This document summarizes a clinical seminar on the management of breast cancer. It provides statistics on breast cancer incidence and risk factors such as genetic predisposition, hormone exposure, radiation exposure, and age. It discusses screening guidelines, staging workup, pathological assessment of biopsies, intrinsic subtypes, and treatment options including surgery, radiation, chemotherapy, endocrine therapy, targeted therapy, and management of ductal carcinoma in situ. Treatment is tailored based on tumor subtype, size, lymph node involvement, and menopausal status, with the goal of reducing the risk of recurrence after primary treatment.

1. Clinical seminar 05/11/2014
CCLLIINNIICCAALL MMAANNAAGGEEMMEENNTT
OOFF BBRREEAASSTT CCAANNCCEERR
Author: Andrea Spinazzola, MD
Group: Prof. Nancy Hynes

2. STATISTICS U.S. 2014
One in 4 deaths is due to cancer
Estimated new cancer cases: 1,665,540. Estimated deaths: 585,720
Average lifetime breast cancer risk for a woman 12.3% (1 in 8 women)
Siegel R, CA Cancer J Clin 2014

3. FEMALE BREAST ANATOMY
The bulk of the breast tissue is adipose tissue
interspersed with connective tissue
Breast ducts comprise only about 10% of the
breast mass
BREAST CANCER RISK FACTORS
 Genetic predisposition (15%)
 Genetic mutation (5%): BRCA1, BRCA2, PALB2
 Exposure to estrogens (endogenous and exogenous)
 Ionising radiation
 Dense breast
 Low parity
 Obesity
 Age

4. BREAST SELF-EXAM

5. SIGNS AND SYMPTOMS
Redness or pitting of the skin (skin of
5
an orange)

6. PAGET’S DISEASE INFLAMMATORY BREAST CANCER

7. SCREENING GUIDELINES
- GENERAL POPULATION -
 NCCN 2014: annual mammography age 40 years - not established
 ACS 2014: annual mammography age 40 years - as long as good health
 USPSTF 2009: biannual mammography age 50-74 years
 ESMO 2013: biannual mammography age 50-69 years
Cancer
Microcalcification

8. IS SCREENING REALLY USEFUL?
 89.835 women aged 40-59 randomly assigned to mammography (five annual mammography screens) or
no mammography
 25 years follow-up
 End-point: deaths from breast cancer
Breast cancer specific mortality Breast cancer specific mortality from
cancers diagnosed in screening period
Conclusion: Annual mammography in women aged 40-59 does not reduce mortality from breast cancer
beyond that of physical examination when adjuvant therapy for breast cancer is freely available.Overall, 22%
of screen detected invasive breast cancers were over-diagnosed
Miller AB, BMJ 2014

9. STAGING WORKUP
History
Menopausal status
Physical examination (including regional nodes)
Full blood count, liver and renal function tests
Biopsy
Serum tumor markers CEA, Ca15.3
Chest + Abdomen CT
Bone scintigraphy
TNM (simplified)
T0 No evidence of primary tumor
Tis Carcinoma in situ
T1 Tumor ≤20 mm in greatest dimension
T2 Tumor >20 mm but ≤50 mm in greatest dimension
T3 Tumor >50 mm in greatest dimension
T4 Tumor of any size with direct extension to the chest wall
and/or to the skin
pN0 No regional lymph node metastasis identified
histologically
pN1 Micrometastasis, metastases in 1–3 axillary lymph nodes
pN2 Metastases in 4–9 axillary lymph nodes
pN3 Metastases in ≥10 axillary lymph nodes, or metastases in
infraclavicular (level III axillary) lymph nodes
M0 No clinical or radiographic evidence of distant metastases
M1 Distant detectable metastases

10. Breast cancer mortality by stage
(source: ACS)
Stage grouping system
5-Year Relative Survival
(source: NCI)

11. PATHOLOGICAL REPORT
 Histological type
 Ductal Carcinoma In-Situ (DCIS)
 Lobular Carcinoma in Situ (LCIS)
 Infiltrating Ductal Carcinoma (IDC)
 Infiltrating Lobular Carcinoma (ILC)
 Special types:
 endocrine responsive: Cribriform, Tubular, Mucinous
 endocrine non-responsive: Apocrine, Medullary, Adenoid Cystic, Metaplastic
 Margins: >1 mm for the invasive component; >2 mm for DCIS
 Grade

12. PATHOLOGICAL REPORT
 Immunohistochemistry
 ER, PgR
 Ki-67 (MIB-1 antibody)
 HER2
 TILs in TNBC? Loi S, Ann Oncol 2014; Ali HR, Ann Oncol 2014; Adams S, JCO 2014

13. INTRINSIC SUBTYPES
A: copy number alteration
B: most commonly mutated cancer-related genes
Ades F, JCO 2014
SURROGATE DEFINITIONS OF IINNTTRRIINNSSIICC SSUUBBTTYYPPEESS
(St Gallen International Expert Consensus 2013)
Intrinsic
subtype
Clinico-pathologic surrogate
definition Notes
Luminal A
Luminal A-like
all of:
ER and PgR +
HER2 -
Ki-67 ‘low’
Ki-67< 14% or 20%
PgR ≥20%
Luminal B
Luminal B-like (HER2 negative)
ER +
HER2 -
and at least one of:
Ki-67 ‘high’
PgR ‘negative or low’
Ki-67 ≥ 14% or 20%
PgR <20%
Luminal B-like (HER2 positive)
ER +
HER2 +
Any Ki-67, Any PgR
Erb-B2
overexpression
HER2 positive (non-luminal)
HER2 +
ER and PgR absent
Basal-like
Triple negative (ductal)
ER and PgR absent
HER2 -
There is an 80% overlap
between ‘triple-negative’
and ‘basal-like’ subtype.
TNBC also includes some
special histological types
Goldhirsch A, Ann Oncol 2013
SSOOMMAATTIICC MMUUTTAATTIIOONNSS AANNDD MMOOLLEECCUULLAARR
AALLTTEERRAATTIIOONNSS

14. TTRREEAATTMMEENNTT

15. ADJUVANT THERAPY
After the main cancer treatment (surgery)
Targets microscopic residual/metastatic disease
Increase the percentage of cure (prevent cancer recurrence) and improve DFS and OS
Agents that are active in the metastatic setting
NEOADJUVANT THERAPY
Before the main cancer treatment (surgery)
Aims to shrink a large cancer, making it easier to remove with surgery
Render resectable an unresectable locally advanced cancer, or result in less demolitive surgery
Agents that are active in the metastatic setting
PALLIATIVE THERAPY
Advanced disease
Relieve symptoms, prolong survival, reduce complications, improve quality of life

16. PRIMARY BREAST CANCER SURGERY
SURGERY OF TTHHEE PPRRIIMMAARRYY TTUUMMOORR
 Mastectomy
 BCS: Lumpectomy, Quadrantectomy, Segmental Mastectomy, Partial Mastectomy

17. MASTECTOMY
RCTs and Meta-analysis have shown:
 Comparable local control and OS
 Better cosmetic outcomes for BCS
VS
BREAST CONSERVING SURGERY (BCS)
BCS → DCIS, stage I-II cancer; not if multicentric disease
BCS must always be followed by adjuvant RT on the residual ipsilateral breast tissue

18. ADJUVANT TREATMENTS
RADIATION THERAPY (RT)
(within 6 months from primary tumor surgery)
On the residual ipsilateral breast tissue if BCS
On the chest wall if T3-T4 tumor
On the ipsilateral lymph node sites if N2-N3 disease
CHEMOTHERAPY
(within 2-6 weeks from primary tumor surgery)
Cyclophosphamide + Methotrexate + Fluorouracil (CMF) [d1,8 q28 6 cycles]
Epirubicin (or Doxorubicin) + Cyclophosphamide (EC or AC) [q21 4-6 cycles]
EC or AC [q21 4 cycles] → weekly Paclitaxel (TAX) [12 cycles] or Docetaxel (T) [q21 4 cycles]
Fluorouracil + Epirubicin (or Doxorubicin) + Cyclophosphamide (FEC or FAC) [q21 6 cycles]
Docetaxel + Epirubicin (or Doxorubicin) + Cyclophosphamide (TEC or TAC) [q21 4-6 cycles]
ENDOCRINE THERAPY (ET)
(if ER+ and/or PgR+)
SERMs: Tamoxifen
AIs: Anastrozole, Letrozole, Exemestane
Surgical or chemical castration

19. ER expression threshold
 GGuuiiddeelliinneess → ER status must be considered positive if ≥1% of tumor cells demonstrate
positive nuclear staining by IHC
ER-positive 1%–9% tumors have clinical and pathologic characteristics different from ER-positive ≥10%
tumors. Similar to patients with ER-negative tumors, patients with ER-positive 1%–9% tumors do not
Yi M, Ann Oncol 2014
Iwamoto T, JCO 2012
appear to benefit from ET
ER IHC: blue 0%, green 1-9%, purple 10%, gold >10%
Relationship between ER IHC status, ESR1 mRNA
expression, and ER-associated gene signature expression OS by (A) estrogen receptor IHC status and by (B) ESR1 mRNA expression

20. ADJUVANT THERAPY
- ENDOCRINE THERAPY -
All patients with invasive HR+ tumor (any T, any N)
If chemotherapy is administered, ET should start at the end of this
ASCO GUIDELINES 2014
PREMENOPAUSE POSTMENOPAUSE
 Tamoxifen 10 years (± ovarian suppression)  AI 5 years
 Tamoxifen 10 years
 Tamoxifen 5 years → AI 5 years
 Tamoxifen 2-3 years → AI 2-3 years
 TOXICITY
 Tamoxifen: endometrial cancer, hot flashes and other menopausal symptoms, deep vein
thrombosis or pulmonary embolism
 AIs: hot flashes and other menopausal symptoms, ischemic heart disease,
osteopenia/osteoporosis, dyslipidemia

21. DUCTAL CARCINOMA IN SITU
 High risk of invasive cancer evolution
 Frequent relapse as DCIS or invasive cancer
MANAGEMENT
A) Mastectomy → 5 years Tamoxifen
B) BCS → RT and 5 years Tamoxifen
LOBULAR CARCINOMA IN SITU
 Uncertainty over the potential risk of evolution toward invasive cancer
MANAGEMENT: surveillance

22. ADJUVANT THERAPY
INVASIVE BREAST CANCER
SURROGATE SUBTYPE TYPE OF THERAPPY NOTES
Luminal A-like Endocrine therapy
Endocrine therapy is the most critical
intervention and is often used alone
Cytotoxics may be added in selected patients:
- grade 3
- N2-3
- age <35 years ?
Luminal B-like (HER2 negative) Endocrine therapy for all patients,
cytotoxic therapy for most
Luminal B-like (HER2 positive) Cytotoxics + anti-HER2 → endocrine
therapy
HER2 positive (non-luminal) Cytotoxics + anti-HER2
Triple negative Cytotoxics
St Gallen International Expert Consensus 2013
Goldhirsch A, Ann Oncol 2013
Risk of recurrence by genomic assays: Oncotype DX, MammaPrint, Mammostrat

23. ADJUVANT THERAPY
- TRASTUZUMAB (Herceptin) -
All patients with HER2-positive tumors ≥ T1c or N+
Administer concurrently with Taxane, then complete 1 year of treatment
OUTCOMES → DFS increase of 12% at 3 years; 33% reduction in the risk of death
Monitor heart function (ECG, ejection fraction)
RREEGGIIMMEENN
 EC (or AC) → Taxane + H → H
 FEC (or FAC) → Taxane + H → H
 Docetaxel + Carboplatin + Trastuzumab (TCH) → H
NSABP trial B-31 + NCCTG trial N9831 BCIRG 006 study
Slamon D, NEJM 2011
Romond EH, NEJM 2005

24. NEOADJUVANT THERAPY
T3-T4 or N+ tumors; locally advanced unresectable tumor; inflammatory breast cancer
HER2-negative HER2-positive Selected HR+
patients
 EC or AC → Taxane
 TEC or TAC
 FEC or FAC
 CMF
 EC or AC → Taxane + Trastuzumab
 FEC or FAC → Taxane + Trastuzumab
 Taxane + Trastuzumab
 Chemotherapy + dual anti-HER2 therapy
Trastuzumab concurrently with neoadjuvant chemotherapy
and continued after surgery for a total of 1 year
 Endocrine therapy
Patients who attain pCR defined as
ypT0 ypN0 or ypT0/is ypN0 have
improved survival. The prognostic value
is greatest in aggressive subtypes.
Cortazar P, Lancet 2014

25. EARLY BREAST CANCER TRATMENT COMPLICATIONS
- LYMPHEDEMA -
More common in patients who have undergone both axillary RT and surgery
 SLNB + radiation therapy → frequency 23%
 ALND + radiation therapy → frequency 35% in node-negative and 48% in node-positive patients
Lawenda BD, CA Cancer J Clin 2009

26. FOLLOW-UP
 Visits every 3 to 4 months in the first 2 years, every 6 months from years 3–5 and annually thereafter
 Ipsilateral (after BCS) and contralateral mammography is recommended every 1 to 2 years
 In asymptomatic patients, there are no data to indicate that other laboratory or imaging tests produce a
survival benefit
 For patients on Tamoxifen an annual gynaecological examination is recommended
 For patients on AI regular bone density evaluation is recommended
 The use of hormone replacement therapy increases the risk of recurrence and should be discouraged

27. RELAPSE
 In the first years the risk of recurrence is higher in patients with ER-negative cancers
 Relapses of breast cancer may occur as late as >20 years after the initial diagnosis, particularly in
Before starting any therapy:
 Biopsy with IHC evaluation
 Restaging: blood analysis, chest + abdomen CT, bone scintigraphy, PET-CT
If IHC markers are discordant between the primary tumor and the relapse
Use targeted therapy (ET and/or anti-HER2 therapy) when receptors are positive in at least one biopsy
LLOOCCAALL RREELLAAPPSSEE
 Surgery ± RT → “adjuvant” therapy
 First-line therapy
ESO-ESMO 2nd international consensus guidelines for advanced
MMEETTAASSTTAATTIICC RREELLAAPPSSEE
 First-line therapy
breast cancer
Cardoso F, Ann Oncol 2014
patients with luminal disease
BBRRAAIINN MMEETTAASSTTAASSIISS
 Specific treatment

28. ADVANCED DISEASE
 Therapeutic decision: age, performance status, menopausal status, previous therapies,
comorbidities, differential toxicities, disease extent, symptoms
 ET should be offered as initial treatment in case of limited and asymptomatic visceral ER+
disease
 Polychemotherapy offers no survival advantage over sequential monotherapy, and is
graved by higher toxicity
 In cases where a rapid tumor shrinkage is required (life threatening disease), a
polychemotherapy may be preferred
 In case of bone metastasis, a bone-modifying agent (BMA) must be administrated together
with cancer specific treatments

29. ADVANCED DISEASE
- HER2-NEGATIVE -
 FFiirrsstt--lliinnee:
 Endocrine Therapy (Tamoxifen, AIs, Fulvestrant)
 Anthracyclines
 Taxanes
 Bevacizumab + Paclitaxel
 Vinorelbine
 Carboplatin (in TNBC)
MEDIAN SURVIVAL 3 YEARS
 FFuurrtthheerr lliinneess:
 Endocrine Therapy
 Everolimus + Exemestane
 Anthracyclines
 Taxanes
 Vinorelbine
 Eribulin
 Gemcitabine
 Capecitabine
 Nab-Paclitaxel
 Metronomic chemotherapy

30. ADVANCED DISEASE
- HER2-POSITIVE (ASCO GUIDELINES 2014) -
 FFiirrsstt--lliinnee:
Pertuzumab + Trastuzumab + Taxane
OUTCOMES
OS: 37.6 months (placebo) VS not
reached (Pertuzumab)
PFS: 12.4 months (placebo) VS 18.7
months (Pertuzumab)
CLEOPATRA trial
Swain SM, Lancet Oncol 2013
 SSeeccoonndd--lliinnee:
T-DM1
Trastuzumab + chemotherapy
Trastuzumab + Lapatinib
 TThhiirrdd--lliinnee::
T-DM1
Trastuzumab + chemotherapy
Trastuzumab + Lapatinib
 FFuurrtthheerr lliinneess::
Chemotherapy ± anti-HER2
ET ± anti-HER2
TH3RESA trial Krop IE, Lancet Oncol 2014 EMILIA trial Verma S, NEJM 2013

31. ADVANCED DISEASE
- TRASTUZUMAB EMTANSINE (T-DM1) -

32. ADVANCED DISEASE
- EVEROLIMUS (Afinitor) -
 mTOR inhibitor (mTORC1 complex)
 Approved for the treatment of:
 Advanced HR+ breast cancer after progression with non-steroidal AIs (BOLERO-2 trial)
 Advanced pancreatic NETs
 Advanced renal cell carcinoma
BBOOLLEERROO--22 ttrriiaall
Baselga J, NEJM 2012
BBOOLLEERROO--33 ttrriiaall
Everolimus + Trastuzumab + Vinorelbine
in Her2+ Trastuzumab-resistant mBC
Andrè F, Lancet Oncol 2014

33. METRONOMIC CHEMOTHERAPY
Andrè N, Nat Rev Clin Oncol 2014
KKEEYY FFEEAATTUURREESS
 Frequent administration, low dose,
minimal drug-free breaks
 Oral administration
 Minimal toxicity
 Cumulative doses of a long-term
metronomic therapy can be similar or even
higher than those of MTD regimens
MMeettrroonnoommiicc tthheerraappyy iinn mmBBCC
Vinorelbine, Capecitabine, Cyclophosphamide, Methotrexate

34. BONE METASTASIS
Radiography CT scan Bone Scintigraphy
 Up to 80% of patients with mBC develop bone metastases
 Complications: pain, disability, hypercalcemia, skeletal-related events (SREs)
skeletal-related events (SREs)
- Radiation to bone (to alleviate pain or prevent fracture)
- Pathologic fractures
- Surgery to bone (to treat or prevent fractures)
- Spinal cord compression (→ paresthesia, incontinence, paralysis)
 SREs occur in up to 64% of patients with mBC (if not treated with BMAs)
 BMAs effect → pain reduction, prevention of SREs, treatment of hypercalcemia
PATHOLOGIC FRACTURE

35. BONE-MODIFYING AGENTS
- ZOLEDRONIC ACID (Zometa) -
 Schedule: 1 vl 4 mg e.v. q28, for 2 years
 Toxicity: hypocalcemia, nephrotoxicity, ONJ
Data on file, Novartis

36. BONE-MODIFYING AGENTS
- DENOSUMAB (Xgeva) -
 Schedule: 1 vl 120 mg s.c. q28, for 2 years
 Toxicity: hypocalcemia, ONJ
Stopeck AT, JCO 2010
Data on file, Amgen

37. OSTEONECROSIS OF THE JAW (ONJ)
Exposure of mandibular or maxillary bone
through lesions in the gums that do not heal
Pain, inflammation of the surrounding soft
tissue, secondary infection or drainage may or
may not be present

38. Zoledronic Acid in the early breast cancer?
 DTCs have been found in the bone marrow (BM) of patients with breast cancer and are an independent prognostic indicator
of increased risk of distant disease development and death
 Patients with detectable DTCs after cytotoxic chemotherapy have a high risk of recurrence Braun S, NEJM 2005
Zoledronic acid decreases the proportion
of patients with DTCs in the BM
Aft R, Lancet Oncol 2010
Rack B, Anticancer Res
2010
no clinical benefit from the addition of
Zoledronic acid to standard adjuvant
treatments for early breast cancer
Coleman R, Lancet Oncol 2014

39. CANCER CACHEXIA
Loss of weight and muscle mass, with or without the loss of
fatty mass, often associated with anorexia, inflammatory
processes, insulin resistance and increased tissue protein
turnover rates
Is associated with poor tolerability of cancer treatment
and reduced quality of life and survival expectations

40. CAUSES OF DEATH IN PATIENTS WITH ADVANCED BREST CANCER
Liver insufficiency
Respiratory insufficiency
Cardiocirculatory failure
Brain metastasis
Infections
Thrombosis or bleeding
Treatment complications