Breast cancer is a major public health problem globally. Treatment involves multidisciplinary care and includes surgery, radiation, chemotherapy, hormone therapy, targeted therapy, and bone modifying agents depending on the stage and molecular characteristics of the cancer. The goals of treatment are to cure early-stage breast cancer through adjuvant therapies and prolong life and improve quality of life for metastatic breast cancer which is not currently curable. Molecular classification of breast cancers into luminal, HER2+, and triple negative subtypes helps guide treatment selection.

1. BREAST CANCER
DR. R. RAJKUMAR M.D. D.M.
Dr. R. RAJKUMAR M.

2. Breast Cancer
• Incidence:
– Invasive breast cancer 1
• 1.4 million new cases in 2008
– Past 25 years
• Breast cancer incidence rates have risen
globally
• Highest rates occurring in the westernized
countries
– Change in reproductive patterns
– Increased screening
– Dietary changes
– Decreased activity
• Mortality
– Mortality has been decreasing
– Especially in industrialized countries.1 American Cancer Society

3. BREAST CANCER IN INDIA
• Around 1 lakh cases /yr
• Peak incidence - 55-59/yr
• Age shift
• Rising numbers
• Late presentation
• Lack of awareness and screening
• Aggressive cancers in young

4. Age shift – cases in seen 30’s& 40’s

5. • Young onset breast cancer
• High grade (aggressive) tumors
• High proliferative tumors
• ER negative tumors
• “Triple negative” (ER-/PR-/HER2-)
tumors
INDIAN Women More Likely to Have:

6. Importance of Pathology: Not all Breast
Cancers Are the Same!!
Estrogen
Receptor (ER) +
75% of Breast
Cancer
HER-2 +
20-25% of Breast
Cancer
Tumor ER and HER2 status critical in selecting therapy in
both early stage and metastatic breast cancer

7. Treatment of Early Stage Breast
Cancer
• Breast cancer most curable when detected early
– Micrometastases (undetectable) can exist at time
of diagnosis in many patients, leading to
eventual recurrence
• Multidisciplinary care critical for best outcomes
– Surgery
– Radiation therapy
– Adjuvant systemic (drug) therapy reduces risk of
recurrence and death
» Should be tailored to the patient and tumor

8. No surgery
mastectomy
chemotherapy + endocrine therapy
chemotherapy + endocrine therapy +
HER2 targeted therapy
Incremental Benefit of Adjuvant
Treatments in Early Stage Breast
Cancer in USA
Survival

9. Adjuvant (Early Stage) Endocrine Therapy
in Breast Cancer
• Tamoxifen has substantial clinical efficacy, less cost, and
several decades of use throughout world
– Still the standard for premenopausal
– Reasonable for many postmenopausal
– Longer duration (> 5 years) may benefit many patients
• Adjuvant aromatase inhibitors: small differences in
recurrences (and in some trials deaths)
– Side effects different
• Ovarian suppression effective as a sole treatment
– Still unclear whether it adds to chemo/tamoxifen

10. Early Breast Cancer Trialists’ Collaborative Group
Clinical Trials of Tamoxifen in Early Stage
Breast Cancer: Disease-free Survival
ER Negative ER Positive
Adjuvant tamoxifen
significantly reduces
recurrence in ER positive
breast cancer
tamoxifen
control
Tamoxifen effective in both pre- and postmenopausal women
Adjuvant tamoxifen
doesn’t impact
recurrence in ER
negative breast cancer

11. Adjuvant (Early stage) Chemotherapy
in Breast Cancer
• Adjuvant chemotherapy reduces recurrences and
deaths
– Reducing dose from that proven to be effective in
clinical trials reduces benefit
– Chemotherapy drugs have significant side effects
• For unselected patients/tumors:
– anthracyclines better than CMF regimens
– taxanes add to anthracyclines – expensive
• Not all patients/tumors benefit from chemotherapy!
• ER-negative, high grade, HER-2+ tumors get most
benefit from chemotherapy

12. Chemotherapy Dose Matters
Adjuvant Chemotherapy - 20 Year Follow-up
Milan Study
Bonadonna G et al, N Engl J Med 332: 901-6,1995
0.9
1.0
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
5 10 15 20
Years after Mastectomy
Disease-free survival
ProbabilityofRelapse-freeSurvival
5 10 15 20
Years after Mastectomy
0.9
1.0
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Overall survival
ProbabilityofOverallSurvival
>85% of dose
<65% of dose
Control
65-84% of dose
If chemotherapy is given, it should be given at full dose

13. Adjuvant (Early Stage) HER-2
Targeted Therapy
• Anti-HER2 monoclonal antibody trastuzumab
(Herceptin) for 1 year is standard
– Reduces recurrence by 1/2 & deaths by 1/3 when
added to chemo in early stage breast cancer
– Trastuzumab going off patent soon, and prices
will drop
• All regimens include chemotherapy in addition to
HER2 targeting therapy

14. Molecular classification &
Prognosis:
• Luminal A= Best prognosis
• Luminal B
• Luminal C
• Normal breast like
• Her 2+
• Basal like= Worst= Triple
Negative
14

15. SUBTYPE
Type Importance
Luminal A ER +, Best overall
survival, Best DFS
Luminal B ER,Her2+,Intermediate
Her 2 +ve ER-, Intermediate
Basal like ER-,PR-, Her2 - Worst
15

16. BREAST CANCER
Stage IV
Any T any N M1
Examples of distant mestastatic disease

17. BREAST CANCER
Sites of distant
metastases
Skin
Liver
Bone
Pleura
Lung
Lymph nodes
Brain

18. Treatment of Metastatic
Breast Cancer
• Metastatic breast cancer is not curable,
but can be very treatable
• Goals:
–Control and regression of disease
–Prolongation of life
–Improvement in symptoms and
quality of life

19. Choices in the Treatment of
Metastatic Breast Cancer
• Choice of treatment is based on many factors:
–Patient age, menopausal status, general
health and functional status
–Tumor ER status, HER-2 status
–Previous treatments
–Extent and sites of disease
– Available therapies in the patient’s country

20. Breast Cancer Systemic Therapies
• Drug treatments that can attack
cancer cells throughout the body
–Endocrine therapy
–Chemotherapy
–Biologically-targeted therapy

21. Endocrine Therapy in Breast Cancer
Estrogen
Cell
Growth
and
Division
Estrogen
Receptor
SERMS (tamoxifen),
SERDSAromatase inhibitors, ovarian
suppression
Endocrine therapy effective only in ER-positive breast cancer
ER/PR staining: CRITICAL IN SELECTING THERAPY!

22. Endocrine Therapy for Metastatic
Breast Cancer
• Endocrine therapy is the preferred choice for ER+
metastatic breast cancer
– Less side effects than chemotherapy
• Exceptions:
– Concern or proof of endocrine resistance
– Need for fast response (location, symptoms)

23. Hormonal Therapies
(FDA indications)
• 1st line therapy:
–Tamoxifen, anastrozole
(Arimidex), letrozole (Femara)
• 2nd line therapy:
–Fulvestrant (Faslodex),
toremifene (Fareston),
exemestane (Aromasin)
• “Palliative”
–Goserelin (LHRH analog,
Zoladex)

24. Chemotherapy

25. Treatment of Metastatic Breast Cancer:
Cytotoxic Agents
• Anthracyclines (doxorubicin, liposomal
doxorubicin)
• Cyclophosphamide
• Taxanes (paclitaxel, docetaxel)
• Antimetabolites (5-FU, capecitabine)
• Gemcitabine
• Vinorelbine
• Carboplatin/cisplatin

26. European School of Oncology Guideline:
Chemotherapy for Metastatic Breast
Cancer
Cardosa F et al, J Natl Cancer Inst 101:1174-1181, 2009
• Sequential single agent chemotherapy generally
preferred choice
– Less toxicity than combination chemo
– No data to support optimal sequence
• Combination chemotherapy reserved for patients
with:
– rapid clinical progression
– life-threatening visceral metastases
– need for rapid symptom/disease control
• Chosen regimen should be evidence-based, with
proven efficacy and acceptable toxicity

27. Biologically-Targeted
Therapy

28. Her2/neu status
• Membrane-associated tyrosine kinase
receptor (aka erbB2) related to EGF
–Expressed in breast cancers, DCIS,
and some other tissues such as heart
–Overexpressed in 25-30% of breast
cancers
–Associated with more aggressive
disease and worse prognosis

29. Measurement of
Her2/neu
• Measured by
immunohistochemistry (IHC)
– Graded 0, 1+, 2+, or 3+
– Based on characteristics of staining
– 0-1 = negative
– 2 = indeterminant, should be followed
with FISH (fluorescent in situ
hybridization) to determine status
(amplified/not amplified)
– 3 = positive
• Fluorescence In Situ Hybridization
(FISH) correlates with response to

30. Four US FDA-Approved Drugs with HER-2
as a Target
cell division
HER-2
nucleus
cancer cell
Trastuzumab (Herceptin)
Anti-HER-2 Antibody
Lapatinib (Tykerb)
Dual HER-1/HER-2
Tyrosine Kinase Inhibitor
Pertuzumab
Anti-HER-2 Antibody
T-DM1
Antibody-Drug
Conjugate
20-25% of breast
cancers overexpress
HER2
Only effective for HER2+ breast
cancer

31. Trastuzumab (Herceptin)
• Humanized monoclonal antibody against her2/neu
• FDA approved for metastatic breast cancer in 1998
• Responses in patients with her2/neu positive breast
cancer
– IHC 3+
– FISH positive
• Single agent therapy has 26% response rate as 1st
line therapy
• May be given as an IV infusion weekly or every 3
weeks

32. European School of Oncology
Guideline: HER2 Targeted Therapy
for Metastatic Breast Cancer
Cardosa F et al, J Natl Cancer Inst 101:1174-1181, 2009
• Anti-HER2 therapy should be offered early to all
HER2+ metastatic breast cancer patients unless
contraindicated (or unavailable)
• Optimal duration of anti-HER2 therapy for
metastatic breast cancer (when to stop) unknown

33. Complications of Breast Cancer
Bone Metastases
Pain
Spinal cord
compression
Radiation
therapy
Orthopedic
surgery
Hypercalcemia
Fractures
The bone is the initial site of recurrence in 35-40% of breast
cancer patients

34. European School of Oncology Guideline:
Bone Metastases in Breast Cancer
Cardosa F et al, J Natl Cancer Inst 101:1174-1181, 2009
• Bone modifying agents should be routinely used in
combination with other systemic therapy in patients
with bone metastases
– Bisphosphonates (pamidronate, zoledronic acid)
– RANK ligand inhibitor (denosumab)
• Agents should be started early, if possible before
onset of bone symptoms
• Should be continued even in presence of disease
progression

35. Zoledronic Acid (Zometa)
• Bisphosphonic acid – inhibitor of
osteoclastic bone resorption
• Indicated for solid tumor patients with
bone metastases
• 4 mg IV over 15-30 minutes
• Check serum creatinine before each
administration
• Comparable in efficacy to pamidronate
•Rosen LS, Cancer J 7:377, 2001

36. Systemic Treatment of Breast
Cancer: Summary
• Main principles of modern oncology
– Multidisciplinary treatment
– Evidence-based medicine
– Individualized (tailored) therapy
• Keep in mind goals of therapy
– Adjuvant: curative intent
– Metastatic: incurable but treatable
• Include psychosocial and supportive care and symptom-
related interventions
• Include patient preferences and active participation
– Patients, families and caregivers should be invited to
participate in decision-making