Local-regional therapy

Radiation therapy

Customizing Local and Systemic Therapies

TITLE LOREM
for women with Early Breast Cancer
IPSUM
The St.Sit
Gallen
DolorInternational
Amet Consensus Guidelines for treatment of early
breast cancer 2021
 Genetic testing and management of hereditary
breast cancers and syndromes
Outlines
Pathology and subtype

Local-regional therapy

Neoadjuvant therapy

Systemic therapy
• Adjuvant treatment

Ductal Carcinoma in Situ

Ipsilateral breast cancer recurrence

 GENETIC TESTING AND
MANAGEMENT OF
HEREDITARY BREAST
CANCERS AND SYNDROMES
Genetic testing and management of
hereditary breast cancers and syndromes

◦ 8 – 10% of all breast cancer

◦ 50% of hereditary breast cancer are BRACA1/2 mutations

Past; genetic counseling and germline genetic Panel recommendation

testing

◦ Age of onset ◦ All breast cancer patients diagnosed at age less

than 65 years
◦ Familial history of breast cancer and related
cancer

◦ Male breast cancer

◦ Tumor subtype related familial cause

Genetic testing and management of
hereditary breast cancers and syndromes
◦ Classified risk of breast cancer  varied opinions for treatment and follow

◦ The degree of penetrance of the gene, and the age of the woman with genetic diagnosis

◦ Routinely exam(67% vote) : BRCA1, BRCA2, ATM, BARD1, BRIP1, CDH1, CHEK2, NBN, PALB2, PTAN, STK11,
RAD51C, RAD51D, and TP53

High penetrance ≥ 3-fold increase risk of breast cancer

• Consideration of risk reducing mastectomy
• BRCA1, BRCA2, TP53, and PALB2

Intermediate penetrance 2-3-fold risk

• Surveillance with MMG and MRI
• BRD1, CHEK2, CDH1, STK11

Low penetrancce 1-2-fold risk

• Strongly favored surveillance without prophylactic mastectomy
• ATM, BRIP1, NF1, RAD51C, RAD51D
 BRCA1 or
BRCA2
◦ OlympiA trial

◦ Early stage breast cancer

◦ Olanparibin the adjuvant setting

◦ Significant reduction in recurrent
risk

◦ The eligibility criteria:

◦ Stage 2, or 3
◦ HER2 negative
◦ Irrespective of ER status/ prior
platinum base treatment
 OlympiA: Background
◦ Inhibition of PARP enzymes leads to synthetic lethality in cells deficient in
homologous recombination repair, such as those with BRCA1/2 mutations1,2
◦ Germline mutations in BRCA1 increase risk of developing TNBC; germline mutations in
BRCA2 increase risk of developing estrogen receptor–positive breast cancer3,4
◦ Olaparib: PARP inhibitor approved by FDA for multiple indications, including
treatment of adults with (suspected) deleterious gBRCA-mutated, HER2-negative MBC
previously treated with CT in (neo)adjuvant/metastatic setting; those with hormone
receptor–positive disease must be previously treated with ET or ineligible for ET5
◦ Current interim analysis of phase III OlympiA trial compares efficacy and safety of
adjuvant olaparib vs placebo in patients with BRCA1/2-mutated, HER2-negative early
breast cancer at high risk of recurrence6,7

1. Farmer. Nature. 2005;434:917. 2. Fong. NEJM. 2009;361:123. 3. Mavaddat. Cancer Epidemiol Biomarkers Prev.
2012;21:134. 4. Atchley. JCO. 2008;26:4282. 5. Olaparib PI. 6. Tutt. ASCO 2021. Abstr LBA1. 7. Tutt. NEJM. 2021;[Epub]. Slide credit: clinicaloptions.com
 OlympiA: Study Design
◦ Prespecified interim analysis of international, randomized, double-blind phase III trial (data cutoff: Mar 27, 2020)
Stratified by HR status (HR+ vs TNBC), prior CT (neoadjuvant
vs adjuvant), prior platinum-based CT (yes vs no)

TNBC Subgroup
Olaparib
Men and women with Prior neoadjuvant tx: no pCR
300 mg BID for 1 yr
gBRCA1/2-mutated, HER2-, Prior adjuvant tx: ≥pN1 or ≥pT2
(n = 921)
high-risk primary BC; completed (n = 1509*)
definitive local tx and ≥6 cycles
of (neo)adjuvant CT containing
anthracyclines and/or taxanes; HR+/HER2- BC Subgroup
ECOG PS 0/1 Prior neoadjuvant tx: no pCR and Placebo
(N = 1836) CPS + EG score ≥3† BID for 1 yr
Prior adjuvant tx: ≥4 LN+ (n = 915)
(n = 325)

 Primary endpoint: iDFS  Prespecified interim analysis of ITT population triggered

 Secondary endpoints: distant DFS, OS, safety
*Excluded n = 2 (both in olaparib arm) due to unconfirmed HER2- status.
†Staging system for BC-specific survival after neoadjuvant tx incorporating
pretreatment clinical stage, ER status, nuclear grade, pathologic stage (range: 0-6).
Tutt. NEJM. 2021;[Epub]. NCT02032823.
when 165 invasive disease or death events occurred in
first 900 patients enrolled (mature cohort); type I error
rate controlled with superiority boundaries per
hierarchical multiple-testing procedure
Slide credit: clinicaloptions.com
PATHOLOGY AND
SUBTYPE
Pathology and subtype

◦ Early stage breast cancer divide into three subgroups base on expression of ER, PR and
HER2 receptors
◦ 3 subtypes:
◦ ER ad/or PR positive and HER2 negative
◦ HER2 positive
◦ Tripple negative
◦ Consequence systemic therapy
◦ All ER positive >> adjuvant endocrine therapy
◦ HER2 positive >> anti HER2 in combination with chemotherapy
◦ TNBC >> Chemotherapy
ER positive subtype

◦ 1% threshold for ER expression >> ET remains controversial

◦ ER expression1%-9%; less than 2% of all ER  less favourable prognosis than ER positive cancers with ≥ 10%,
basal-like genomic signature, response to NAC alike to TNBC

◦ Characterize the herogeneityof ER positive  prognostic markers for recurrence risk

◦ Phenotype: Grade, proliferation
◦ Genotype: multigene assays (70-gene signature test, 21-gene recurrence score)

◦ Classified as (correlate with genomic markers of risk)

◦ Luminal A-like: low grade, low Ki67, strong ER/PR expression
◦ Luminal B-like: higher grade, higher ki67, lower levels of ER/PR expression

* Controversy the precise threshold for ki67

 1% threshold for ER expression >> ET remains controversial

ER expression1%-9%; less than 2% of all ER  less favourable

prognosis than ER positive cancers with ≥ 10%, basal-like
genomic signature, response to NAC alike to TNBC

Genomic Characterize the herogeneity of ER positive  prognostic

markers for recurrence risk

signature in ER • Phenotype: Grade, proliferation

• Genotype: multigene assays (70-gene signature test, 21-gene recurrence

positive score)

Classified as (correlate with genomic markers of risk)

• Luminal A-like: low grade, low Ki67, strong ER/PR expression

• Luminal B-like: higher grade, higher ki67, lower levels of ER/PR expression

* Controversy the precise threshold for ki67

Triple negative

◦ Prognostic marker: tumor infiltrating

lymphocyte(TILs) and PD1/PDL1 in early or late stage
TNBC

◦ Predictive marker for benefit of check point inhibitor:

PDL1 test in advanced TNBC
* PDL1 expression>> not shown improvement in
pathological complete response
LOCAL-REGIONAL
THERAPY
Local-regional therapy
Imaging and breast surgery
◦ Imaging:
◦ MRI: prior neoadjuvant therapy for BCT planning of patient
high sensitivity, but less specificity  unnecessary mastectomy
◦ Excision-specimen Xrays confirmation of known calcification >> the panel did not identify a
routine role

◦ Surgery
◦ Breast:
◦ Surgery depend on the size of the tumor and breast volume, the extent of radiological changes in breast, the cosmetic outcome
◦ ‘no ink on tumor’ margins is the standard for IDCA, regardless o f tumor histology or grade, or the patient’s
age.
Local-regional therapy
Imaging and breast surgery

◦ Axilla:
◦ Elderly patients may not require sentinel lymph node biopsy; metastasis finding to axillary nodes
is not likely to change treatment

Sentinel node biopsy

• standard approach in patients with a clinically negative axilla
• Negative sentinel nodes  no further
• cT1-2N0 with plan breast radiation after BCT or axillary radiation after mastectomy  SLNBx –
positive 1-2 nodes  no further axillary surgery (ACOSOGZ0011 trial, 10981-22023 AMAROS trial)
Axillary node dissection
• Clinical nodes positive
• cN0; positive > 2 nodes
•Radiation therapy is to be omitted
•Axillary staging  affect systemic or radiation recommendations
Local-regional therapy
Radiation therapy
◦ Technique:
◦ Conventional whole breast radiation therapy: dose 45-50Gy  25-28 daily fractions
◦ Hypofractionated radiation therapy: Moderate, Ultra
◦ Partial breast irradiation
◦ Boost

• 15-16 fractions • 5 fractions • 10-16 Gy in 5-8 daily

• Strongly recommendation: fractions
irrespective of tumor
• The panel: did not std
subtype, age treatment • High grade
• Postmastectomy* radiation •  With caution: elderly • EIC
and/or regional nodal with low risk tumors • TNBC or HER2
irradiation
subtype
• Age < 50

Moderately
Ultra-short Boost
Hypofractionated
 Local-regional therapy
Radiation therapy
◦ Location:
◦ Breast
◦ Lymph nodes:

* Against partial breast RT approaches in lobular tumors, present LVI, women less than age 40, women with
hereditary breast cancer
** Against using genomic signatures to determine whether to use radiation
*** Against regional nodal irradiation: T2N0 tumors,
in neoadjuvant setting TNBC and HER2:  RT: cT2N0  pCR
 RT: initial cN+
◦ Omitted RT in Age ≥ 70 year with
 stage 1
 ER-positive breast CA and on endocrine therapy
 shorter life expectancies
NEOADJUVANT
THERAPY
Neoadjuvant Therapy
•CMT regimen: T and either anthracycline or
platinum-base
◦ For women with stag 2 or 3 tumors HER2
•AntiHER2: Trastuzumab + Pertuzumab

◦ HER2 positive, Tipple negative

◦ Aim:
•CMT regimen: dose-dense anthracycline
◦ Down staging and Taxane-base
•Not recommended: check point inhibitor
◦ Prognostic marker
TNBC •60% against routine use of carboplatin

◦ Inoperable  Operable

◦ Management after neoadjuvant systemic therapy

•pCR 10%: equal rate for endocrine therapy
◦ Adjuvant after neoadjuvant vs CMT
•Endocrine therapy, favored in low grade/ or
◦ Axillary management after neoadjuvant genomic risk tumors
ER •Short-term decline in ki67  favored
positive prognostic finding
 Adjuvant after neoadjuvant
◦ pCR is a prognosis maker after NST  DFS and OS

◦ Risk stratification base on pCR ER Ꚛ • Endocrine therapy

Proceed to HER2 • Anti HER2

pCR
standard adjuvant
TNBC •-

Adjuvant
After NST
ER Ꚛ •Endocrine therapy

Residual
tumor
HER2 •TDM1

TNBC •Capcitabine
•Olanparib in BRCA
Axillary management after neoadjuvant
◦ ycN+  ALND

◦ cN1 ycN0  SLNBx

◦ Real world data: Radiation replace ALNDx: initial cN0  SLNBx: residual cancer (only 1 positive node and ER
positive tumor)
73% of the panel : residual macro-metastasis >2mm. In SLNBxor just positive 1 of 3 SLN
controversy in micrometastasisor ITCs
◦ Axillary RT alternative to ALND: on going trial
SLNBx after NST

◦ Technique for minimize the FNRs:

◦ Dual technique
◦ ≥ 3 nodes
◦ Resection of the metastatic node during SLNBx:
◦ Clipping
◦ US guide wire localization
◦ Radioactive seed

◦ Clipping  Decrease FNR to 2-4%

◦ FNR = 6.8% in clipped node was with in the SLN specimen Vs 13.4%
without clipped node

Boughey JC.,etal. Annual of Surgery; 2016

Cabio glu N.,et al . Annual of Surgery; 2018
SYSTEMIC THERAPY
Systemic Therapy
ER positive
◦ Indicated for CMT:
◦ Stage 1 or node-negative: consider for tumor size and tumor biology(molecular type)
 prefer regimen: Anthracycline/cyclophosphamide/ taxane combination
 panellist: 46% : 4EC or 4AC
 Higher tumor burden : 96% panellistsrecommended standard or dd(39%)
anthracycline/cyclosphosphmide/taxane combination
 Premenopausal patients:
chemotherapy induced ovarian function suppression(OFS)  47% monitoring estradiol levels
 Node negative; RS 16-25: (53%)consider OFS with tamoxifen/ AI,
(25%) CMT + ET High risk feature*:
 Node positive; RS < 25: (30%) CMT +ET, (26%) CMT + consider ET • Age < 40
 ≥ Stage 2: (71%) OFS ( particularly in age < 40; 94%) • nodes positive,
(52%) ODS only if high risk feature*, (43%) OFS to all patients • high ki-67,
 Post-menopausal patients: • luminal B like,
 Skip CMT: stage≤ 2,ER-positive, HER-2 negative, low risk signatures RS ≤ 25 • intermediate-high risk
 CMT: Higher anatomical stages: pT3, pN1 or > 3 positive LN genomic signature
Systemic Therapy
ER positive
◦ Endocrine therapy
◦ Appropriate threshold ≥1% Vs. ≥10% (50:50)
◦ Recommending in any tumor size including microinvasive cancer
 Extension of endocrine therapy in premenopausal patients : beyond 5 years
 Node positive: (34%) additional 2-3%, (53%) for 10 years
 High risk: (41%) OFS(if still premense)+AI, (45%) additional tamoxifen only 5 years
Systemic Therapy
HER2 positive
◦ Indicated for
CMT+antiHER2
◦ Tumor size: ≥5mm.(51%), ≥ 6
mm.(23%)
◦ Smaller lesion(smaller than
5mm., microinvasion) (26%)

◦ Adjuvant Neratinib: 64% after

trastuzumab/pertuzumab
and/or trastuzumab emtansine
base as(neo)adjuvant therapy
Systemic Therapy
TNBC
◦ Indicated for CMT:
◦ Tumor size : ≥5 mm.(46%), < 5mm.(35%), microinvasive disease (9%)

◦ Immune check point Inhibitors in TNBC:

◦ Should not use in neoadjuvant setting
◦ (90%) Stage 2,3 ; not treated in neoadjuvant setting, but receiving adjuvant CMT  should not revieve PD1/PDL1
targeted treatment

◦ PARP Inhibitor in TNBC: iDF improvement at least 5% at 3 years

◦ Recommend Olaparib to patients with BRCA1/2 associated breast cancer
 Ductal carcinoma in situ

◦ Surgery: Extension of disease; BCT + RT or mastectomy

◦ RT after BCT reduce recurrence risk of DCIS or invasive
◦ Adjuvant endocrine therapy  reduce recurrence risk and prevent contralateral disease

• Age >70 • Effective as standard • Larger areas of DCIS

Add Boost
Moderate
Omit RT

Hypofraction

• DCIS with low risk • High risk of recurrent

feature • Margins < 2mm.
• Comedonecrosis
 Ipsilateral breast cancer recurrence

◦ In breast cancer recurrent 5-15% of all recurrent cancer events in women with early-stage
breast cancer, who were treated with BCT and RT
◦ Treatment: Mastectomy Vs. repeat BCT
◦ Repeat BCT: favored by low risk( small, luminal A type)
◦ Radiation therapy might not be required
◦ Re-irradiation could be option: (50/50)
 ipsilateral recurrence or 2nd breast cancer arising > 5 years after initial BCT+RT
◦ Adjuvant therapy: prior treatment, tumor biology
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