Current Concepts in Breast Cancer Treatment

1. Breast Cancer: Current
Treatment Options
Fiifi Brakatu

2. Principles of Non-metastatic Breast Cancer Therapy
● Eradicate tumor from the breast and regional lymph nodes and prevent
metastatic recurrence
● Local Therapy - surgical resection and removal of axillary lymph nodes
● Systemic Therapy - Pre-operative (neoadjuvant), postoperative (adjuvant) or
both
○ Guided by molecular subtype
○ Endocrine therapy for all HR+ tumors (with some requiring chemo as well)
○ Trastuzumab-based ERBB2-directed antibody therapy + chemotherapy for all ERBB2+ tumors
(with endocrine therapy given in addition, if concurrent HR positivity)
○ Chemotherapy alone for triple-negative breast cancer

3. Principles of Metastatic Breast Cancer Therapy
Prolong life and palliation of symptoms
Same approach to systemic therapy as non-metastatic breast ca
Surgery and radiation are typically used for palliation only in metastatic disease

4. Nipple Discharge
3% of women with nipple discharge <40yrs age diagnosed with
breast ca
33% for those >40yrs
Most common cause of bloody nipple discharge - Intraductal
Papilloma
Characteristics of a nipple discharge that likely to be malignant
● Bloody discharge
● Spontaneous discharge
● Persistent discharge >1wk
● Unilateral nipple discharge

5. Workup for Nipple discharge
Mammography
Ductal fluid cytology
Ductography
Ductoscopy
Duct excision - best means of
diagnosing underlying pathology

6. Cystic lesion on USG
USG aspiration
If bloody or recurrent - send for cytology

7. Phylloides Tumor
Has malignant potential
● >5 mitoses/HPF
WLE with 1cm margin
Haematogenous spread is rare
It does not spread to the Lymph Nodes -
No need for SLNB or Axillary dissection

8. Radial Scar
Sclerosing Papillary Proliferations or Benign
Sclerosing Ductal Proliferations
Calcifications on mammography - looks like a
small invasive cancer
Has malignant potential
Treatment - Excisional Biopsy

9. DCIS
It is a pre-malignant lesion
Treatment -
● Breast Conservation Therapy
○ Lumpectomy + Radiation + Hormonal Therapy (if hormone-receptor +ve)
○ 2mm margin - spreads along basement membrane
● Mastectomy + SLNB - Indications
○ Large lesion
○ Multifocal disease
○ If patient has any contraindication to adjuvant radiation
● NB: 25% of DCIS may show an invasive component on the final pathology

10. Mastectomy and BCT have EQUAL survival rates, although recurrence rate is
slightly higher with BCT
Whole breast radiation after lumpectomy in BCS will decrease the risk of
recurrence by 50%, although no impact on overall survival in long term studies

11. LCIS
It is NOT a pre-malignant lesion
It increases risk of breast ca in both breasts if present
Treatment:
WLE - To rule out invasive component or DCIS
If no invasive component/DCIS present but a positive LCIS margin - You’re
surgically complete (ie. you don’t need negative markings)
Hormonal Therapy if Hormone-receptor positive
Patient counselled that there is risk of Invasive Ductal Ca in both breasts
● 0.5% risk of invasive ca per year
● Individualized discussion on Prophylactic Bilateral Mastectomy

13. TNM Grade
T1 - 0-2cm
T2 - 2-5cm
T3 - >5cm
T4 - Any size that
invades skin or chest
wall
NB: Invasion of
Pectoralis major not
considered chest wall
invasion
T4d = Inflammatory
breast ca
N1: 1-3 LNs
N2: 4-9 LNs
N3: >10 LNs or
Supraclavicular or
Infraclavicular LNs
Mx - Can’t be assessed
Mo - No Mets
M1 - Distant Mets

14. Staging
Stage 1 - small tumor with no LN spread/mets - T1N0M0
Stage 2 - Larger tumor (T3N0) or minor nodal involvement (T2N1)
Stage 3
● 3a and 3 b - Local invasion (T4N0)/more LN involvement (T3N2)
● 3c - Any T with N3 (clavicular LNs jumps lesion to 3c)
Stage 4 - Any distance metastasis

15. Nottingham Prognostic Index (NPI)

16. General Surgical Considerations

17. Early-Stage Breast Cancer
Stages 1 & 2
Primary Surgery (Lumpectomy or Mastectomy) to breast and Regional Lymph
Nodes +/- Radiation Therapy(RT)
Breast-Conserving Therapy (BCT) is preferred if possible
● Lumpectomy + SLNB + Whole breast radiation + Adjuvant Chemo/Hormonal
Therapy
● Lumpectomy should have negative surgical margins before RT
Patients who are Her2-positive or Triple negative may be treated by neoadjuvant
therapy first followed by surgery

18. Contraindications to BCT
● Pregnant patients requiring radiation during pregnancy
● Multicentric disease
● Persistent positive pathologic margins after re-excision
● Diffuse pleomorphic calcifications on Mammogram or MRI
● Patient with previous chest radiation - relative
● Patients with connective tissue diseases eg scleroderma - relative
● Tumor >5cm (relative - depends on lump/breast ratio)
● Disease that cannot be addressed by excision of a single breast tissue region
with satisfactory cosmetic result

19. Locally Advanced Operable Tumors
Stage 3A
● Mastectomy or
● Neoadjuvant therapy to downstage tumor, then BCT if possible

20. Locally Advanced Inoperable Tumors
Stage 3B and 3C
More Extensive Nodal Involvement
Neoadjuvant Therapy followed by Surgery if the patient responded to it

21. Metastatic Disease
Stage 4
Treatment is by Primary Chemotherapy
Optimize analgesia

22. Local Therapy for Non-Metastatic Breast Cancer
Total Mastectomy
Breast-Conserving Therapy

23. Mastectomy
Indicated for patients who do not qualify for BCT or those who opt for it
Types:
● Simple (Total) Mastectomy
● Modified Radical Mastectomy (MRM)
● Skin-Sparing Mastectomy (SSM)
● Nipple-Areolar Sparing Mastectomy (NSM)
● Radical (Halstead) Mastectomy

24. Simple Mastectomy
Complete removal of breast and the pectoralis
major fascia
It is typically done with a Sentinel Lymph Node
Biopsy (SLNB)

25. Modified Radical Mastectomy
Complete removal of breast and
the pectoralis major fascia +
removal of level I and 2 axillary
lymph nodes
Survival rates are equivalent with
radical mastectomy with less
morbidity (Fisher et al, Level 1)
Used in patients with
biopsy-proven axillary metastases
or those who failed to map for
SLNB

26. Skin-Sparing Mastectomy
Majority of the natural breast skin
envelope is preserved
Entire breast parenchyma and NAC
are excised and the skin of the
breast + inframmamry fold are
preserved
Periareolar, Tennis Racket or
Teardrop incisions may be used

27. Nipple Areolar Sparing Mastectomy
Preserves the epidermis and dermis of the
NAC but removes the major ducts within the
nipple lumen, while preserving the blood
supply
Indications : For peripheral tumors <2cm with
a tumor to NAC distance >2cm
Inframammary, Midlateral, Circumareolar or
combination of these incisions may be used
Circumareolar incision has a higher risk of
nipple necrosis

28. Radical (Halstead) Mastectomy
Rarely used in modern practice
En bloc removal of breast, overlying skin, Pectoralis major and minor muscles and
the entire axillary contents (levels 1, 2 and 3 nodes)

29. Complications of Mastectomy
Seroma
Wound Infection
Skin flap Necrosis
Nipple Necrosis
Postmastectomy Pain
Phantom Breast Syndrome
Arm morbidity - arm swelling, shoulder stiffness, etc
Brachial plexopathy

30. Surgical Management of the Axilla
Considered separately from surgical therapy of the breast
Diagnostic purpose - determines anatomic extent of the breast cancer
Therapeutic - removal of cancerous cells
Decision is based on whether:
● Axillary lymph nodes are involved at the time of diagnosis
● Neoadjuvant systemic therapy is administered
ALND (clearance) was the gold standard until…

32. n=891
Tumor <5cm in diameter
SLNB alone vs ALND
10yr overall survival -
86.3% (SLNB) vs 83.6
(ALND)
10yr DFS -
80.2%(SLNB) vs
78.2(ALND

33. Evaluation of the Axillary Nodes
Palpable Axillary Nodes
● USG + FNA or CNB
ALL patients that have invasive tumors with
impalpable/biopsy-negative axilla need to have SLNB at
the time of surgery
If axilla is CLINICALLY POSITIVE - Modified Radical
Mastectomy + ALND
Z11 trial - Patients with small tumor (T1 and T2) disease
and <3 clinically positive nodes after SLNB had BCT +
Whole breast radiation vs ALND
Results equivalent

34. Sentinel Lymph Node Biopsy
Indications:
● Early breast ca with clinically negative nodes
● DCIS with planned mastectomy or suspicious features

35. So who needs an ALND?
Only Level 1 and 2 ALND for breast ca
● Clinically positive nodes confirmed by USG
and FNA or CNB
● SLNB that were not initially identified after
re-excision
Level 3 dissection is done for patients with
Melanoma who have a positive SLNB
Chronic Lymphedema following a ALND can
result in Stewart-Treves Syndrome (a
lymphangiosarcoma)

36. Nerves at Risk in Axillary Lymph Node Dissection
Intercostobrachial Nerves - most
commonly injured
Long Thoracic Nerve
Thoracodorsal
Medial Pectoral Nerve
Lateral Pectoral Nerve

37. Systemic Therapy
Medical treatment of breast cancer using endocrine,chemotherapy and/or biologic
therapy
Adjuvant or Neoadjuvant
Hormone receptor-positive patients - Endocrine therapy
ERBB2+ patients - Trastuzumab (herceptin)

38. Molecular Subtypes - Old Classification
Lumina A : ER+, PR + or -, HER2 neg, KI67 <14%
Lumina B : ER+, PR + or -, HER2 pos or neg, KI 67 >14%
Her2 neu enriched : ER-, PR -, HER2 pos, KI67 <14% or >14%
Triple Negative (Basal) : ER-, PR -, HER2 neg, KI67 <14% or >14%
NB: Receptor status - ER or PR is positive if >⅜
Lumina A has the best prognosis

39. Molecular Subtypes - New Classification
● Estrogen Receptor alpha (ERa) - expressed in 70% of invasive breast ca
○ Steroid hormone and transcription factor - activates oncogenic pathways in breast ca
○ Expression of Progesterone Receptor (PR) is a marker of ERa
○ Tumors that express ER or PR in at least 1% of cells are categorized HR+
● Epidermal Growth Factor 2 (ERBB2, formerly Her2 or Her2/neu)
○ A Transmembrane receptor Tyrosine in epidermal growth factor
○ Amplified or overexpressed in 20% of breast cancers
● Triple Negative
○ 15% of all breast cancer - poorly understood
○ Lack of expression of ER, PR or ERBB2+
○ High risk of distant relapse in first 3-5yrs following diagnosis (Foulkes et. al)

40. Endocrine Therapy
Indications:
● All hormone-positive tumors should receive oral SERM (Tamoxifen) or
Aromatase Inhibitor (Anastrozole, Exemestane, Lestrozole) for
postmenopausal women, taken daily for 5years
○ Decreases recurrence by 50% within 1st 5years of diagnosis (EBCTCG Trial)
Side effects of tamoxifen - VTE, Increased risk of endometrial ca (partial agonist in
the uterus)
HR+/ERBB2- patients - Decision on adding chemo depends on anatomic stage
and tumor grade - using 21-gene recurrence score and 70-gene assay

41. Chemotherapy
Demonstrated efficacy in Triple-negative
breast ca
Adjunct to Endocrine or Trastuzumab therapy
Low Risk Patients - TC, AC or CMF are
reasonable regimens
High Risk Patients (High nodal disease/ Triple
Negative) - AC-T is the most appropriate
choice

42. Chemotherapy
MDT Discussion
● Individual risk of relapse
● Predicted sensitivity to Rx based on oncotyping
Tumors > 2cm
High grade tumors
Positive Lymph Nodes
Triple Negative Tumors >0.5cm (no survival advantage with chemo if tumor is <0.5cm)
High 21-gene recurrence score
NB: In hormone-receptor positive patients with node-negative tumors with favorable oncotypes - Adjuvant hormonal
therapy alone is enough, No need for chemotherapy.

43. Regimen
AC-T is the regimen of choice
Taxanes (eg. Paclitaxel and Docetaxel) - peripheral
neuropathy
Adriamycin (Doxorubicin) - Cardiomyopathy
Cyclophosphamide - Haemorrhagic Cystitis
● Give mesna to reduce risk of haemorrhagic cystitis

44. Indications for Neo-Adjuvant Chemotherapy
● Locally Advanced Inoperable Tumors - Inflammatory, T4, N2, N3 lesions
● Downsize tumors that have a big lump/breast ratio for BCT (requested by
patient)

45. ERBB2-targeted therapy
Trastuzumab (Herceptin) is a monoclonal antibody that
targets the extracellular domain of ERBB2
Choice of therapy for ERBB2+ patients - given for 1 year
Given with standard adjuvant chemotherapy

46. Radiation Therapy
May be delivered to:
● The whole breast or portion of the breast (after lumpectomy)
● The chest wall (after mastectomy)
● The regional lymph nodes
○ Radiation to paraclavicular, axillary and internal mammary LNs in addition to breast or chest
wall improves DFS but not overall survival (Whitlam et.al)
○ Not universally given in node-positive patients but considered for those with higher nodal
burden or high-risk biology
Post-lumpectomy whole-breast radiation is standard for BCT
● Reduction in both locoregional and distant recurrences by 50% and reduction
in deaths by one-sixth (EBCTCG Trial)

47. Radiotherapy
Give radiotherapy AFTER Chemotherapy
For tumors with 4 or more +ve LNs, radiation to the supraclavicular, infraclavicular
and axillary LNs is recommended
Tumors in central or inner quadrants of the breast - for the Internal Mammary LNs
For women with 1-3LNs - usage of radiation depends on the individual tumor
characteristics
● For a woman Age >70yrs with clinically-negative LNs and ER+ T1 breast ca,
lumpectomy + hormonal therapy is enough - No need for radiotherapy

48. Radiotherapy after Mastectomy
After mastectomy, radiation to chest wall and regional
lymph nodes if:
● Positive axillary lymph nodes AND
● Tumors >5cm or Positive Tumor margin

49. Metastasis
Common sites - Bone,
Lung, Brain and Liver
Isolated Tumor Deposits
<0.2mm are NOT
considered metastatic
disease
Spreads to bone via the
Batson’s plexus -
valveless venous system

50. Inflammatory Breast Cancer
Rapid diffuse involvement of entire breast with
cutaneous erythema, peau d’orange
● Peau d’orange results from dermal lymphatic
invasion by cancer cells
T4d tumors ie at least Stage 3B
Treatment:
● Start with Chemoradiation followed by a Modified
Radical Mastectomy

51. Paget’s Disease of the Breast
Eczematous ulceration of the skin and nipple
Marker of underlying malignancy
Generally Hormone-receptor Negative and Her2+
Cells have a clear cytoplasm and enlarged nuclei
Treatment:
● BCT - if patient qualifies for it
● Mastectomy (including NAC) + SLNB

52. Breast Cancer in Men
<1% of breast cancer
Risk factors:
● Strong family history
● Klinefelter Syndrome
● BRCA 2 mutation - accounts for 15% of
breast cancer in men

53. Breast Cancer in Pregnancy
1st Trimester
● Modified Radical Mastectomy - because they
cannot undergo adjuvant radiation and
chemotherapy
Late 2nd and 3rd trimester
● BCT + Adjuvant Chemotherapy and
Post-Delivery Breast Radiation
○ SLNB is done with a modified isotope radiotracer dosing
- methylene blue is contraindicated in pregnancy!

54. Fertility Preservation

55. Older women
HR+ seniors who are not candidates for
surgery or with lower life expectancy
● Primary Hormonal therapy with Tamoxifen or
Anastrozole
● Radiotherapy

56. Osteoclast Inhibitors - EBCTCG Trial
4mg of Zoledronic Acid
in 500mls NS - run
slowly over 30min
Every 6months
For 2years

57. Take Home Message
Tumor Biology is everything when it comes to breast cancer!

58. REFERENCE