Breast cancer handout

1. BREAST CANCER
PHITJIRA SANGUANBOONYAPHONG
PHARM D., BCOP
FACULTY OF PHARMACEUTICAL SCIENCES
UBON RATCHATHANI UNIVERSITY
OUTLINE:
¡ Epidemiology
¡ Etiology
¡ Risk factors
¡ Screening and prevention
¡ Diagnosis
¡ Treatments
INTRODUCTION:
¡ Breast cancer
o The most frequent malignancy in women
o Heterogeneous disease on the molecular
level
https://doi.org/10.1038/s41572-019-0111-2
EPIDEMIOLOGY:
CA Cancer J Clin 2020;70:7-30.

2. EPIDEMIOLOGY:
CA Cancer J Clin 2020;70:7-30.
EPIDEMIOLOGY:
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ETIOLOGY:
¡ Unknown etiology
¡ Genetics: represent 5-10% of all breast cancer
¡ Tumor suppressor gene
o BRCA 1, BRCA 2
o p53
¡ Progression gene
o HER2 (Human Epidermal Growth Factor Receptor-2, erbB-2)
ETIOLOGY:
¡ BRCA1 and BRCA2
o Tumor suppressor gene
o Relative rare in general population (1:300 for BRCA1 and 1:800 for BRCA2)
o Probability for breast and ovarian CA by 70 yr
o BRCA 1 : 57% (breast) and 40% (ovary)
o BRCA 2 : 49% (breast) and 18% (ovary)
o Non carrier have cancer risk as normal population
o Individual likely to get benefit for testing
male
related

3. ETIOLOGY:
¡ Characteristics Associated with an Increased Likelihood of
BRCA1 and BRCA2 Mutations
Personal History Family History
Breast cancer at an early age (≤ 45 years)
2 first degree relatives with diagnosis, at least 1
diagnose at ≤ 50 years
Bilateral breast cancer at age ≤ 50 years
A first- or second-degree relative with cancer at age 45 y
or younger
Triple-negative breast cancer at age ≤ 60 years
Others cancer associated with BRCA mutation
ETIOLOGY:
¡ P53
o Tumor suppressor gene
o 20% of breast cancer have mutation, inactivation, loss or down-
regulated expression of p53
o Associated with Li-Fraumeni syndrome
q < 1% associated of breast cancer associated with this syndrome
ETIOLOGY:
¡ HER2 (Human Epidermal Growth Factor Receptor-2, erbB-2)
o Proto-oncogene
o Amplified/overexpressed in approximately 20-25% of all breast cancers
o Impart poorer prognosis
o HER2 status should be determined on every primary invasive breast
cancer
ETIOLOGY:
¡ HER2 (Human Epidermal Growth Factor Receptor-2, erbB-2)
Nat. Rev. Clin. Oncol. 2012; 9:16–32.
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4. RISK FACTORS:
¡ Gender (Female)
o Male breast cancer can occur approx. 1% (associated with BRCA-2)
¡ Age
o ≥ 50YO increase risk by 6.7 times
¡ Familial
o 1st degree relatives with breast cancer portends a 2-fold higher risk
o The risk can increase 3- to 4-fold if a 1st degree relative was diagnosed at an age < 50Y
¡ Benign breast disease
¡ Early thoracic irradiation encompassing the chest/breast area before age 30
RISK FACTORS:
¡ Endogenous estrogen exposure
o Early age of menarche (typically defined as ≤ 12 y/o)
o Late age of natural menopause (typically defined as ≥ 55 y/o)
o Early induced menopause (bilateral salpingo-oophorectomy or BSO) before 50 y/o
decreases risk, with further risk reduction as the age of BSO decreases
o Age at birth of first child ≥ 30 y/o or nulliparity
¡ Exogenous estrogen exposure
o Oral contraceptive is non-significant increase risk when compared to who had never used OC
o Longer duration use of hormone replacement therapy increase risk
RISK FACTORS:
¡ Obesity
o Postmenopausal; higher weight increase risk
¡ Breast density
¡ Physical inactivity
¡ High fat diet
¡ Alcohol consumption
SCREENING AND PREVENTION:
¡ Risk estimation
o Gail model risk assessment toolà to determine RR to develop breast cancer at 5 years or
during lifetime
q Risk reduction (prevention) requirement when 5-yr RR ≥ 1.66&%
q Factors included
• Age
• No of 1st degree relatives with invasive breast cancer
• Nulliparity or age at first birth
• No of previous benign breast biopsies
• Atypical hyperplasia in a previous breast biopsy
• Race
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5. SCREENING AND PREVENTION:
¡ Screening methods for early detection
1. Breast self examination (BSE)
o Perform monthly; week after menses
2. Clinical breast examination (CBE)
3. Mammography
o Report result as BI-RADS (0-6)
4. Breast MRI
o Adjunct to mammography
Health Care Women Int. 2003; 24: 773-793.
SCREENING AND PREVENTION::
¡ Screening recommendation
SCREENING AND PREVENTION:
¡ Screening recommendation
¡ High risk group defined as
o Prior thoracic RT between the ages of 10 – 30 y
o Women ≥ 35 y with 5-year Gail model risk of
invasive breast cancer ≥ 1.7%
o Known genetic predisposition
o Women with a history of LCIS and a >20%
lifetime risk
o Prior history of breast cancer
SCREENING AND PREVENTION:
¡ Prevention recommended for
o High risk group (in the previous slide)
o Patient preference for risk reduction therapy
¡ Prevention method
o Bilateral total mastectomy ± reconstruction
o Bilateral salpingo-oophorectomy (BSO)
o Agents for risk reduction:
q Premenopausal – tamoxifen or clinical trial
q Postmenopausal – tamoxifen, raloxifene,AI, or clinical trial
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6. PATHOLOGY:
¡ Histology subtypes
Nature Reviews Disease Primers. 2019; 5(66): 1-31.
DIAGNOSIS:
¡ Determination of the ER, PR and HER2 status is mandatory for all
patients with invasive breast cancer
¡ Hormonal status (ER/PR)
o Testing by immunohistochemistry
o Considered ER/PR positive when nuclear staining > 1% of invasive tumor cells
¡ Ki-67
o Used to determine proliferation and predicts chemosensitivity
o Relevant for luminal type breast cancer (HR positive, Her-2 negative)
o Cut off value ≥ 20% classified as high level
Nature Reviews Disease Primers. 2019; 5(66): 1-31.
DIAGNOSIS:
¡ HER2 (Human Epidermal Growth Factor Receptor-2, erbB-2)
o Simplified HER2Testing Algorithm for Breast Cancer
Arch Pathol Lab Med. 2018;142:1364–1382
ASCO/CAP suggested
o Positive result : IHC 3+ or 2+ with positive FISH
INTRINSIC SUBTYPES OF BREAST CANCER:
Subtypes ER PR HER-2 Ki-67
Luminal A + ≥20% - Low (< 20%)
Luminal B
qHER-2 negative
qHER-2 positive
+
+
-
-
-
-
High (≥20%)
Any
HER-2 Overexpression - - + Any
Triple negative breast
(Basal type)
- - - Any
Annals of Oncology. 2013; 24: 2206–2223.
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7. BREAST CANCER AND HISTOLOGIC
MOLECULAR SUBTYPE:
STAGING:
STAGING: STAGING:
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8. MANAGEMENT OF BREAST CANCER:
¡ Treatment modalities divided into 3 modalities
qSurgery
qRadiation
qPharmacologic treatments
o Chemotherapy
o Endocrine therapy à HR positive
o Anti-HER2 à HER-2 positive
o CDK4/6 inhibitors
o mTOR inhibitor
MANAGEMENT OF BREAST CANCER:
¡ Surgery
o 2 main types of surgery to remove breast cancer
qBreast conservative surgery (BCS) aka Lumpectomy
qMastectomy
o 2 types of surgery to remove nearby lymph node
qSentinel LN biopsy
qAxillary LN biopsy
American cancer society latest update 2019
MANAGEMENT OF BREAST CANCER:
¡ Surgery
o Mastectomy with axillary LN dissection (ALND)
o BCS + ALND + whole breast RT
qMeta-analysis of XRT vs. no XRT after BCS showed
• Reduction in the 10-year risk of first recurrence by 15.7% (95%CI 13.7-17.7, p<0.00001)
• Reduction 5-year risk of breast cancer death by 3.8% (95%CI 1.6-6.0, 2p<0.00005)
o Benefit in
q All Ductal carcinoma in situ (DCIS)
q Invasive breast cancer (all stage I, II, IIIA and resectable IIIB or IIIC)
American cancer society latest update 2019
Lancet 2011; 378: 1707–16
MANAGEMENT OF BREAST CANCER:
¡ Radiation required in
o All BCS (recommended)
o ALN positive ≥ 4 (recommended), 1-3 LV (Considered)
o ALN negative
• T > 5 cm
• Positive margin
• T ≤ 5 cm with closely margin (< 1 mm)
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9. MANAGEMENT OF BREAST CANCER:
¡ Chemotherapy Recommended in
¡ Stage I-IIIA (as adjuvant tx)
o All lymph node positive
o LN (-)
q ER (+)
• Tumor size 0.6-1 cm à Consider in high risk group
• Tumor size > 1 cm à all patients
q ER (-)
• Tumor size 0.6-1 cm à Consider in high risk group
• Tumor size ≥ 1 cm à all patients
o All HER-2 (+)
High risk group
o Histology grade 3
o Triple negative
o LVI positive
o Oncotype DX Recurrence score ≥ 31 points
o HER2-positive
MANAGEMENT OF BREAST CANCER:
¡ Chemotherapy Recommended in
o Stage IIIB-IIIC (Neoadjuvant therapy)
o Stage IV
o All triple negative breast cancer
EARLYTO LOCALLY ADVANCED
BREAST CANCER MANAGEMENT
(STAGE I-III)
NCCNV1.2021
Early breast
cancer
ER negative
HER-2 positive
Node (+) or
Node (-) with
T>1cm
Adj.CMT+
Trastuzumab
HER-2 negative
Node (+) or
Node (-) with
T>1cm
Adj. CMT
ER positive
HER-2 negative
Node (+)
Adj. CMT
followed by
adj. ET
Node (-)
T ≤ 0.5 cm
Adj. ET
T >0.5 cm
Oncotype Dx
RS ≥ 31
Adj. CMT
followed by
adj. ET
RS < 31
Adj. ET
HER-2 Positive
Node (+) or
Node (-) with
T>1cm
Adj.CMT+
Trastuzumab
followed by adj. ET
CMT = Chemotherapy
ET = Endocrine therapy
Adj.=Adjuvant treatment
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10. AFTER PREOPERATIVETREATMENT: CONVENTIONAL CMT
¡ Regimen for adjuvant can use for neoadjuvant
¡ Preferred regimen for HER-2 negative
CONVENTIONAL CMT
¡ Regimen for adjuvant can use for neoadjuvant
¡ Preferred regimen for HER-2 positive
Paclitaxel + trastuzumab may be considered for patients with low-risk T1,N0,M0, HER2-positive disease,
particularly those not eligible for other standard adjuvant regimens due to comorbidities
PHASE III ECOG 1199:ADJUVANT PACLITAXEL
VS DOCETAXEL, BOTH Q3W AND QW, IN EBC
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11. PHASE III ECOG 1199:ADJUVANT PACLITAXEL
VS DOCETAXEL, BOTH Q3W AND QW, IN EBC
Sparano J, et al. N Engl J Med. 2008;358:1663-1671.
PHASE IIITRIAL COMPARING ACWITHTC AS
ADJUVANTTHERAPY FOR OPERABLE BREAST CANCER
J Clin Oncol.2006; 24:5381-5387.
J Clin Oncol. 2009; 27:1177-1183
The primary end point of this trial was the overall DFS.
The secondary endpoint was the overall survival.
TCVSTAXAC IN HER2- BREAST CANCER
(ABC JOINT ANALYSIS):
J Clin Oncol. 2017; 35:2647-2655.
ADJUVANT ANTI-HER 2:
¡ N9831/NSABP B-31 Joint Analysis:AC-TH vs ACT
J Clin Oncol.2011; 29:3366-3373
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12. BCIRG 006:AC-TVSTCH OR AC-TH:
Slamon D, et al. N Engl J Med. 2011;365:1273-1283.
Slamon D, et al. SABCS 2015. Abstract S5-04.
BCIRG 006: DFS AND SAFETY
Slamon D, et al. N Engl J Med. 2011;365:1273-1283.
PHASE III APHINITY: DUAL HER2TARGETING
IN ADJUVANTTHERAPY OF EBC:
N Engl J Med 2017;377:122-31.
PHASE III APHINITY: DUAL HER2TARGETING
IN ADJUVANTTHERAPY OF EBC:
N Engl J Med 2017;377:122-31.
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13. KATHERINE:TRASTUZUMAB EMTANSINEVS
TRASTUZUMAB AS ADJUVANTTHERAPY FOR HER2+ EBC
NEJM. 2019;380:617.
KATHERINE: DFS
NEJM. 2019;380:617.
ANTI-HER-2: ANTI-HER-2:
Name
FDA
approved
indication
Mechanism of action Dose range Toxicities
Trastuzumab Humanized
monoclonal
antibody
HER2 (+)
breast
cancer
(adjuvant,
metastatic)
o extracellular domain IV
of HER2
o 4 mg/kg LD, then 2
mg/kg weekly
o 8 mg/kg LD, then 6
mg/kg every 3 weeks
o Black box warning:
cardiotoxicity: avoid
concurrent with anthracyclines
o infusion reactions
o embryo-fetal toxicity
o pulmonary toxicity
(pneumonitis)
Pertuzumab o extracellular domain II of
HER2
o Block heterodimerization
with HER 1, 3, 4
o 840 mg LD then
420 mg q3 weeks
o Cardiotoxicity (1.2%)
o Hand-foot syndrome
o Infusion reactions
Trastuzumab
emtansine
(TDM-1)
Antibody drug
conjugate
HER2 (+)
breast
cancer
o HER2 block
o Inhibit microtubule
polymerization
o 3.6 mg/kg q 3 weeks
o Not interchangeable
with trastuzumab
o Cardiotoxicity
o Hepatotoxicity
o Pulmonary toxicities
o Peripheral neuropathy
Cancer Pharmacology and Pharmacotherapy Review. 2016
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14. ANTI-HER-2:
Future oncol. 2017; 14(7): 1-14.
CHEMOTHERAPY RELATED CARDIAC
DYSFUNCTION:
Shakir DK, et al. J Clin Med Res. 2009;1:8.
Type I Type II
Characteristic Cellular death
Damage starts with 1st dose
Cellular dysfunction
Pathology Biopsy changes No typical biopsy changes
Cumulative dose Related Not related
Reversible Permanent Reversible
Anticancer agents involved Anthracyclines Trastuzumab, lapatinib
CHEMOTHERAPY RELATED CARDIAC
DYSFUNCTION:
Treatment factors
o Type of drug
o Dose of each cycle
o Cumulative dose
o Schedule of administration
o Route of administration
o Combination with other cardiotoxic-
drug or radiation
Patient factors
o Age
o Presence of cardiovascular risk factor
o Previous cardiovascular disease
o Prior mediastinal radiotherapy
Ann Oncol. 2010;21 Suppl 5:v277.
J Clin Oncol.2016; 35:893-911.
ASCO RECOMMENDATION:
¡ For patients who undergo with anthracycline
o Evaluation cardiac function at baseline by ECHO or MUGA scanning
o For patients with a LVEF >50% at baseline:
q Consider repeating after reaching 250-300 mg/m2
q Repeat after reaching 400 mg/m2 in patients with known risk factors of cardiac failure
or after 450 mg/m2 in the absence of risk factors
q Discontinue doxorubicin if:
ØFunctional signs of cardiotoxicity and/or
ØAbsolute decrease in LVEF ≥ 10% associated with a decline to a level of < 50%.
typeotardiotoxicity
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15. ASCO RECOMMENDATION:
¡ For patients who undergo with trastuzumab
o Assess LVEF prior to initiation, every 3 months and every 6 months for at least 2 years
following completion of adjuvant Trastuzumab
o Withhold trastuzumab for at least 4 weeks for any of the following
q ≥ 16 absolute decrease in LVEF from baseline
q LVEF below institutional limit of normal and ≥ 10 absolute decrease from baseline
o Resume if LVEF returns to normal limits and absolute decrease from baseline is ≤ 15
(within 4 –8 weeks)
o Permanently discontinue if persistent (> 8 weeks) LVEF decline or if suspended ≥ 3
occasions for cardiomyopathy
ADJUVANT ENDOCRINETHERAPY:
N Engl J Med.2001; 344(4):276-285.
ENDOCRINETHERAPY:
¡ Selective Estrogen Receptor Modulators (SERMs)
¡ Aromatase Inhibitors (AI)
¡ Selective Estrogen Receptor Downregulators
(SERDs)
¡ Ovarian ablation for premenopausal status
o LHRH agonist/antagonist
o Surgery
Nat Rev Cancer. 2003;3:821–831.
SELECTIVE ESTROGEN RECEPTOR
MODULATORS (SERMS)
¡ Tamoxifen
¡ MOA:
o Selectively stimulate or inhibit the
estrogen receptors of different target
tissues
o Inhibit the estrogen receptor found in
breast cells
o Activate the estrogen receptor present
in uterine endometrial cells
¡ Usual dose 20 mg/day
Clinical Interventions in Aging 2014:9 1437–1452
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16. META-ANALYSIS OFTAMOXIFEN ALONE IN
PREMENOPAUSAL WOMEN
EBCTCG, et al. Lancet. 2011;378:771-784.
13.2%
9.2%
META-ANALYSIS OFTAMOXIFEN ALONE IN
PREMENOPAUSAL WOMEN
EBCTCG, et al. Lancet. 2011;378:771-784.
§ Tamoxifen side effect
o Hot flashes
o Vaginal discharge, sexual dysfunction
o Menstrual irregularity
o Significantly increased risk ofVTE
o Non significant increased risk of strokes
o Increased the risk of uterine cancer
o Limited to women over 55 years
SELECTIVE ESTROGEN RECEPTOR
MODULATORS (SERMS)
s t e r o i d s 7 2 ( 2 0 0 7 ) 829–842
J Clin Oncol 2010;28:3784
J Clin Oncol. 2019; 37:636-646.
¡ Tamoxifen
o Prodrug
o Metabolized through multiple enzymes to be more
active compound (Endoxifen and 4-
hydroxytamoxifen)
q CYP2D6 is considered the rate-limiting enzyme
o ASCO recommendation
o Drug-drug interaction between tamoxifen and
CYP2D6 inhibitors should be avoid
SELECTIVE ESTROGEN RECEPTOR
MODULATORS (SERMS)
s t e r o i d s 7 2 ( 2 0 0 7 ) 829–842
J Clin Oncol 2010;28:3784
J Clin Oncol. 2019; 37:636-646.
¡ CYP 2D6 and tamoxifen
¡ Strong to moderate inhibitors should be avoided during tamoxifen
¡ Agents can be use
o citalopram, escitalopram, and venlafaxine
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17. AROMATASE INHIBITORS:
§ Letrozole (Femara®) 2.5 mg/day
§ Anastrozole (Arimidex®) 1 mg/day
§ Exemestane (Aromasin®) 25 mg/day
§ Blocks estrogen production from
other tissue
§ Recommended in postmenopausal
patients
AROMATASE INHIBITORS:
¡ Menopause definition
o Prior bilateral oophorectomy
o Age ≥60 y
o Age <60 y and amenorrheic for 12 or more months in the absence of chemotherapy,
tamoxifen, toremifene, or ovarian suppression and follicle-stimulating hormone (FSH)
and estradiol in the postmenopausal range
o If taking tamoxifen or toremifene, and age <60 y, then FSH and plasma estradiol level
in postmenopausal ranges
NCCN V1.2021.
ADJUVANT HORMONALTRIAL
DESIGN:
¡ Direct comparison;
o Supporting trial;ATAC, BIG1-98,TEAM
¡ Switching
o Supporting trial; IES,ARNO/ABCSG combined analysis
¡ Sequencing
o Supporting trial;ABCSG 8 alone (arms A & C), BIG 1-98 sequencing arms (C&D)
¡ Extended adjuvant
o Supporting trial; MA-17R, NSABPB-33,ABCSG-6a
ADJUVANT HORMONALTRIAL
DESIGN:
J Clin Oncol. 2010; 28:3784-3796
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18. ADJUVANT HORMONALTRIAL
DESIGN:
J Clin Oncol. 2010; 28:3784-3796
ENDOCRINETHERAPY SIDE EFFECTS :
¡ Cardiovascular toxicity
o AI increase risk of hypercholesterolemia
o Tamoxifen increase risk of venous thromboembolism (VTE)
¡ Gynecologic toxicity
o More common in tamoxifen (á risk of uterine cancer, benign endometrial, hysterectomy,
and vaginal discharge)
¡ Menopausal symptoms
o Hot flashes (Tamoxifen > AI)
o Vaginal dryness (AI >Tamoxifen)
J Clin Oncol. 2010; 28:3784-3796
ENDOCRINETHERAPY SIDE EFFECTS :
¡ Musculoskeletal toxicity
o AIs are associated with greater loss of bone mineral density and fractures
o Bisphosphonate therapy can mitigate AI-associated loss of bone density
§ AIs cause a musculoskeletal/arthralgia syndrome
o pain, stiffness, or achiness
o a 2-4 week break will dramatically reduce symptoms
J Clin Oncol. 2010; 28:3784-3796
JCO Oncol Pract. 2020; 16:733-739
ENDOCRINETHERAPY SIDE EFFECTS :
¡ Endocrine toxicities management
ASCO EDUCATIONAL BOOK
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19. METASTATIC BREAST CANCER
MANAGEMENT(STAGE IV)
NCCNV1.2021
GENERAL CONSIDERATION:
¡ Goals of therapy: palliation, prolongation of life (if possible) and to maximize quality
of life
¡ Bone and soft tissue metastases tend to have a better prognosis and are more likely
to respond to endocrine therapy.
¡ Symptomatic visceral metastases generally require chemotherapy due to need for
rapid response.
Metastasis
breast cancer
Visceral
involvement
Systemic
therapy
HER-2 positive
CMT+antiHER-
2
HER-2 negative
CMT ±
Atezolizumab
No visceral
involvement
HR positive
HER-2 positive
ET
±AntiHER-2
HER-2 negative
ET
HR negative
HER-2 positive
CMT +
antiHER-2
HER-2 negative
CMT ±
Atezolizumab
ENDOCRINETHERAPY IN ADVANCED
BREAST CANCER:
¡ Evolving standard of care endocrine therapy landscape regimens for
HR+/HER2- MBC
Anastrozole PI. Exemestane PI. Letrozole PI. Fulvestrant PI. Everolimus PI. Palbociclib PI. Ribociclib PI.Abemaciclib PI. Alpelisib PI. Brufsky. Cancer Treat Rev. 2017;59:22.Lim E. Oncology (Williston Park). 2012;26:688.Croxtall. Drugs. 2011;71:363.Cohen. Oncologist. 2001;6:4.
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20. COMBININGTARGETED AND ANTIESTROGEN THERAPIES
TO OVERCOME RESISTANCE IN HR+ ADVANCED BC
¡ ~ 50% of HR+ MBCs do not benefit
from ET due to resistance
¡ Mechanisms of resistance may include
loss/alteration of ER expression;
overexpression/activation of GF
receptors; or activation of downstream
signal transduction pathways
Brufsky. Oncologist. 2018;23:528. AlFakeeh. Curr Oncol. 2018;25:S18.
ENDOCRINETHERAPY IN ADVANCED
BREAST CANCER:
SELECTIVE ESTROGEN RECEPTOR
DOWNREGULATORS (SERDS)
¡ Fulvestrant
¡ Binds to Estrogen receptor and
antagonizes receptor
¡ Down-regulates receptor
expression
¡ Dose: 500 mg IM on D1, 15, 29
and once monthly thereafter
Oncol Ther (2017) 5:17–29
SELECTIVE ESTROGEN RECEPTOR
DOWNREGULATORS (SERDS)
and.line Erbulin
metastatis are
tamoxifen
proliferation
aso becomeitiness
spine
t
i
min
abetter

21. CDK 4/6 INHIBITORS:
¡ The Role of CDK4/6 in Breast Cancer
o Growth of HR+ MBC is dependent on
cyclin D1, a direct transcriptional target of
ER
o Cyclin D1 activates CDK4/6, resulting in
G1-S phase transition and cell cycle entry[1]
o Some cell-line models of endocrine
resistance show dependence on cyclin D1
and CDK4/6[2,3]
1. Asghar. Nat Rev Drug Discov. 2015;14:130. 2. Miller. Cancer Discov. 2011;1:338. 3. Thangavel. Endoc Relat Cancer. 2011;18:333.
CYCLIN D1 AND CDK4/6 REGULATE G1-S CHECKPOINT, DRIVE
CELLULAR PROLIFERATION DOWNSTREAM OF SIGNALING
PATHWAYS:
Lange. Endocr Relat Cancer. 2011;18:C19. Kundsen. Trends Cancer. 2017;3:39.Otto. Nat Rev Cancer. 2017;17:93.Corona. Drug Des Devel Ther. 2018.12:321. Tripathy. Clin Cancer Res. 2017;23:3251-3262.
IMPACT OF CDK4/6 INHIBITION ON PFS
FIRST-LINE SETTING:
Phase III
Study
PALOMA-2[1,2] MONALEESA-2[3,4] MONARCH-3[5,6] MONALEESA-3[7,8] MONALEESA-7[9]
Setting 1st line 1st line 1st line 1st and 2nd line 1st line*
Endocrine
partner Letrozole Letrozole
Letrozole
or anastrozole
Fulvestrant
Tamoxifen, letrozole,
or anastrozole
CDK4/6
inhibitor Palbociclib Ribociclib Abemaciclib Ribociclib Ribociclib
No. patients 666 668 493 365 672
HR 0.563 0.56 0.54 0.55 0.55
PFS, mos 27.6 vs 14.5 25.3 vs 16 28.18 vs 14.76 33.6 vs 19.2 23.8 vs 13.0
ORR, % 55.3 vs 44.4 52.7 vs 37.1 59 vs 44 40.9 vs 28.7† 41 vs 30
1. Finn. NEJM. 2016;375:1925.2. Rugo. Breast Cancer Res Treat. 2019;174:719.3. Hortobagyi. NEJM. 2016;375:1738. 4. Hortobagyi. Ann Oncol. 2018;29:1541. 5. Goetz. JCO. 2017;35:3638.6. Johnston. NPJ Breast Cancer. 2019;5:5. 7. Slamon. JCO. 2018;36:2465.
8. Slamon. NEJM. 2020;382:514. 9. Tripathy. Lancet Oncol. 2018;19:904.
*1st line ET; up to 1 prior line of CT permitted in advanced setting (14% of patients had received CT in advanced setting). †Includes 1st and 2nd line.
IMPACT OF CDK4/6 INHIBITION ON PFS:
SECOND-LINE SETTING
Phase III Study PALOMA-3[1,2] MONARCH-2[3] MONALEESA-3[4,5]
Setting 2nd line 2nd line 1st and 2nd line
Endocrine partner Fulvestrant Fulvestrant Fulvestrant
CDK4/6 inhibitor Palbociclib Abemaciclib Ribociclib
No. patients 521 669 346
HR 0.50 0.536 0.57
PFS, mos 11.2 vs 4.6 16.9 vs 9.3 14.6 vs 9.1
ORR, % 25 vs 11 48.1 vs 21.3 32.4 vs 21.5*
Different Patient Populations
Any # prior ET
1 prior CT allowed
Only 1 prior ET
No prior CT allowed
*ORR includes 1st- and 2nd-line patients.
0-1 prior ET
No prior CT allowed
1. Cristofanilli. Lancet Oncol 2016;17:425. 2. Turner. NEJM. 2018;379:1926.
3. Sledge. JAMA Oncol. 2020;6:116. 4. Slamon. JCO. 2018;36:2465. 5. Slamon. NEJM. 2020;382:514.
me
combination
p
survival.iprogressionfree arrolea
trozole
aIs corallo
inhibitors c cidib
then
this
way
line serbstmtor
inh lwpt.no
Advanced
stageat first
liner craweslantteverolimus
I
arpositivey t.uwestanttcbr.am
inhibitors ribocidib
roleotendocrinet
Serbs

22. CDK4/6 INHIBITORS: COMPARISON OF KEY DOSING
AND ADMINISTRATION CHARACTERISTICS
Characteristic Palbociclib[1-3] Ribociclib[4,5] Abemaciclib[5,6]
Target (IC50,nM) CDK4 (11); CDK6 (15) CDK4 (10); CDK6 (39) CDK4 (2); CDK6 (10)
Route PO PO PO
Dose, mg 125 QD 600 QD Monotx: 200 BID
Combo with ET: 150
BID
Schedule 3 wks on/1 wk off 3 wks on/1 wk off Continuous
Half-life, hr 27 32.6 17-38
1. DeMichele. Clin Cancer Res. 2015;21:995. 2. Hamilton. Cancer Treatment Rev. 2016;45:129.
3. Costa. Ann Oncol. 2017;28:44. 4. Infante. Clin Cancer Res. 2016;22:5696. 5. Barroso-Sousa.
Breast Care. 2016;11:167. 6. Dickler. Clin Cancer Res. 2017;23:5218.
¡ Abemaciclib,palbociclib, and ribociclib can be taken with or without food
¡ Medication should be taken at approximately the same time each day
¡ Avoid concomitant use of strong CYP3A4 inhibitors and inducers
TOXICITY MONITORING AND MANAGEMENT:
¡ Key AEs With CDK4/6 Inhibitors: Monitoring and Prevention
TOXICITY MONITORING AND MANAGEMENT:
¡ Dose Modifications
Dose Level
Abemaciclib +
Fulvestrant or AI
Abemaciclib
Monotherapy
Palbociclib Ribociclib
Recommended starting dose 150 mg BID 200 mg BID 125 mg/day 600 mg/day
First dose reduction 100 mg BID 150 mg BID 100 mg/day 400 mg/day
Second dose reduction 50 mg BID 100 mg BID 75 mg/day 200 mg/day
Further dose reductions
Discontinue if further
dose reductions needed
beyond 50 mg BID
50 mg BID
Discontinue if further
dose reductions needed
beyond 75 mg/day
Discontinue if further
dose reductions needed
beyond 200 mg/day
TOXICITY MONITORING AND MANAGEMENT:
¡ Management of Interstitial Lung Disease/Pneumonitis
¡ Rate of ILD/pneumonitis with CDK4/6 inhibitors ranges from 1.0% to 3.3%
¡ Grade 3/4 AEs occurred in 0.1% to 0.6% of patients
¡ Patients should be counseled on importance of contacting healthcare provider in case of dry
cough with/without fever[1-3]
¡ Monitor regularly for pulmonary symptoms or radiologic changes indicative of ILD or
pneumonitis (eg, hypoxia, cough, dyspnea, interstitial infiltrates)[1-3]
¡ If pneumonitis suspected, interrupt therapy immediately
¡ Seek pulmonary consultation and consider early institution of corticosteroids[4]
¡ Permanently discontinue if recurrent symptomatic or severe ILD/pneumonitis
1. Abemaciclib PI. 2. Palbociclib PI. 3. Ribociclib PI. 4. Jazieh. Expert Rev Anticancer Ther. 2019;19:917.
www.wm
oordneutropeniapneumonitis
disc
on
every
day
2
minion
g
ra
ds
w
wnor
then
diam
Hold

23. ENDOCRINE RESISTANCE IN ER-
POSITIVE BREAST CANCER:
qPI3K/mTOR pathway is frequently altered in HR+ BC and
has been implicated in resistance to endocrine therapies
q~ 40% of HR+ BC harbor a PIK3CA mutation, leading to
hyperactivation of the PI3K pathway
qPI3K signaling promotes estrogen-independent growth of
ER+ BC cells, and this growth is inhibited by the addition of
PI3K inhibitors to antiestrogens[6-8]
Future Med. Chem. (2015) 7(12) 1511-19.
BOLERO-2: EXEMESTANE ± EVEROLIMUS IN
NONSTEROIDAL AI–REFRACTORY ABC:
Baselga J, et al. N Engl J Med. 2012;366:520-529.
BOLERO-2: IMPROVED PFSWITH
MTOR INHIBITION:
Yardley. Adv Ther. 2013;30:870. Baselga. NEJM. 2012;366:520.
BOLERO-2:TOXICITY
¡ Understanding and Modifying Toxicity Associated With Everolimus
q Phase II SWISH trial: steroid mouthwash‡
essentially eliminated stomatitis in
postmenopausal patients with HR+/HER2- MBC
receiving everolimus + exemestane
Grade ≥ 2 stomatitis was 2.4
(n = 2) by 8 wks in SWISH vs 27.4% by 8 wks in
BOLERO-2 (primary endpoint) and 33% over total
study duration
Rugo. Lancet Oncol. 2017;18:654.
mtor Inhibitors combination
n
wn.es
into
resistance
combination
bettersurvival
but.mn
stomatitis
a
Is
alone
a oexamethasone stomatitis
imgnomia.mg
ml

24. APPROACHTOTHERAPY FOR HR+/HER2-
MBC: MOVE TO PERSONALIZATION
1. Cardoso. Ann Oncol. 2018;29:1634. 2. Abemaciclib PI. 3. Palbociclib PI. 4. Ribociclib PI. 5. Alpelisib PI. 6. Fribbens. JCO. 2016;34:2961. 7. Bardia. SABCS 2017. Abstr PD5-08. 8. Everolimus PI. 9. Olaparib PI. 10.
Talazoparib PI. 11. Modi. JCO. 2020;38:1887. 12. Smyth. Cancer Discov. 2020;10:198. 13. Bardia. ASCO 2018. Abstr 1004.
ANTI-HER-2 IN ADVANCED BREAST
CANCER:
PHASE III CLEOPATRA STUDY:TRASTUZUMAB AND
DOCETAXEL ± PERTUZUMAB IN HER2+ MBC
Baselga J, et al. N Engl J Med. 2012;366:109-119.
PHASE III CLEOPATRA STUDY: PFS AND OS
Baselga J, et al. N Engl J Med. 2012;366:109-119.
HR
positive HER 2 positive
Herceptin
1
then
f
mid
line
rat
itine addthis.be
er
combination pertuzumab
in
survival

25. CURRENT APPROACH FOR SEQUENCINGTHERAPY
1. Giordano. JCO. 2018;36:2736.
PHASE III EMILIA STUDY:T-DM1VS
LAPATINIB/CAPECITABINE IN HER2+ MBC
Verma S, et al. N Engl J Med. 2012;367:1783-1791.
PHASE III EMILIA STUDY:T-DM1VS
LAPATINIB/CAPECITABINE IN HER2+ MBC
Verma S, et al. N Engl J Med. 2012;367:1783-1791.
TUCATINIB: HER2-SELECTIVETKI
Borges. ASCO 2016. Abstr 513. Borges. JAMA Oncol. 2018;4:1214.
emtan.me
better
better become
andine
docetaxel
intelineirrorias
it

26. HER2CLIMB: PHASE II STUDY DESIGN
Murthy. SABCS 2019. Abstr GS1-01. Murthy. NEJM. 2019;382:597.
HER2CLIMB: PFS AND OS:
Murthy. SABCS 2019. Abstr GS1-01. Murthy. NEJM. 2019;382:597.
TUCATINIB:
¡ Indication:
o Combination with trastuzumab/ capecitabine for treatment of advanced, unresectable or
metastatic HER2+ BC, including patients with brain metastases, who have received ≥ 1
previous HER2-targeted therapy
¡ Dose: 300 mg taken orally twice daily with or without food
¡ Tucatinib can cause severe diarrhea; administer antidiarrheal treatment as clinically indicated
¡ Tucatinib can cause severe hepatotoxicity
o Monitor ALT,AST, and bilirubin prior to starting tucatinib, q 3 wks during treatment, and as
clinically indicated
¡ Management of AEs may require temporary interruption, dose reduction, or discontinuation
TUCATINIB:
¡ Dose modification
Dose Level Tucatinib
Recommended starting dose 300 mg BID
First dose reduction 250 mg BID
Second dose reduction 200 mg BID
Third dose reduction 150 mg BID
Further dose reductions
Permanently discontinue in patients unable to tolerate
150 mg BID
norbecome
ind
line
means
as
it
bid
HER 2 positive

27. MANAGEMENT OF METASTASIS TNB:
¡ Chemotherapy
o Single agent and combination regimen can be used
o Combination chemotherapy provides little higher rate of response
q E1193 trial
ØSingle agents (Doxorubicin, Paclitaxel) showed equivalent efficacy
ØCombination (Doxorubicin+Paclitaxel) showed superior overall response rates and
time to TTF
Ø Combination did not improve either survival or quality of life compared to
sequential single-agent therapy
o Continue 1st line chemotherapy until progression
J Clin Oncol. 2003; 21(4): 588-92.
MANAGEMENT OF METASTASIS TNB:
¡ Chemotherapy
PHASE III EMBRACETRIAL OF ERIBULIN
VSTPC FOR HEAVILY PRETREATED MBC
Cortes J, et al. Lancet. 2011;377:914-923.
PHASE III EMBRACETRIAL
Cortes J, et al. Lancet. 2011;377:914-923.
Triple
neg
i
nothing Doxorubicin
pm
expression i iatezolizumab
itinesingle
agent withimmunotx
c
Paclitaxel
pmpositive pin
expression no
scorepembrolizumab
Chemotherapy
and
line Erbulin
r e
just
improve
L
single
agent ok
mid
line a new
drug
anti
microtubule
I
am
for

28. ADDITIONALTARGETEDTHERAPIES AND ASSOCIATED
BIOMARKER TESTING FOR RECURRENT OR STAGE IV DISEASE IMMUNOTHERAPY:
ROLE OF COMBINATION BETWEEN
CMT AND ICIS:
Annals of Oncology 30: 219–235, 2019
ATEZOLIZUMAB + NAB-PACLITAXEL IN PATIENTSWITH
UNTREATED ADVANCEDTNBC (IMPASSION130):
NEJM. 2018;379:2108.
air
oiligand
program
death
imith
tripienegas chemotx
recombinationoverall
survival
nanoalbuminbound
paclitaxel

29. IMPASSION130 UPDATE: OS IN ITT
POPULATION AND OS BY PD-L1 STATUS:
KEYNOTE-355: STUDY DESIGN
Lancet 2020; 396: 1817–28
KEYNOTE-355: PFS
Lancet 2020; 396: 1817–28
Early breast
cancer
ER negative
HER-2 positive
Node (+) or
Node (-) with
T>1cm
Adj.CMT+
Trastuzumab
HER-2 negative
Node (+) or
Node (-) with
T>1cm
Adj. CMT
ER positive
HER-2 negative
Node (+)
Adj. CMT
followed by
adj. ET
Node (-)
T ≤ 0.5 cm
Adj. ET
T >0.5 cm
Oncotype Dx
RS ≥ 31
Adj. CMT
followed by
adj. ET
RS < 31
Adj. ET
HER-2 Positive
Node (+) or
Node (-) with
T>1cm
Adj.CMT+
Trastuzumab
followed by adj. ET
CMT = Chemotherapy
ET = Endocrine therapy
Adj.=Adjuvant treatment
Gbenititlunddpm
ipositive
alone survival
orbenitithrawcombinedpositivesarezio

30. Metastasis
breast cancer
Visceral
involvement
Systemic
therapy
HER-2 positive
CMT+antiHER-
2
HER-2 negative
CMT ±
Atezolizumab
No visceral
involvement
HR positive
HER-2 positive
ET
±AntiHER-2
HER-2 negative
ET
HR negative
HER-2 positive
CMT +
antiHER-2
HER-2 negative
CMT ±
Atezolizumab
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