Back to the basics!
--> Genetic Predispositions for Breast Cancer?
~ at least four mutations/syndromes.
• BRCA mutations account for 15-20% of familial breast cancers, 5-10% of all breast cancers
• Other Genetic syndromes
– Li-Fraumeni (p53 mutation)
– Cowden (PTEN mutation)
– Peutz-Jeghers (STK11 mutation)
– CDH1 (lobular carcinoma and diffuse gastric cancer)
– PALB2
How do you treat stage 1 TNBC?
Stage 1 --T1, N0, M0 or T1 Nmini M0
Neoadjuvant Anthracycline + taxane +/- carboplatin
Adjuvant Capecitabine if residual disease
How do you treat Stage I (cT1N0 ) HER 2 + disease?
Surgery--> on pathology if tumor is < 0.5 cm then No systemic therapy (ET prn)
If between 0.5-2 cm then TH x 12 wk, H to 6-12m
[TH here is paclitaxel + Trastuzumab]. The trial that supported it was De-Escalation of Therapy--APT Trial.
3 year disease free survival was 98.7%.
Do all patients need chemotherapy?
No!
•T-DM1 side effects
Side Effect Profile of T-DM1
Fatigue / asthenia
Nausea
Musculoskeletal pain
Thrombocytopenia (low platelets — dose-limiting toxicity)
Elevated liver enzymes (AST/ALT)
Constipation
T/F
PARP Inhibitors for BRCA germline mutation carriers in HER2 +disease
False, used in HER2 neg (TNBC and HR+HER2-)
How do you treat stage II/III TNBC?
Neoadjuvant
Carboplatin + Paclitaxel + Pembro x 12 weeks
Doxorubicin + Cyclophosphamide + Pembro x 12 weeks
Surgery
Pembrolizumab 200 mg Q3W x9 cycles
[KEYNOTE-522 Trial]
How do you treat stage II/III disease?
Neoadjuvant Rx
Chemo + H (HP if LN+)
Surgery
pCR --H or HP to 1y
Residual disease --T-DM1 x 14 cycles
Consider neratinib x 1y if ER+
Chemo used is • TCH(P)(node positive)
T--Docetaxel.
C--Carboplatin.
• ACTH(P) also ok but higher risk of cardiac toxicity
A--doxorubicin.
C--cyclophosphamide.
T--Paclitaxel
When to proceed with chemotherapy without genomic assay?
– Premenopausal and LN+
– Postmenopausal with 4+ LN
Aromatase Inhibitors types?
mechanism?
Side effects?
--> Non-steroidal--Anastrozole, Letrozole
Steroidal--Exemestane
--> Aromatase inhibitors block the enzyme aromatase, which converts androgens (androstenedione, testosterone) into estrogens (estrone, estradiol)
--> Side effects/Risks: – Muscle and joint aches – Vaginal dryness – Bone loss – Hot flashes
Lobular Carcinoma-in-Situ has 8-10 X more risk of developing cancer in bilateral breasts?
True!
Per the Keynote 522 trial for TNBC, do you need to check PDL1 status?
--> Benefit independent of PDL1 status-don’t need to check.
-- pCR in pembro arm was ~ 65% as compared to ~51% in placebo (13.6 % absolute difference)
--> Event free survival at 3 years--~85 % vs ~77% at 36 months; 7.7% absolute improvement
1) Which trial showed benefit of pertuzumab in patients with node+ disease ?
2) Which trial supported benifit of adding Neratinib after adjuvant trastuzumab & chemotherapy in ER/HER +disease
1) Aphinity Trial, . NEJM 2017
2) ExteNET
1) When to consider genomic assay?
What is the Recurrence Score when you definitely add chemotherapy?
1) – Node negative breast cancer
– Post-menopausal with 1-3 LN+
2) Recurrence Score >=26 --Chemo + endocrine
Mechanism and side effects of Tamoxifen?
Tamoxifen is a selective estrogen receptor modulator (SERM). Its mechanism of action depends on the tissue type: Breast tissue → acts as an antagonist, Endometrium & bone → acts as a partial agonist, Liver → agonist effects: decreases LDL cholesterol.
Side effects/Risks: – DVT/PE – Uterine cancer (esp 50+) – Hot flashes – Cataracts – Menstrual irregularities
TNM staging?
T1 ≤2 cm
T2 >2 BUT ≤5
T3 >5
T4 Tumor of any size with direct invasion to chest wall (T4a) &/ to the skin (T4b).
N1- mets to movable ipsilateral axillary LN's.
N2a- mets to fixed/matted ipsilateral axillary LN's
N2b mets to ipsilateral internal mammary LN's without axillary LN involvement
N3a - mets to Ipsilateral infraclavicular LN w/wo axillary LN involvement.
N3b -mets to ipsilateral internal mammary LN's with axillary LN involvement
N3c -mets to ipsilateral supraclavicular LN's
What was the absolute difference in DFS and OS of adding capecitabine in adjuvant setting if residual disease is present per Create-X trial?
Options A -->14% absolute difference in DFS and 8.5% in OS
Option B --> 24% absolute difference in DFS and 8.5% in OS
Option C-->14% absolute difference in DFS and no improvement in OS
Option D --> No improvement in DFS and 8.5% improvement in OS
Option A--> 14% absolute difference in DFS and 8.5% in OS
KATHERINE study?
Stage II/III HER2-positive breast cancer who recieved Neoadjuvant chemo and HER 2 directed therapy and found to have Residual invasive tumor in breast or axillary nodes received TDM vs Trastuzumab 11% improvement in 3-year IDFS 88.3% vs 77.0%
1) 65 year old lady with score 21 what do you do?
2) 45 year old women with score 21 what do you do?
Postmenopausal
0-25 Endocrine only
>=26 Chemo + endocrine
Premenopausal
0-15 Endocrine only
16-25 Chemo + endocrine, or consider endocrine with ovarian suppression? [6.5% difference in Distant Recurrence Rate for RS 21-25, vs 1.6% for 16-20 ]
>=26 Chemo + endocrine
Abemaciclib?
MOA?
Approved in which setting?
Side effects?
CDK4/5 inhibitors, cell cycle arrest in G1 phase, reduced cellular proliferation.
Resected HR+/Node+ breast cancer patients at high risk of recurrence (>+4+ axillary LN's or 1-3 LN's with one of the following- size> 5, Grade3, Ki67> 20), you give abema x2 years and ET 5 years.
Toxicity: diarrhea, neutropenia