicrotubule agent DM1
What is Lapatinib
A tyrosine kinase inhibitor against EGFR1 and HER2
Results in inhibition of signaling pathways downstream of HER2.
Tell me about the CLEOPETRA Trial
Phase III RCT, n=800
Her2+, MBC
2 arms, Q3weekly:
1) Trastuzumab+Docetaxel (75) + Pertuzumab (840mg loading dose, then 420mg)
2) Trastuzumab+Docetaxel (75) + Placebo
~10% received Trastuzumab in adjuvant/Neoadj setting.
4-year f/u:
- Med OS 57 months vs 40m; HR 0.7; diff of 16m
- med PFS improved by 6 months, HR 0.7
- med duration of response improved by 8 m
30m f/u:
- med OS 38m in placebo group, not reached in Pertuzumab group. HR 0.7
- med PFS 12m vs 9m HR 0.7
5-10% with complete radiological response
Usually achieves best response to tx after 6-12m, usually discontinue chemo and continue Trastuzumab +/- Pertuzumab
What results in falsely elevated tumor markers
Up to 20% successfully to may experience marker ‘flare’ during first 1 or 2 months after treatment initiation, ?secondary to release of Ag by cytolysis
Abnormal LFTs
Vit B12 deficiency and megaloblastic anemia
Thalassemia patients
Sickle cell disease
Between Densoumab and Zoledronic acid for metastatic bone lesions, which is better?
Densoumab is more effective in delaying or preventing SREs
2010 JCO Alison Stopeck
N=2000 Met breast cancer with bone mets 2 arms: 1) SC Denosumab 120mg + IV Placebo 2) SC placebo + IV Zoledronic acid 4mg (adjusted for CrCl) Q4weekly dosing Daily Ca+Vit D supplements
RESULTS:
1) Longer to first on-study SRE HR 0.8
2) Longer time to first and subsequent on-study SREs HR 0.8
3) OS/PD ?Rates of AREs similar
4) ONJ 2% with Denosumab, 1.4% with Zoledronic acid. Not sig
Tell me about the FIRST Study
Robertson JCO 2009
Aim: compare Anastrozole vs Fulvestrant as 1st-line
(Fulvestrant given as double the approved dose in this study)
Fulvestrant given as IM 500mg Days 0, 14, 28 then Q28days
Phase II, n=200
Post-menopausal advanced HR+ Breast CA
RESULTS:
Clinical Benefit Rate = proportion of patients experiencing Objective response/SD for 24 weeks or more.
CBR ~ 70%
ORR similar 35%
TTP longer for Fulvestrant. NR in study vs 12m for Anastrozole. HR 0.6
Updated analysis 2012 Breast Cancer Res Treat by Robertson
- TTP 23.5m (Fulvestrant) vs 13m for Anastrozole
- 34% reduction in is of progression. R 0.66
- Best Overall response to subsequent therapy and CBR similar
- Median OS 54m vs 48m (Anastrozole)
How does Fulvestrant work?
Fulvestrant is an anti estrogen that leads to Estrogen receptor degradation
Has estrogen Antagonsitic activity
No estrogen agonistic effect
Any benefit in Fulvestrant after prior AI therapy in advanced breast cancer?
Yes. James Ingle JCO 2006
Phase II study
N=80
HR+, max one prior hormonal agent in addition to 3rd generation AI
RESULTS:
Clinical Benefit rate of 35%
Median TTP 3months
Median survival time 20m
What are the side effects of Fulvestrant?
Fatigue Hot flashes Nausea Injection site reaction Anorexia Arterial gigs Diarrhea Alopecia Neuroses sorry difficulties Dyspnoea
Why Fulvestrant 500mg and not 250mg?
Angelo Di Leo JCO 2010, CONFIRM Study
N=700 ER+ post-menopausal Advanced breast cancer
S/p prior endocrine therapy.
2 arms:
1) Fulvestrant 500mg IM Day 0, 500mg IM Day 14 and 28 then Q28days
2) IM Fulvestrant 250mg Q28 days
RESULTS:
1) PFS longer for 500mg dose. HR 0.8, 20% reduction in risk of progression.
2) ORR ~ at 10%
3) Clinical Benefit rate 45% (500mg dose) vs 40%
4) Duration of Clinical benefit 14m (250mg) vs 17m
5) OS 23m (250mg) vs 25m
What is Palbociclib ?
Oral, Small-molecule inhibitor of cyclin-dependent kinases (CDKs)4 & 6
CDK4 and CDK6 promote progression from G1 phase to S phase of the cell cycle.
Growth-inhibitory activity in ER+ Breast cancer cells
Synergy with anti-estrogens
What is PALOMA-1?
Finn Lancet Oncol 2015
Randomized Phase 2
Treatment-naive
Post-menopausal, Advanced ER+, HER2-
N=165
2 cohorts:
1) ER+, HER2-
2) ER+, HER2-, cancers with amplification of cyclin D1 (CCND1), loss of p16 (INK4A or CDN2A) or both
In each cohort, randomized to 2 arms:
1) Letrozole 2.5mg OD
2) Letrozole 2.5mg OM + PO Palbociclib 125mg OD 3w/1w Q28days
RESULTS:
Med PFS 10.2m (Letrozole) vs 20m (Palbociclib)
Cohort 1: PFS 6m vs 26m
Cohort 2: PFS 11m vs 18m
G3/4 neutropenia 50% (Palbociclib) vs 1% (Letrozole)
What is PALOMA-3
Turner NEJM 2015
Aim: to assess efficacy of Palbociclib and Fulvestrant in advanced breast cancer
N=500
Advanced HR+ breast cancer
HER2-
S/p prior endocrine therapy
2 arms:
1) Palbociclib + Fulvestant
2) Placebo + Fulvestrant
Premenopausal/peri menopausal also received Goserelin.
RESULTS:
Med PFS 9m (combi) vs 4m
Any evidence of combining Everolimus with a hormonal agent?
Yes.
TAMRAD study
Bachelot JCO 2012
Phase 2 study n=100
Post-menopausal women, AI-resistant MBC
HR+, HER2-
2 arms:
1) Tamoxifen 20mg/d + Everolimus 10mg/d
2) Tamoxifen 20mg/d
RESULTS:
1) 6m CBR 60% (Combi) vs 40%
2) TTP 8.5m (Combi)vs 4.5m
3) Risk of death reduced by 55% HR 0.45 in favor of Combination therapy.
What are the size-effects of Everolimus?
Stomatitis Infections Rash Pneumonitis Hyperglycemia
Tell me about the EMILIA study
N=1000
Her2+, advanced breast cancer
S/p Taxane + Trastuzumab
2 arms:
1) TDM1 + Capecitabine
2) Lapatinib + Capecitabine
Pri end points: PFS, OS, safety
Sec end points: PFS (Invx-assessed), ORR, Time to symptom progression
Results:
1) Improved PFS: 6.5m to 9.6m
2) Improved OS 25m to 31m
3) Improved ORR 30% to 45%
4) Less toxicity
- except for higher incidences of thrombocytopenia and transaminases
Tell me about the CLEOPETRA study
Phase 3, Met Breast CA, 1st line
Multi centre, multicountry
N=800
2 arms:
1) Docetaxel + Trastuzumab + Pertuzumab
2) Docetaxel + Trastuzumab + Placebo
Primary End-points: PFS
Sec End-points: OS, PFS(assessed by invx), ORR, safety
Results (at 50m f/u):
1) Increased mOS 56m from 41m
2) Increased mPFS 19m from 12.5m
3) Increased duration of response 20m from 12.5m
4) Improved ORR 80% vs 70%
S/e:
- No increase in rate of LV dysfunction (1-2%)
- Increased diarrhea, neutropenia, rash, mucosal inflammation, dry skin, serious G3/4 febrile Neutropenia with Pertuzumab
What is the difference between Pertuzumab and Trastuzumab?
They bind at different epitope of the HER2 Extracellularly domain.
Pertuzumab binds HER2 at the subdomain II
Trastuzumab binds at subdomain IV
What is the difference between 3-weekly and weekly Pac?
Seidman JCO 2008
CALGB 9840 study
2 arms:
1) 3-weekly Pac (175mg/m2)
2) Weekly Pac (80mg/m2)
Herceptin subsequently incorporated into study when it was available.
RESULTS: - Improved OS 30%--> 40% - Improved PFS 5MinRelax --> 9m - Improved OS 12m --> 24m (All significant)
Tell me the evidence for chemo after complete resection in a patient with local recurrence.
CALOR study
Study investigated adjuvant chemo in Isolated locoregional recurrence, after complete resection is achieved.
N=160
S/p op for locally recurrent disease
2 arms:
1) Chemo
2) Observation
RT mandatory for those with R1 resection
All patients advised to undergo RT.
f/u 5 years
Results: - improved 5y OS: 75% --> 90% - improved overall DFS: 55%-->70% - Benefit of adjuvant chemo mostly seen in ER- disease. >> 5y DFS 65% vs 35% >> 5y OS 80% vs 70%
Define Skeletal-related events
Bone fractures
Bone pain requiring RT
Spinal cord compression
Hypercalcemia
How often do you need to give bisphophonates in breast CA + bone mets?
Once every 3-5 week schedule in conjunction with anti-neoplastic therapy
Recent data from a phase III study showed zoledronic acid administered once every 12 weeks vs the current standard of once every 4 weeks does not compromise efficacy
- SRE rate was 22% when administered once every 4 weeks, vs 23% when administered once every 12 weeks.
What is the expected timeframe that disease flare can be expected in bony mets?
2 months to 12 months after initiating therapy
Any evidence for endocrine therapy post-resection of loco-recurrence in breast cancer?
Weber et al SAKK23/82 study Ann Oncol 2003
Phase III
N=160
HR+ or HR-unknown locally recurrent breast cancer
S/p resection of disease
2 arms:
1) Tamoxifen
2) observation
F/u 11 years
RESULTS:
Median DFS 6.5 years vs 2.5 years (no tam)
5y DFS 60% vs 30%
No difference in median OS = 11 years
What is the percentage of breast cancers that express HER2 ?
15-20%
What is Lapatinib ?
A TKI against EGFR1 and HER2 that results in the inhibition of signaling pathways downstream of HER2.
What is Pertuzumab ?
A monoclonal Ab that binds the extracellular dimerization domain of HER2 and prevents it from binding to itself or to other members of the EGFR family
Tell me about the original Slamon paper
NEJM 2009
Phase III
N=450
Anthracyclines-naive MBC 4 arms: 1) Doxorubicin + Trastuzumab 2) Doxorubicin 3) Epirubicin + Trastuzumab 4) Epirubicin
RESULTS:
Combination therapy resulted in a significant improvement in:
- TTP 7m vs 5m
- mOS 25m vs 20m
S/e:
Significant cardiotoxicity
What is the evidence to combine Herceptin with chemo, instead of giving Herceptin alone in MBC?
HERTAX trial
N=100
2 arms:
1) Docetaxel + Herceptin
2) Herceptin –> Docetaxel on PD
RESULTS: Sequential use resulted in:
- similar PFS 10m vs 9m
- lower mOS 20m vs 30m
- lower ORR 55% vs 80%
- lower incidence of neuropathy 30% vs 60%
** study did not address what happens if Herceptin –> Herceptin/Docetaxel
When was TDM1 evaluated as a first-line treatment?
MARIANNE trial
N=1000
Progressive or Recurrent LABC or Tx-naive MBC
3 arms:
1) Herceptin + Taxane
2) TDM1 + Placebo
3) TDM1 + Pertuzumab
RESULTS:
- mPFS 13.7m vs 14.1m vs 15.2m
» No significant difference in PFS in arm 2 cf arm 1 or arm 3 cf arm1 or arm 3 and arm 2
- OR 68%, 60%, 64%
What is the evidence for TDM1 in 2nd line setting?
EMILIA trial
N =1000
S/p trastuzumab + Taxane
2 arms:
1) TDM-1
2) Capecitabine + Lapatinib
RESULTS (19m f/u):
- Improved PFS with TDM1: 10m vs 6m
- Improved OS 30m vs 25m
- Improved ORR 45% vs 30%
- Decreased G3/4 toxicity verbal 40% vs 55%
Most common s/e with TDM-1 = thrombocytopenia and transaminases
- also higher overall rate of bleeding (30% vs 15%)
Any evidence for Lapatinib as 1st line treatment for MBC?
Yes. NCIC CTG MA.31
N=650
2 arms:
1) Lapatinib + Paclitaxel
2) Trastuzumab + Paclitaxel
RESULTS: Lapatinib results in:
- Shorter PFS 9m vs 11.5m
- ~OS
- Higher rate of toxicity and hence higher discontinuation rate
Most serious s/e o Lapatinib:
- Diarrhea, rash, anorexia
Any evidence in HER2 + disease for chemotherapy-free regimen?
Yes, Blackwell JCO 2012, with Lapatinib + Trastuzumab
N=300 MBC with PD after one or more prior Trastuzumab-containing regimen. 2 arms: 1) Lapatinib 2) Lapatinib + Trastuzumab
RESULTS: Combination results in:
- Improvement in PFS 11w vs 8w
- Improvement in OS 14m vs 10m
- If exclude cross-over, mOS is 14m vs 8m
What is the evidence for TDM-1 after multiple HER2-directed therapies?
TH3RESA study
N=600
Unresectable, LA, recurrent or MBC
S/p at least 2 HER2-directed regimens, with PD on Beh Trastuzumab and Lapatnib-containing regimens)
2 arms:
1) TDM-1
2) Physician’s choice
RESULTS: TDM-1 results in:
- Improved PFS 6m vs 3m
- Improved OS NR vs 15m
