MANAGEMENT OF EARLY OPERABLE HER2+ BREAST CANCER

1. MANAGEMENT OF EARLY HER2+
BREAST CANCER
Prof. S. Subbiah et al

2. EARLY BREAST CANCER
• NCI Definition:
• Breast cancer that has not spread beyond the breast or the
axillary lymph nodes.
• This includes ductal carcinoma in situ & Stage I, IIA, IIB & IIIA
breast cancers.
Prof. S. Subbiah et al

3. T1mi ≤1mm
1a 1-5mm
1b 6-10mm
1c 1-2cm
T2 2.1-5cm
T3 >5cm
T4a Chest wall
4b Ulceration, satellite nodules,
peau d’ orange of skin
4c 4a+4b
4d Inflammatory carcinoma
N1 I/L level I,II- mobile
N2a I/L Level I, II- fixed/Matted
2b I/L internal mammary
N3a I/L infraclavicular nodes
3b I/L Internal mammary +
axillary nodes
3c I/L Supraclavicular nodes
TNM STAGING
Prof. S. Subbiah et al

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5. PEROU & SORLIE MOLECULAR
CLASSIFICATION
Prof. S. Subbiah et al

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8. CLINICAL PROGNOSTIC STAGING
EXAMPLE TAKEN : IB
Prof. S. Subbiah et al

9. cT0N1, cT1N1, cT2NO- IB (AJCC STAGING)
G1 Luminal A IB
Luminal B (Triple positive) IB
HER2 + IIA
TNBC IIA
G2 Luminal A IB
Luminal B (Triple positive) IB
HER2 + IIA
TNBC IIB
G3 Luminal A IIA
Luminal B (Triple positive) IB
HER2 + IIA
TNBC IIB
CLINICAL PROGNOSTIC STAGING
Prof. S. Subbiah et al

10. HER2 +
• HUMAN EPIDERMAL GROWTH FACTOR 2/CD 340, ErbB2 gene,
Chromosome 17
• 25% of Breast cancers
• Diagnosed: HER2 overexpression (IHC),Gene amplification (FISH)
• Associated with adverse prognosis with higher risk of recurrence,
• Triple positive: Lack or lower levels of ER expression & relative
resistance to endocrine therapy & CMF based chemotherapy.
Prof. S. Subbiah et al

11. HER 2 +: IHC & DUAL PROBE FISH
2018 ASCO/CAP GUIDELINES
GROUP IHC HER2/CEP
RATIO
HER 2 COPY
NUMBER
RESULT
1 - ≥2 ≥4 POSITIVE
2 0 - 2+ ≥2 <4 NEGATIVE
2 3+ ≥2 <4 POSITIVE
3 0 - 1+ <2 ≥6 POSITIVE
3 2+, 3+ <2 ≥6 POSITIVE
4 0 - 2+ <2 ≥4, <6 NEGATIVE
4 3+ <2 ≥4, <6 POSITIVE
5 - <2 <4 NEGATIVE
Prof. S. Subbiah et al

12. HER 2 TARGETED THERAPY
TRASTUZUMAB
PERTUZUMAB
TDM-1
Fam TZ DERUXTECAN
MARGETUXIMAB
Prof. S. Subbiah et al

13. • Targets HER 2: TZ,
• Drugs preventing HER2 dimerization: Pertuzumab
• Antibody drug conjugate: T-DM1
• Targets HER2 & Immune cells: Margetuximab
• Drugs targeting Tyrosine kinase moiety of HER 2: Lapatinib,
Neratinib.
• Drugs targeting the down stream pathway of HER2 :
PI3K/AKT/mTor: Afatinib, Dacotinib, ibrutinib,…
Prof. S. Subbiah et al

14. TRASTUZUMAB
• Humanized IgG 1 targets domain IV of HER2/ErbB2 member of
EGFR/Erb B family of tyrosine kinases.
• 1st mAb approved by FDA for treatment of Solid tumors & as adjuvant
therapy. Herceptin.
• Risk factors: borderline left ventricle ejection fraction, HTN, Age
>65yrs.
• Optimal duration: 1 year.
TRASTUZUMAB
PERTUZUMAB
TDM-1
Fam TZ DERUXTECAN
MARGETUXIMAB
Prof. S. Subbiah et al

15. • 8mg/kg iv D1 followed by 6mg/kg iv D1* every 21 days
• 4mg/kg iv D1 followed by 2mg/kg iv weekly
• Adverse effect: CARDIOMYOPATHY/ Cardiac dysfunction. More
with anthracycline based chemotherapy- Doxorubicin, Epirubicin.
(2% vs 1%)
• CARDIOMYOPATHY:
• 1-4%
• EF decreases by 10%
• Monitored by: 2D ECHO, Radionuclide ventriculography.
Prof. S. Subbiah et al

16. • Short course (9weeks) Concurrent TZ+ Chemotherapy is better
than no TZ.
• After Adjuvant chemotherapy, Concomitant RT +TZ , Endocrine
therapy+ TZ.
Prof. S. Subbiah et al

17. PERTUZUMAB
• Perjeta
• Humanized IgG1 mAb – binds domain II of HER2
• PZ+ TZ+ Docetaxel: approved 1st line for HER2+ metastatic breast
cancer
• HER2+ , locally advanced, inflammatory, high risk early breast
cancer (>2cm node±)
• CLEOPATRA trial.
• 840 mg/kg iv D1 followed by 420mg/kg iv D1 * every 21 days
• A/E: Diarrhea, no increased risk of cardiomyopathy.
TRASTUZUMAB
PERTUZUMAB
TDM-1
Fam TZ DERUXTECAN
MARGETUXIMAB
Prof. S. Subbiah et al

18. TDM-1
• Ado- trastuzumab emtansine (Kadcyla) – ADC- (Antibody drug
conjugate) composed of TZ linked to DM1 (potent derivative of
maytansine)
• EMILIA trial- increased PFS, OS in progressive disease after TZ
based chemotherapy.
• 3.6mg/kg iv D1 * every 21 days
TRASTUZUMAB
PERTUZUMAB
TDM-1
Fam TZ DERUXTECAN
MARGETUXIMAB
Prof. S. Subbiah et al

19. FAM TZ DERUXTECAN
• Enhertu, fam-TZ- Deruxtecan-nxki
• ADC, composed of TZ+ Cytotoxic topoisomerase inhibitor
• DESTINY-Breast01 trial- approved for metastatic breast cancer
• In progressive disease after TZ, PZ, TDM-1 based chemotherapy.
• 5.4mg/kg iv D1 * every 21 days
TRASTUZUMAB
PERTUZUMAB
TDM-1
Fam TZ
MARGETUXIMAB
Prof. S. Subbiah et al

20. MARGETUXIMAB
• Margenza
• Chimeric IgG1 mAb
• SOPHIA I trial
• Metastatic HER2+ breast cancer refractory to other HER2+ agents.
• 15mg/kg iv D1 * every 21 days
TRASTUZUMAB
PERTUZUMAB
TDM-1
Fam TZ DERUXTECAN
MARGETUXIMAB
Prof. S. Subbiah et al

21. Prof. S. Subbiah et al

22. • Stage I, HER2+ : Paclitaxel+ TZ for 12 weeks, 1yr of TZ- low
recurrence rate.
• Stage II, III HER2+:
• Addition of Pertuzumab with TZ- decreased breast cancer
events.
• Neoadjuvant Chemo + TZ+ PZ- preferred approach- high rates
of pCR & Surgical downstaging. Enabling tailored adjuvant ±
TDM-1 for residual disease.
• NERATINIB: HER2, EGFR inhibitor (ExeNet Study)- reduce
recurrence in ER+, HER2+ (not in ER-, HER2+), no OS benefit.
Prof. S. Subbiah et al

23. PREOPERATIVE SYSTEMIC
THERAPY
• BENEFITS:
• Facilitates Breast Conservation (unicentric, high grade, TNBC or
HER2+)
• Render inoperable tumors operable
• Prognostic marker for recurrence risk- especially in TNBC,
HER2+
• To identify pts with residual disease –
• Can tailor adjuvant treatment by addition of supplemental
adjuvant regimens (TNBC, HER2+)
• Allows time for Genetic testing.
Prof. S. Subbiah et al

24. • OPPORTUNITIES:
• SLNB can be done if cN1 turns cN0
• Can modify systemic therapy if no response or progressive
disease
• Limited RT fields if cN1 turns cN0/ pN0
• To test novel therapies and predictive biomarkers.
Prof. S. Subbiah et al

25. • CAUTIONS:
• Overtreatment if over-staged.
• Undertreatment locoregionally with RT if under-staged.
• Disease progression.
Prof. S. Subbiah et al

26. INDICATIONS FOR NACT
• Operable breast cancer:
• HER 2 + and TNBC, if ≥cT2 or ≥cN1
• Large tumor – before BCS
• cN+ likely becomes cN0
• Considered for cT1cN0- HER2+ and TNBC
• Inoperable breast cancer:
• IBC
• Bulky or matted cN2 axillary nodes
• cN3 nodes
• cT4 tumors
Prof. S. Subbiah et al

27. • CONTRAINDICATIONS:
• Extensive in-situ disease (EIC) with invasive disease extent not
known
• Multi-centric disease
• Poorly delineated extent of tumor
• Tumors which are not palpable or clinically assessable.
Prof. S. Subbiah et al

28. WORK UP PRIOR TO NACT
• CBC,
• Comprehensive metabolic panel – LFT & ALP
• CT Chest ± contrast
• Abdominal ± pelvic CT or MRI with contrast
• Bone scan or NaF PET/CT (2B)
• FDG PET/CT (optional)
• Breast MRI (optional)
Prof. S. Subbiah et al

29. BREAST & AXILLA EVALUATION
PRIOR TO NACT
• Core biopsy of breast with placement of image detectable clips or
marker(s)
• Axillary imaging with USG or MRI
• Biopsy + clip placement of suspicious and/or clinically positive
axillary lymph nodes.
Prof. S. Subbiah et al

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31. PCR
• Absence of residual invasive cancer in breast and axilla after
preoperative therapy.
• Strongest prognostic marker for long term DFS, lower local
recurrence rate mainly for TNBC, HER2+.
• Clinical response rate for NACT: 50-85%
• pCR – 15-40%, >50% (TNBC, HER2+)
• BCS rates : 25% to 40% , 60% (TNBC, HER2+)
Prof. S. Subbiah et al

32. • 42 HER2+ operable breast cancer – randomized to 4* Paclitaxel followed by
4* Fluorouracil, Epirubicin, cyclophosphamide ± Trastuzumab *24 weeks
• Study stopped prematurely because of superiority of trastuzumab arm.
T-FEC pCR 25%
T-FEC+ TZ 66.7%
Buzdar et al
TECHNO TRIAL
NOAH TRIAL
CTNeoBC analysis
NeoALTTO trial
Prof. S. Subbiah et al

33. • BUZDER et al:
• Gianni et al:
TZ arm Only chemo
pCR 65% 26%
3yrs DFS 100% 85%
OS 100% 95%
TZ arm Only chemo
pCR 38% 19%
3yrs DFS 71% 56%
Buzdar et al
TECHNO TRIAL
NOAH TRIAL
CTNeoBC analysis
NeoALTTO trial
Prof. S. Subbiah et al

34. • T1,T2- 70%, T3- 30%
• N0/N1- 94%
• pCR- 38.7%, cCR- 28%, cPR- 55%,
STABLE- 16%, PROGRESSION- 1%
pCR Partial response
3yrs DFS 88% 71.4%
3 yrs OS 96% 85%
Buzdar et al
TECHNO TRIAL
NOAH TRIAL
CTNeoBC analysis
NeoALTTO trial
Prof. S. Subbiah et al

35. TZ arm Only chemo
PCR 45% 23%
5 yrs DFS 58% 43%
5 yrs OS 74% 63%
Buzdar et al
TECHNO TRIAL
NOAH TRIAL
CTNeoBC analysis
NeoALTTO trial
Prof. S. Subbiah et al

36. • T2 61%, cN1 -46%, HER2+ 17%
• 10 yr DFS -
pCR Partial response
All
subtypes
70% 50%
HER 2 + 65% 40%
Buzdar et al
TECHNO TRIAL
NOAH TRIAL
CTNeoBC analysis
NeoALTTO trial
Prof. S. Subbiah et al

37. • In each study 50% HR+, 50% HR-
• 60% T2, 80% N0/1
• pCR- 33%
• 3YRS
A- L B- TZ C- L+TZ
24.7% 29.5% 51.3%
pCR Non pCR
DFS 86% 72%
OS 94% 87%
Buzdar et al
TECHNO TRIAL
NOAH TRIAL
CTNeoBC analysis
NeoALTTO trial
Prof. S. Subbiah et al

38. • BERENICE, TRYPHAENA: Chemotherapy+ TZ ± PZ
• No difference in cardiotoxicity with the addition of PZ.
• NEOSPHERE, PEONY: Neoadjuvant - Chemotherapy+ TZ ± PZ
• KRISTINE : Chemotherapy + TZ+ PZ vs TZ- emtansine (T-DM1)+ PZ
• NEOSPHERE,KRISTINE & PEONY- investigated pCR rate
Prof. S. Subbiah et al

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41. • 1067 pts, cT1-3 N0,1, HER2+
• 215 NACT with TZ, 852 Upfront surgery
• Unmatched analysis: upfront Surgery is better than NACT
• Propensity matching model: (141 match) DFS, LRR is better in
NACT
• Inverse probability weighting model:
• No difference in DFS, OS between partial responders after
NACT & upfront surgery.
• In pCR after NACT- DFS, OS is better than Upfront surgery.
Prof. S. Subbiah et al

42. POST NACT
• Residual viable tumor – patchy
• MRI – better than mammogram/USG
• 14 randomized trials, 5500 pts , T1-3 N0-3: no difference in LRR
(BCS vs NACT-BCS)
• NSABP B18 Study: same 10yr LRR (NACT- Mastectomy 12.3% or
BCS 10.3%)
• In BCS post NACT: pattern of treatment response and volume of
viable disease near margins of lumpectomy specimen should
be considered when giving adequate margin.
Prof. S. Subbiah et al

43. MARGINS
• Margins consensus guideline for invasive cancer: No ink on tumor
(SSO/ASTRO)– does not apply to post NACT-BCS.
• If Patchy response in specimen – a negative margin after BCS,
may still have viable tumor cells in breast- unlikely controlled
by RT.
• Evaluation of surgical margins & extent of viable tumor- may
dictate resection of additional breast tissue even margins are
negative in consecutive surgeries.
• Positive margins after BCS:
• Stage I,II: Re excision/ mastectomy
• Stage III: May need Mastectomy
Prof. S. Subbiah et al

44. • ACOSOG Z1071 trial: SLNB after NACT N0- false negative rate:
12.6%.
• To overcome,
• 3 or more SLNB are removed
• Pre NACT- Clipping of involved node & removing clipped
node.
• IHC to identify low volume disease.
• Nodal positivity after NACT: adjuvant RT to axilla.
Prof. S. Subbiah et al

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46. • pCR after NACT in HER2+: continue maintenance TZ * 1 yr ± PZ.
• Residual disease after NACT in HER2+: Adjuvant TDM-1 * 14
cycles (cat I). Improved 3yr DFS 77% to 88%.
• KATHERINE TRIAL
Prof. S. Subbiah et al

47. TAKE HOME POINTS
• Similar long term outcomes in both Neoadjuvant and Adjuvant
chemotherapy.
• pCR to NACT- extremely favorable DFS & OS, particularly if all treatment is
given preoperatively.
• Co-relation between Pathological response and long-term outcome is
strongest for TNBC > HER2+ > ER+.
• HER2+ : NACT with Trastuzumab. NACT with Pertuzumab for ≥cT2, ≥cN1
• Tumor response during NACT– assessed by both imaging and clinical
examination.
• Preferred : standard chemotherapy is completed before surgery, if not
should be completed as adjuvant.
• Operable breast cancer if progressed during NACT, alternate
chemotherapy or Surgery if resectable.
Prof. S. Subbiah et al

48. HER2+ OPERABLE EARLY BREAST CANCER
PLAN FOR BCS PLAN FOR MASTECTOMY
1. PRIMARY MAPPING
2. NODAL IMAGING & MAPPING
MRI
NACT + TZ MRI
pCR Partial Response PROGRESSIVE,
INOPERABLE
ADJUVANT + TZ ADJUVANT + TDM-1 II LINE + PZ/TDM-1
NACT+ TZ
MAMMOGRAM ± USG
BCS/MASTECTOMY
Prof. S. Subbiah et al

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