Overview to therapeutics of

breast cancer-part 1
Dr/Azza Mansy
Associate professor of clinical pharmacy and head of clinical
pharmacy department- AlMenofia University
 Breast cancer
Incidence
• Incidence has increased , whilst mortality rates have decreased due to better screening
programs and improved targeted treatments.
• The most common type of cancer and the most common cause of cancer-related
mortality among women worldwide.
• 10-20% of all recurrences are isolated locoregional , while 60%-70% are distant
metastases in one “anatomical structure,” or in multiple locations
• In Egypt, it represents 37% of all female cancers presenting to National Cancer Institute,
Cairo University.
• Egyptian breast cancer is particularly aggressive with dominance of advanced stage and
young age at diagnosis & more poorly differentiated histology
Breast anatomy
• Breast tissues:
• fat,
• muscle,
• lobules (glands that make milk)
• ducts (tubes that carry milk to nipple)
 Histological types of breast cancer (BC)
• Ductal carcinoma
Invasive ductal carcinoma (IDC): invade basement membrane of duct
ductal carcinoma in situ (DCIS): if not

• Lobular carcinoma: likewise;

invasive lobular carcinoma (ILC)
lobular carcinoma in situ (LCIS; most favorable prognosis)).

• Inflammatory breast cancer:

One of the most aggressive forms of BC
sudden onset; can develop in wks ;
unlike other BCs that can take yrs to develop into
identifiable mass
 Risk factors for breast cancer
Potentially controllable, e.g.
Known
• Some reproductive History: Late 1st
pregnancy (≥ 30 yrs) or no pregnancy (Null
parity)
• Long term use of HRT or OC pills (estrogen).
• alcohol drinking,
• obesity (postmenpausal)
Uncontrollable, e.g
• Gender: F >>>>>>>>> M (1%)
• Advancing age (>50)
• first-degree relatives breast cancers (esp if <50)
• Genetic mutation (esp. BRCA1 and BRCA2)
• Personal history of BC
• Breast pathology: atypical hyperplasia, DCIS
(surgically removed)
• Some reproductive History: Early menarche (<12
yrs), late menopause (>55 yrs), Late 1st pregnancy
(≥ 30 yrs) or no pregnancy (Null parity)
• Exposure to large amounts of chest wall radiation.
• Density of breast tissue
Risk factors for BC
in women
 Classification of pts risk for developing BC
High risk patients
(a) Cancer breast.
(b) have a known BReast CAncer (BRCA; BRCA1 or BRCA2; produce tumor suppressor
gene (TSG) proteins responsible for the repair of double-strand DNA breaks (DSBs))
gene mutation
(c) untested for BRCA gene mutation but have a first-degree relative with a BRCA
mutation, OR
(d) Have a strong family history of BC (>1 first-degree relatives breast cancers)

Average risk patient: NOT

doesn’t have a personal history of BC, a strong family history of BC, or a genetic mutation
known to increase risk of BC, and has not had chest radiation therapy before the age of 30
BRCA testing
Standard in:
• Personal diagnosis of BC at < 45

• Personal diagnosis of ER/PR/HER2 –ve BC at < 60

• Multiple family members with early onset breast or ovarian cancer

• Bilateral BC
 Screening
• For average-risk patients
1- Clinical breast examinations: 20- 39 yrs: q < 3 yrs then annually starting at 40
(insufficient evidence to support)

2- Mammography (±US): annually since 40 yrs & thereafter

(some guidelines recommend biennial > 50-55 yrs)
breast US: can be added after mammogram to differentiate
fluid- filled cysts (usually benign) vs masses

• For high risk patients

• Annual mammography & breast MRIs (if needed)
starting at 30 yrs.
 Screening
MRI allows a contrasted view of breast so more sensitive to detecting BC than
mammography.

breast tissue in younger pts can be denser due to higher levels of estrogen, making
mammography less sensitive.
 Prevention
• The key with any cancer.
• For high risk patients :
1- Prophylactic mastectomy with reconstruction:
optional, very successful (dec risk by 90% in +ve BRCA gene mutation, oophrerectomy dec.
risk by 50% in these pts).

2- Chemoprevention = hormonal therapy:

selective estrogen receptor modulator (SERM): proved efficacy in 1ry & 2ry prevention
FDA labeling
***in premenopausal & postmenopausal women
Aromatase inhibitors: proved efficacy in 2ry prevention & non finished 1ry prevention
studies off labeled use
***in postmenopausal women
 Chemoprevention
I- selective estrogen receptor modulator (SERM):oral
• = “designer estrogens” = those having estrogen R agonist, antagonist, or both activities
1- Tamoxifen:
- 20 mg daily
- risk reduction of BC persists for at least 5-10 years beyond 5-8 year course of treatment.
2- Raloxifene:
- 60 mg daily.
- risk reduction as tamoxifen (controversial)

• tamoxifen: agonistic (estrogenic) on bone, serum lipids & endometrial tissue &
antagonistic (antiestrogenic) on breast.
• raloxifene: agonistic on bone & serum lipid & antagonistic on endometrial & breast.
 Chemoprevention
• AE of SERM
1- increased risk for thromboembolic disease (DVT, PE, stroke) esp. in women > 50 yrs.
2- hot flashes & leg cramps
3- wt gain
4- risk of endometrial cancers

Tamoxifen vs raloxifen
• Tamoxifen > hot flashes, uterine cancer, cataracts than raloxifen
• Raloxifen > leg cramps and wt gain than tamoxifen
• So raloxifene has less toxicity.
 Chemoprevention
Contraindications of both :
• active or past history of thromboembolic disease,
• anticipated extended immobility
• for >72 hrs before immobilization as that associated with surgery

2- Aromatase inhibitors (AIs; oral):

• M.O.A:
• Inhibit conversion of androgens to estrogens in ovary in premenopausal women & in
extraglandular tissue (peripheral, adrenal & breast) in postmenopausal women
→↓level of circulating & at target estrogens
 Chemoprevention
• There are two classes of AIs:
Nonsteroidal AIs (anastrozole and letrozole)
steroidal AI (exemestane).

AIs vs SERM
• Unlike SERMs, they may accelerate bone loss, with arthralgia & more fracture risk in
post-menopausal women.
• However, they cause fewer AEs than SERMs: do not have the risk of blood clots or
uterine cancer → used in contraindication to SERM
• If AI used in premenopausal: + ovarian ablation (e.g., oophorectomy or LHRH agonists)
 Chemoprevention
Luteinizing hormone–releasing hormone (LH-RH) agonists
• E.g. goserelin
• M.OA. Ovarian suppression (largest source of estrogen; 60% chance of infertility) for
premenopausal patients
• minimal AEs; amenorrhea, hot flashes & occasionally N
 Diagnosis
• patient history,
• physical examination
• radiographic examinations (localized non-cyclic breast pain, suspicious finding on a
screening, palpable mass on self/physican examination)
1- bilateral mammogram ± breast ultrasound
3- MRI if needed

• Once a mass identified, tissue diagnosis either with:

core (better than fine) biopsy, OR
excisional biopsy
 Staging of breast cancer
• Aim
evaluate the extent of disease
Aid in determining therapeutic modality

• Conducted via TNM classification:

T, N: evaluated by physical, radiological examination & from surgical specimen
M: evaluated by radiologic examinations including CT scan of chest, abdomen, pelvis,
bone scan, MRI brain &PET-scans.

• Acc. to American Joint Commission on Cancer 2002:

• Stage insitu (CIS): carcinoma is situ (Tis), N0,M0
• Stage I: small tumors (<2 cm; T1) N0, M0
 Staging of breast cancer
• Stage II:
- T1 with lymph node involvement OR
- larger tumors (>2 cm and ≤5 cm; T2), N1 or N0 OR
- More large tumors (>5 cm; T3) with N0
All with M0.
• Stage III:
- T3, N1 OR
- any T, N2 or N3 OR
- Tumor invading skin or chest wall (T4) ± lymph node involvement
all with M0.
• Inflammatory BC is by default at least stage III
• Stage IV: any T, any N, M>1
 Clinical presentation of BC
At any stage: nipple discharge other than milk (clear yellow or bloody)
early-stages (insitu- II= localized)
• Usually painless lump found upon breast examination either by pt or clinician or on
routine mammogram.

Stage III (locally advanced)

+ swelling of affected breast &/or arm or nipple retraction

• Inflammatory BC:
• red breast with the look of an orange peel ”peau d’orange”
• delayed diagnosis because skin has the appearance of cellulitis
that don’t respond to a trial of antibiotics.
 Clinical presentation of BC
Patients with metastatic disease (stage IV)
• symptoms reflecting metastatic site as:
bone pain with bone metastases
SOB or dyspnea with lung metastases,
abdominal pain with liver metastases,
headaches/N/V with brain metastases.
 Prognostic Factors
• Allow individualized management decisions
I: Factors related to patients:
Young age at diagnosis (<35) indicates poor prognosis
Race: mortality → black> white>Hispanics>Asian

II: Pathologic factors:

1- T, N & M status
As T & N inc. ⇒ prognosis is worse
large tumors = many cell divisions = more mutations that are highly associated with higher
risk of developing drug resistance
M indicates the worst prognosis
 Prognostic Factors
2- estrogen receptor (ER) and progesterone receptor (PR) status:
ER or PR +ve tumors (2/3 of cases) have slower-growing, indolent disease with more
favorable prognosis than ER/PR -ve disease
scores of 0-2 are -ve, 3 - 8 are +ve
3- human epidermal growth factor receptor 2 (HER2= ERBB2) status.
HER2 +ve tumors (25% of cases) denote more aggressive disease.
Immunohistochemistry determines overexpression of HER2 protein (HER2/neu) and
results are reported as 1+, 2+, and 3+.
Patients with 3+ overexpression are considered +ve for HER2.
If a patient has 2+ overexpression (equivocal test) → further testing with fluorescence in
situ hybridization (FISH) → evaluates a ratio of number of gene copies of HER2 compared
to control
 Prognostic Factors
4- tumor grade
• determines degree of differentiation of tumor cells
• undifferentiated tumor are more rapidly growing & spreading than well differentiated
tumor
G1: Well differentiated (low grade)
G2: Moderately differentiated (intermediate grade)
G3: Poorly differentiated (high grade)
G4: Undifferentiated (high grade)
 Prognostic Factors
5- Ki-67 score:
• indicative of mitotic index
• Ki-67 is nuclear protein found in all active phase of growing, dividing cells except resting
phase(G0)
<10 %: low score
10-20: border line
>20 %: high score= tumor is more aggressive & spread quickly.

III- genomic profiling :

Oncotype DX assay:
• predict the risk of recurrence and extent of chemotherapy benefits in women with ER/PR
+ve HER2 –ve and N0 disease
 Prognostic Factors
• analyzes the activity of 21 genes that can affect how a cancer is likely to behave and
respond to treatment including Ki-67

• a score of 0-10 (low): hormone therapy only

• mid-range score (11-25) avoid chemotherapy, esp.if >50 yrs,
• a score of 26-100 (high) addition of chemotherapy to hormone therapy.
 Molecular Subtypes Of BC
According to prognostic factors BC is subdivided into 4 main categories for therapeutic
decision:

Basal-like Luminal A
ER-, PR- and HER2- (triple ER+&/or PR+, HER2-, low
-ve BC). Ki67 and low tumor grade.
High tumor grade

Luminal B
ERBB2/HER2-enriched
ER+ and/or PR+, HER2+
Has amplified/overexpressed
or HER2-with high Ki67
HER2, ER-& PR-.
and high tumor grade.
Prognostic significance of Molecular Subtypes Of
BC
Incidence
• Luminal A > basal like> luminal B > HER2 enriched

Survival
• Luminal A (better response to luminal B to endocrine therapy) > luminal B>
HER2 enriched> basal like (refractory to chemotherapy & difficult to treat)