MM - 2013-03-21 - Systemic Therapies For BC

Systemic therapies for breast cancer
MIHAI MARINCA
Department of Medical Oncology
Gr. T. Popa University of Medicine & Pharmacy
Iasi Regional Oncology Institute
Iasi, Romania
March 21, 2013 Iasi, Romania

Outline
 Rationale
 Choice
 Neoadjuvant setting
 Adjuvant setting
 Metastatic setting
Outline
 Rationale
 Choice
Cancer
Merriam-Webster
Concise Encyclopedia
can·cer
noun \ˈkan(t)-sər\
Any of a group of more than 100 distinct

diseases that are characterized by the
uncontrolled multiplication of abnormal
cells. Cancerous cells and tissues have
abnormal growth rates, shapes, sizes,
and functioning […]
Tumorigenesis model: Cell
Paracrine
interaction
Tumorigenesis model: Cell types
Real world
Tumorigenesis model: Tissue
Cancer
Cancer
Tumor microenvironment
Hanahan D & Coussens LM, Cancer Cell 2012

Angiogenesis model
Ausprunk DH, Folkman J. Paku S, Paweletz N.

Microvasc Res, 1977 Lab Invest, 1991
Metastasis model
New paradigm?
Podsypanina K. et al. Science 2008.

Biologic hypothesis
Gene expression
Signalling pathways in cancer
Signalling pathways in breast cancer
IGFR
EGFR/ErbB
Plasma membrane
SOS
RAS
ER Cell survival P13-K RAF
Cytoplasm Akt p90RSK MEK
MAPK
Growth factor
Basal
ER p160 CBP transcription
Estrogen ER machinery
Nucleus Cell growth
Adapted from Johnston et al. ERE ER target gene
Clin Cancer Res, 2005 transcription
Signalling pathways in breast cancer
Aromatase Trastuzumab
IGFR
inhibitors
EGFR/ErbB
Plasma membrane
Pertuzumab
Lapatinib
SOS
RAS
ER Cell survival PI3K RAF
Cytoplasm Akt
Everolimus
p90 RSK
MEK
MAPK
Growth factor
Basal
Tamoxifen ER p160 CBP transcription
Estrogen ER machinery
Nucleus Cell growth
Adapted from Johnston et al. ERE ER target gene
Clin Cancer Res, 2005 Chemotherapy transcription
Malignant phenotype
Proliferation genes ER signalling

(GGI) Hormone
pathways
therapy
Chemotherapy
Apoptosis
HER-2 signalling
pathways
Immune response Trastuzumab
Invasive
capacity
Chemotherapy
Angiogenesis
Chemotherapy
Stem cells
Hanahan D & Weinberg R, Cell 2000

Malignant phenotype, revisited
Deregulating Avoiding
cellular immune
energetics destruction
Genome Tumor-
instability & promoting
mutation inflammation

Malignant phenotype, revisited

Outline
 Rationale
 Choice
Prognostic vs. predictive factors
 Prognostic factor = measurement taken at time of diagnosis or

surgery that is associated with patient’s anticipated outcome in the
absence of systemic therapy.
vs.
 Predictive factor = measurement that predicts response or lack of
response to a specific treatment.
Patient
population
at diagnosis
Prognosis
Patient Disease
population relapse /
at diagnosis Death
No treatment
Prognosis Prediction
Patient Disease Tumor

population relapse / response /
at diagnosis Death Survival
No treatment Treatment
Treatment
Prediction
Prognosis Prediction
Patient Disease Tumor

population relapse / response /
at diagnosis Death Survival
No treatment Treatment
Clinical & pathological factors
 Patient’s age (< 35 years vs. > 65 years)

 Histology (medullar/colloid/tubular vs. IBC)
 Disease stage (tumor size, N+ number? %?)
 Histologic grade (Scarff-Bloom-Richardson)
 ER (and PR) expression & intensity levels
 Her2/neu status (amplification? 17 polisomy?)
 Tumor involvement of lymphovascular spaces
 Resection margins (breast-conserving surgery)
 Treatment (quick access to care, adequacy of care,
optimal delivery of care, appropriate amount of care)
Other (potential) factors
 Markers of proliferation
– S-phase fraction (% cells labelling with thymidine/bromodeoxyuridine)
– cellular expression of Ki-67 or MIB-1 (% cells in the G1 phase)
– mitotic index
 Oncogene and TSG products
– Bcl-2 ↑, TP53 ↓, cyclin D1 ↑, Nm23 (p19) ↓
 Measures of the plasminogen activator system
– concentrations of urokinase plasminogen activator (UPA) and its inhibitor,
plasminogen activator inhibitor-1 (PAI-1)
 Measurements of tumor angiogenesis
– number of capillaries counted with IHC methods (labelled antibodies
against factor VIII in vascular endothelium)
 Detection of occult micrometastases in the bone marrow
– IHC techniques
Molecular factors
ER- ER+
PNAS vol 98, no 19, 10869-10874, 2001
Clinical evolution
Genomic factors
Genomic profiling (gene signatures)

– Genomic Grade Index (GGI) – 14 genes
– Recurrence Score (OncotypeDx®) – 21 genes
– p53 – 32 genes
– Amsterdam (MammaPrint®) – 70 genes
– Rotterdam – 76 genes
– Invasiveness – 186 genes
– Wound-response – 512 genes
…
Therapeutic decision
 BC – largely curable in initial stages

– frequently improved long-term survival in advanced stages
 Therapeutic conduct – conditioned by:

– Disease stage
– Performance index
– Age at diagnosis
– Menopausal status
– Hormonal dependence
– HER2/neu expression
 Operable breast cancer

– Stage 0, I, IIA, IIB, partially IIIA (T3 N1)
• Therapeutic objective – cure
• Initial treatment – surgery (breast-conserving surgery, BCS; or
modified radical mastectomy, MRM), sometimes CT
– subsequent therapy dependent on pathology data
inoperable breast cancer

Stages IIIA (T0-3 N2), IIIB (T4 N0-2) and IIIC (T0-3 N3)
Therapeutic objective – palliation, increased survival and/or cure
Initial treatment – systemic (CT/HT/targeted therapy)
 Favorable response surgery (usually MRM),
followed by adjuvant CT/HT + radiotherapy (RT)
 Unfavorable response RT (TD 50Gy)
» Favorable response MRM
» Unfavorable response continue RT (TD 70Gy)
 Operable breast cancer

– Stage 0, I, IIA, IIB, partially IIIA (T3 N1)
• Therapeutic objective – cure
• Initial treatment – surgery (breast-conserving surgery, BCS; or
modified radical mastectomy, MRM), sometimes CT/HT
– subsequent therapy dependent on pathology data
 Inoperable breast cancer
– Stages IIIA (T0-3 N2), IIIB (T4 N0-2) and IIIC (T0-3 N3)
• Therapeutic objective – palliation, increased survival and/or cure
• Initial treatment – systemic (CT/HT/targeted therapy)
 Favorable response surgery (usually MRM),
followed by adjuvant CT/HT + radiotherapy (RT)
 Unfavorable response RT (TD 50Gy)
» Favorable response MRM
» Unfavorable response continue RT (TD 70Gy)
 Metastatic or relapsed breast cancer

– Stage IV (T0-4 N1-3 M1) and
relapsed cases
• Therapeutic objective
– usually – palliation
– in a minority of patients (especially loco-regional relapse) – cure
• Initial treatment
– systemic therapy or
– RT, preceded or not by surgical excision of relapse
Theoretical model Decision-making process
Paternalism Physician makes decision
Physician as agent Physician makes decision after

considering patient input
Shared decision-making Physician and patient make

decision together
Informed Patient makes decision after

considering physician input
Consumerism Patient makes decision

Theoretical model Decision-making process Preference
Paternalism Physician makes decision 18%

Physician as agent Physician makes decision after 17%
considering patient input
Shared decision-making Physician and patient make 44%

decision together
Informed Patient makes decision after 22%

considering physician input
Consumerism Patient makes decision 9%

Evidence-based medicine
Systemic therapy protocols
 Many guidelines…
 Many regimens…
Outline
 Rationale
 Choice
Neoadjuvant therapy for breast cancer
 Indications and advantages:

– Women who desire BCS but are not candidates for the procedure (large
tumor relative to the size of the breast)
– Ability to determine if the tumor is sensitive to the particular agent
– Reduced need for surgical re-excision
– Less tumor volume needed to excise (improved cosmetic result)
– Possible survival advantage in premenopausal women
 Cancers most likely to benefit:
– Unicentric
– Higher-grade
– ER-negative (and Her2 negative)
Neoadjuvant therapy for breast cancer
 Contraindications for neoadjuvant therapy and/or BCS:

– Situations where an initial surgical approach is unlikely to successfully
remove all disease, or to provide long-term local control
– Multicentric carcinoma (separate quadrants)
– Diffuse malignant-appearing microcalcifications
– Extensive intraductal component (EIC) precluding a cosmetic resection
– Pregnancy
– History of collagen disease (scleroderma or lupus, but not RA)
– Prior chest irradiation
– Women who prefer treatment by mastectomy
Neoadjuvant setting: Chemotherapy
 Prospective RCTs of neoadjuvant chemotherapy (NACT)

– high clinical (cRR) and pathological response rates (pRR)
• EORTC (FEC): 49% cRR 4% pRR
• NSABP B-18 (AC): 79% cRR 13% pRR
• NSABP B-27 (AC→T): 91% cRR 19% pRR
– only 25-30% of patients not candidates for BCS at presentation had the
procedure after preoperative therapy
• difficulty of assessing the extent of residual viable tumor after NACT
• patchy nature of cancer cell death in response to NACT
– MRI promising compared with mammography and ultrasound, but
may underestimate or overestimate extent of residual disease.
van der Hage JA, et al. J Clin Oncol 2001 ;19(22):4224.

Fisher B, et al. J Clin Oncol 1988 ;16(8):2672.
Bear HD, et al. J Clin Oncol 2006;24(13):2019.
Neoadjuvant setting: Chemotherapy
 Meta-analysis of 9 RCTs of NACT compared with postoperative CTx

– no increase (or decrease) in survival
– elevated risk of local-regional recurrence (RR 1.22; 95%CI 1.04-1.45)
• some due to the inclusion of studies in which patients with cCR did
not have surgery, but apparent even in patients undergoing surgery
 NSABP B-18
– local recurrence rates 15% in patients requiring NACT vs. 7% in initial
candidates for BCS.
Mauri D, et al. J Natl Cancer Inst 2005;97(3):188.
Fisher B, et al. J Clin Oncol 1988;16(8):2672.
 Increased rates of local recurrence after NACT may reflect

differences in the meaning of a negative excision margin
– volume of tissue resected is smaller than original cancer volume
– evaluation of surgical margins and extent of viable tumor is essential
– percutaneous placement of marker clips prior to the initiation of CTx
 For women who are candidates for BCS at presentation, NACT offers
little benefit outside a clinical trial.
Neoadjuvant setting: Chemo + targeted therapy
 HER2 overexpression: trastuzumab (H) + NACT

 RCT (42 pts): 4 x paclitaxel → 4 x FEC ± H qw, 24 wks
• pCR rate 26% vs. 65%
• 22 additional pts with NACT+H: pCR rate 54.5%
• significant improvement in DFS (median FUP 36.1 months)
• no increase in cardiac dysfunction
Buzdar AU, et al. Clin Cancer Res 2007;13(1):228.
– Higher pCR rates confirmed in subsequent clinical trials

– Consistent with the survival benefit observed for trastuzumab when given
with CTx in the adjuvant setting
– May increase the rate of BCS
Neoadjuvant setting: Endocrine therapy
 Less experience!
 P3RCT (337 ER+ postmenopausal pts not candidates for BCS): TAM
20mg daily or LET 2.5mg daily, 4 mos
– BCS in 35% and 45%, respectively
– higher RR to LET particularly in tumors overexpressing HER1 or HER2
Eiermann W, et al. Ann Oncol 2001;12(11):1527.
Ellis MJ, et al. J Clin Oncol 2001;19(18):3808.
 IMPACT: ANA 1mg daily, TMX 20mg daily, or ANA+TAM, 3 mos

– BCS in 44%, 31% and 24%, respectively (p=0.23)Smith IE, et al.. J Clin Oncol 2005;23(22):5108.
 pCR is rare with the short duration of treatment used in the
neoadjuvant setting and does not appear to have the same
prognostic significance as with NACT; failure to achieve CR should
not be interpreted as evidence of resistance to endocrine therapy.
 Preoperative Endocrine Prognostic Index (PEPI): combination of
molecular and clinical factors appearing to predict benefit from ETx.
Ellis MJ, et al. J Natl Cancer Inst 2008;100:1380-8.
Outline
 Rationale
 Choice
Adjuvant setting
 Goal: to prevent BC recurrence by eradicating micrometastatic

deposits of tumor present at the time of diagnosis.
– Approximately half of the recent decline in BC mortality in the US and
Western Europe has been attributed to the widespread use of adjuvant
therapy. Berry DA, et al. N Engl J Med 2005;353(17):1784.
 3 systemic treatment modalities widely used as adjuvant therapy in

current practice:
– (1) endocrine treatments (tamoxifen, AIs, or ovarian suppression) for
HR+ tumors (either for ER, PR, or both)
– (2) anti-HER2 therapy (trastuzumab) for tumors overexpressing HER2
– (3) chemotherapy, used irrespective of tumor HR or HER2 status,
based largely on features such as tumor size, nodal status, and the
patient’s other health considerations.
Adjuvant setting: Endocrine therapy
 Tamoxifen (TAM) – historic standard

 EBCTG meta-analysis: >60 trials, >80000 women, 15 yrs FUP
– TAM administered for 5 years
• 41% reduction in the annual rate of BC recurrence (HR 0.59)
• 34% reduction in the annual death rate (HR 0.66)
• Durable gains independent of patient age or menopausal status,
nodal status, and use of adjuvant CTx
Early Breast Cancer Trialists Group. Lancet 2005;365(9472):1687.
– Shorter durations – also beneficial, but with less impact

– Extended duration in patients without evidence of tumor recurrence – no
further improvements in DFS or OS
Bryant J, et al. J Natl Cancer Inst Monogr 2001;30:56.
– Not effective in preventing recurrence of HR– BC

Fisher B, et al. J Clin Oncol 2001;19(4):931.
IBCSG. J Natl Cancer Inst 2002;94(14):1054.
 Aromatase inhibitors (AI) – clinical studies
HR for Absolute Difference
Timing/Setting Trial AI n DFS in DFS (%)
Upfront; y 0 ATAC ANA 9,366 0.87a 2.8 @ 5 y
BIG 1–98 LET 8,010 0.81 2.6 @ 5 y
Sequential; after 2–3 y of TAM IES EXE 4,742 0.68 4.7 @ 3 y
ARNO/ABCSG ANA 3,224 0.60 3.1 @ 3 y
Extended; after 5 y of TAM MA17 LET 5,187 0.58 4.6 @ 4 y
NSABP B-33 EXE 1,598 0.68 2.0 @ 4 y
Howell A, et al. Lancet 2005;365(9453):60.

Thurlimann B, et al. N Engl J Med 2005;353(26):2747.
Coombes RC, et al. N Engl J Med 2004;350(11):1081.
Jakesz R, et al. Lancet 2005;366(9484):455.
Goss PE, et al. J Natl Cancer Inst 2005;97(17):1262.
Mamounas EP, et al. Breast Cancer Res Treat 2006;100(suppl 1)(abst 49).
 AI to be used in most postmenopausal women with early-stage HR+

BC, but many critical questions still open
– up-front or switch?
– duration?
• studies of extended ETx – ongoing benefits beyond 5 years after
diagnosis, but safety and efficacy data exist for a maximum duration
of 5 years Goss PE, et al. J Natl Cancer Inst 2005;97(17):1262. [
Mamounas EP, et al. Breast Cancer Res Treat 2006;100(suppl 1)(abst 49).
 Differences in side effect profiles between tamoxifen and AI therapy

may inform treatment selection.
 TAM remains the treatment of choice in pre- or perimenopausal
women or where is question of residual ovarian function
– In particular, women with CTx-induced amenorrhea are not suitable
candidates for AI treatment.
Smith IE, et al. J Clin Oncol 2006;24(16):2444.
 Role of ovarian suppression (OvS) plus TAM or CTx – still unclear

– effective adjuvant therapy for premenopausal women
– at least as effective as adjuvant CTx in preventing BC recurrence
 Early RCTs
– not limited to patients with HR+ tumors, or failed to incorporate TAM, or
included CTx for younger women
 Recent observations
– Very young women (<35 years) appear to have a substantially worse
prognosis than patients who do enter menopause with CTx
– RCT: CTx alone, CTx plus OvS, and CTx plus OvS plus TAM
• addition of TAM clearly improved results
• younger women (<40 years) appeared to benefit from OvS
• study design did not address whether OvS would add to TAM benefits
– The Adjuvant Breast Cancer Ovarian Ablation or Suppression Trial: TAM
alone vs TAM plus OvS in premenopausal women
• no substantial improvement in DFS
• only 40% of patients were ER+, and 80% also received adjuvant CTx
Adjuvant setting: Chemotherapy
 Multiple cycles of polychemotherapy – well established strategy for

lowering the risk of BC recurrence and improving survival.
 Initial trials – high risk, N+ BC; subsequent trials – lower risk, N– BC
 Long-term FUP (Oxford overview) – benefit irrespective of age, ER
status, adjuvant ETx
– advantages for multiple cycles (4-8) compared with single-cycle
regimens.
– superiority of anthracycline-based CTx compared with CMF-based,
nonanthracycline regimens.
 Current challenges:
– to select subsets of patients that might preferentially benefit from CTx
or conversely be spared adjuvant CTx
– to optimize the dosing and scheduling of CTx
 Introduction of taxanes into early-stage BC treatment – important

advance
 First report = CALGB 9344: doxorubicin dose escalation and
incorporation of sequential paclitaxel after 4 cycles of AC
– sequential paclitaxel therapy improved DFS and OS in N+ BC
 Other studies – incorporation of taxanes as substitutes or sequential
additions to anthracycline-based regimens
– use of taxanes can contribute to significant improvement in outcomes,
especially among women with N+ BC
 RCT: AC followed by either T or P (taxanes given either q3w or qw)
– no significant differences between the taxanes in BC recurrence.
 Ongoing studies: TAC vs. AC → P q2w
 Chemotherapy dose and schedule – major area of clinical

investigation
 Dose escalation of cyclophosphamide or doxorubicin
– no lower risk of recurrence
 RCT: paclitaxel or docetaxel q3w vs. AC → taxane qw
– modest absolute advantages (NS) with weekly paclitaxel and q3w
docetaxel compared with the other treatment schedules.
 Neoadjuvant study: weekly paclitaxel yielded superior rates of pCR
compared with paclitaxel q3w
 CALGB 9741: AC → paclitaxel q3w or q2w at the same doses
– accelerated CTx led to lower risk of recurrence and improved survival
– no difference between concurrent (AC → P) or sequential CTx (A/P → C)
 CTx schedule, particularly with taxanes, may have an impact on
antitumor efficacy.
 Growing interest in adjuvant regimens that might spare patients

exposure to anthracycline-based CTx
 Historical options: CMF – equivalent to AC
 More recently: TC vs. 4 x AC
– 1,016 women with N– or 1-3 N+ (intermediate-risk)
– improvement in DFS and OS with TC
 Among higher risk patients, it is unclear if anthracyclines can be
safely omitted.
 NSABP B-30: AC → T vs. 4 x TAC vs. 4 x AT in N+ BC
– sequential AC → T superior to 4 x TAC
– 4 x TC might not be sufficient for higher risk N+ BC patients (?)
 Clinical studies and retrospective analyses have shown that CTx can
be of benefit to women with N+ and N–, ER+ or ER– BC, regardless
of age or menopausal status, even in tumors 1 cm or less
 Should specific regimens be employed or can adjuvant CTx be
disregarded in certain clinically-/biologically defined subgroups?
– CTx leads to statistically significant gains in relative risk reduction, often
translating into very small differences in absolute risk of recurrence,
especially in earlier stage disease or if adjuvant ETx improves outcome
– many CTx trials (particularly those involving ER+ tumors) are
confounded by the endocrine effects of CTx-induced amenorrhea
– most RCTs do not take into account the molecularly defined BC subsets
(“all comers”) and over-/underestimate CTx benefits in certain subtypes
– where absolute advantages of CTx are modest, weighing patient
preferences and directly quantifying benefits for specific patients led to
further individualization of CTx choices.
 HR status may be an important predictor of benefit from CTx.

– Retrospective analyses in N– BC: ER– tumors derive substantial benefit
from the addition of CTx to TAM
– A retrospective review of CALGB trials for N+ BC: gains of CTx are most
noticeable among patients with ER– tumors
– Not all retrospective studies have shown a clear relationship between ER
status and the benefit of CTx, and precise thresholds of ER expression
are not well established.
 HER2 was widely studied as a predictor of benefit from adjuvant CTx.
– HER2 overexpression may be associated with a relative benefit from
anthracycline-based CTx, as opposed to HER2– tumors
– Taxanes may be especially critical in tumors that either lack ER
expression or express HER2
– The reported interactions are not uniform across all trials and are largely
derived from unplanned, retrospective analyses, which also predate the
widespread use of adjuvant trastuzumab.
Adjuvant setting: Targeted therapy
 HER2 expression – historically adverse prognostic factor

– higher risk of recurrence
– early risk of recurrence
– relative resistance to CMF-based chemotherapy.
– relative resistance to adjuvant ETx even when hormone receptors are
present.
 2005: reports from 5 RCTs that examined the addition of trastuzumab
to CTx as adjuvant treatment for HER2 overexpressing BC
– significant improvements in DFS (reduction in risk of 50% on average)
and in OS, even after a short duration of follow-up.
– Subset analyses: comparable relative risk reduction regardless of tumor
size, nodal status, or HR status
 Rapid incorporation of trastuzumab into standard treatment
recommendations for women with HER2-positive BC.
Chemotherapy HR for HR for
Trial n (CTx) Regimen Trastuzumab Regimen DFS OS

NSABP B-31/
NCCTG N9831 3,351 AC → P 1 year concurrently with CTx (P!) 0.48 0.67
HERA 3,401 Various 1 year sequentially after CTx 0.64 0.63

9 weeks concurrently with CTx
FinHER 232 V or D → FEC (V or D!) 0.42 0.41
BCIRG 006 3,222 AC → D 1 year concurrently with CTx (D!) 0.61 0.59
1 year concurrently with CTx
CbD vs. AC → D (CbD!) 0.67 0.66
Romond EH, et al. N Engl J Med 2005;353(16):1673.

Piccart-Gebhart MJ, et al. N Engl J Med 2005;353(16):1659.
Joensuu H, et al. N Engl J Med 2006;354(8):809.
Slamon D, et al. Breast Cancer Res Treat 2006;100(suppl 1):52.
Smith I, et al. Lancet 2007;369(9555):29.
 Key questions regarding optimal use of adjuvant trastuzumab

– Duration of trastuzumab therapy (conventionally 1 year)
• Length of treatment arbitrarily chosen in the major adjuvant trials.
• FinHER: benefit for trastuzumab despite the short treatment exposure
• HERA: 1 year is better than 2 years of trastuzumab
– Delivered sequentially after CTx (HERA trial) or concurrently with CTx
(NSABP B-31/NCCTG N9831, and BCIRG trials).
• Limited direct comparisons in NCCTG N9831 suggest that for women
receiving anthracycline- and taxane-based CTx, concurrent
trastuzumab during the taxane phase of treatment yielded superior
results compared with sequential therapy.
– Effectiveness in the absence of CTx
– Optimal CTx backbone
– Role for women with smaller (particularly <1cm) node-negative tumors.
Outline
 Rationale
 Choice
Metastatic setting
 Metastatic (stage IV) breast cancer is defined by tumor spread

beyond the breast, chest wall, and regional lymph nodes.
 When radiologic or clinical findings are equivocal, tissue biopsy is
imperative, and ER, PR, and HER2 should be redetermined.
 Therapy is not generally considered curative, and should be
individualized
 Treatment goals in metastatic breast cancer (MBC):
– prolongation of life
– control of tumor burden
– reduction in cancer-related symptoms or complications
– maintenance of quality of life and function
 Measured end points for efficacy of therapy for MBC:
– response rate (RR)
– time to tumor progression (TTP)
– overall survival (OS)
Metastatic setting
 Prognostic factors in advanced/recurrent/metastatic breast cancer

– Tumor biology (grade, ER status, HER2 status)
– Performance status
– Cancer-related symptoms
– Disease-free interval
– Prior adjuvant therapy
– Prior therapy for metastatic disease
– Response/duration of prior therapy for metastatic disease
– Sites of recurrence
– Number of sites of recurrence
Metastatic setting: Special sites
 Lytic bone metastases

– IV bisphosphonates (pamidronate or zoledronic acid) lessen the pain
associated with bone lesions and prevent complications of skeletal
metastases (fracture, hypercalcemia).
– Denosumab, a RANKL inhibitor administered SC, had a modest
improvement in skeletal-related events compared to zolendronic acid,
with no evidence of renal dysfunction Stopeck AT, et al. J Clin Oncol 2010;28:5132-9.
– EBRT at selected tumor sites

– surgical stabilization or repair of the bone or joint when necessary.
 Brain metastases
– Therapy remains inadequate, but generally includes WBRT, possibly
surgical resection or stereotactic RT to specific lesions.
– Leptomeningeal disease may achieve symptomatic improvement with
WBRT, or intrathecal CTx with methotrexate or cytarabine
– Some systemic therapies (ETx, anthracyclines, alkylators, capecitabine,
and lapatinib) may have antitumor activity in the brain, but none is
“standard of care” or a substitute for local therapy.
Metastatic setting: Endocrine therapy
 The first therapy for advanced breast cancer was oophorectomy, and
in the 100 years since then, there has been steady progress in the
development of hormonal therapy for metastatic disease.
 Treatment options
– Ovarian suppression/ablation
• premenopausal women
– Selective estrogen receptor modulators
• tamoxifen, toremifene
– Aromatase inhibitors
• anastrozole, letrozole, exemestane
• postmenopausal women
– Antiestrogens
• fulvestrant
• postmenopausal women
– Progestins
• megestrol, medroxyprogesterone
– Other steroid hormones
• high-dose estrogens, androgens
• principally of historical interest
 Single-agent therapy is the standard approach; combining endocrine

agents has not been shown to improve outcomes.
 Many women will be candidates for multiple, sequential types/lines of ETx.
– First-line treatment is associated with 8-12 months of tumor control, and
second-line treatment with 4-6 months.
– Individual patients may experience substantially longer TTP.
– Sequential single-agent second- and third-line ETx are often effective, although
typically for shorter durations than initial therapy.
 ETx can cause regression of soft tissue and bone and visceral metastases.
 Eventually most women with ER+ MBC will progress despite first-line ETx.
 Resistance to treatment does not seem to be associated with loss of
hormone receptor expression by the tumor cells.
 Indications for (induction) CTx :
– symptomatic tumor progression
– pending visceral crisis
– resistance to multiple endocrine therapies
 Tamoxifen – historic standard as treatment for ER+ MBC

– 50% RR and median duration of response of 12-18 months in treatment-
naive patients
– Flare reactions (5-10%) often signal exquisite tumor sensitivity to ETx,
but must be distinguished from overt tumor progression
 In premenopausal women with MBC, OvS plus TAM can improve
survival, but premenopausal women with metastatic tumor despite
TAM use are candidates for OvS and AI therapy.
 Most women with recurrent BC will be postmenopausal and are
candidates for either TAM, AIs, fulvestrant or progestational agents.
– AIs preferred initial agents if TAM given in the adjuvant setting, and may
have modest clinical advantages also in women naive to antiestrogens
– Fulvestrant has comparable activity to AIs in TAM-treated women
 The optimal sequencing of ETx for postmenopausal women treated
with adjuvant AIs is not clear
– TAM, fulvestrant, progestins, possibly different AI are reasonable options
Metastatic setting: Chemotherapy
 CTx remains a mainstay of treatment in MBC, irrespective of HR

status, and is the backbone of many novel treatments.
 Tumor response to CTx is a surrogate for longer control and survival
– First-line treatment is associated with higher RR and longer tumor control
than second-line, and so forth.
– The magnitude of gain must be realistically weighed against the side
effects of treatment.
 Single-agent CTx remains the preferred approach
– facilitates better understanding of which drugs are contributing to benefit
or side effects, allowing appropriate treatment modification
– is generally associated with less toxicity
 Patients with extensive visceral disease or pending visceral crisis
may preferentially require initiation of combination CTx.
 There is no one single path or algorithm for treating MBC patients.
Metastatic setting: Chemotherapy
 Recent advances
– Capecitabine has clinical activity in anthracycline- and taxane-resistant
BC and improves response and survival as first-line treatment when
added to single-agent docetaxel
– Gemcitabine yields higher RR and survival when paired with paclitaxel
compared with paclitaxel therapy alone
– Ixabepilone, an epothilone chemotherapy agent, has substantial activity
as a single agent or in combination with capecitabine in anthracycline-
and taxane-resistant BC
– Eribulin, a synthetic analog of halochondrin B, is a non-taxane
microtubule dynamics inhibitor extracted from a marine sponge
• EMBRACE (locally recurrent or MBC with at least 2 prior regimens):
mOS 13.2 vs. 10.65 months in the ‘standard of care’ arm (p=0.04).
Cortes J, et al. Lancet 2011;377:914-23.
– Dose escalation of taxane therapy with paclitaxel has not shown clinically
important improvements, but weekly paclitaxel improves RR and TTP
compared with q3w administration
– High-dose CTx with autologous bone marrow or stem cell support did not
demonstrate clinical improvement
Metastatic setting: Anti-HER2 therapy
 Trastuzumab plus first-line CTx for HER2+ MBC improved RR, TTP, and
OS
– taxanes, vinorelbine, platinum analogs and other CTx agents have shown
clinical activity and safety when paired with trastuzumab
– concurrent administration of trastuzumab with anthracyclines should be
avoided
– the role of combination CTx plus trastuzumab remains controversial
– the optimal timing for initiation of trastuzumab or the optimal CTx backbone
are not well characterized
– in some settings (selection unclear), trastuzumab may be considered as
single-agent therapy or in combination with endocrine therapy
– the role of treatment beyond progression in the metastatic setting has not
been studied, but recent data suggest that ongoing anti-HER2 treatment may
be important for patients with tumor progression on trastuzumab.
 Lapatinib is a novel dual-TKI that targets both the HER2 and EGFR TK
signaling pathways
– studied as second-line anti-HER2 therapy for patients progressing after
chemotherapy and trastuzumab
– combination of lapatinib plus capecitabine was associated with a longer period
of tumor control and improvement in RR, but not survival.
Metastatic setting: Antiangiogenesis therapy
 VEGF-targeted therapies are approved for use in advanced

colorectal, non-small cell, and renal carcinomas. Experience to date
suggests that similar principles hold for patients with MBC.
 Bevacizumab is the most studied antiangiogenic agent in BC.
– initial RCT (prior anthracycline-/taxane-based CTx): bevacizumab plus
capecitabine did not improve TTP or survival, but modestly enhanced RR
– ECOG E2100: paclitaxel ± bevacizumab as first-line treatment for MBC –
clinically meaningful improvements in RR and TTP
– Subsequent studies in the first- or second-line setting (RIBBON-1,
RIBBON-2) led to improved TTP, but not OS (except a subgroup analysis
of TNBC in RIBBON-2). Robert NJ, et al. J Clin Oncol. 2011;29:1252-60.
 To date there are no specific markers that identify tumors or patients

likely to benefit from antiangiogenic therapy.
 It is not clear whether CTX is an mandatory for achieving benefit with
these agents.
Metastatic setting: Emerging agents
 Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors

– olaparib was studied in patients with BRCA1- or BRCA2-associated
cancers, showing robust responses
– BSI-201 with gemcitabine plus carboplatin improved RR, TTP, and OS in
TNBC patients in phase 2, but yielded no OS advantage in a phase 3
trial
O’Shaughnessy JA et al. Proc. of ASCO 2011
 Novel classes of anti-HER2 drugs

– pertuzumab, which binds to HER2 and HER3, has shown activity in
combination with trastuzumab in trastuzumab-resistant patients
– T-DM1, a derivative of trastuzumab created by chemical linkage with the
maytansine CTx moiety, has also been shown to achieve responses in
trastuzumab-resistant BC
– neratinib, a dual-kinase inhibitor that targets both the HER2 and EGFR
proteins, has activity in both trastuzumab-treated and trastuzumab-naïve
HER2-positive BC.
Metastatic setting: Pipeline
 2012: 479 drugs in development  247 different targets, divided

for the treatment of BC, plus 192 into 61 classifications of
suspended and ceased drugs. molecular function:
Auxiliary transport protein activity Molecular function unknown
Catalytic activity Motor activity
 Pipeline Breakdown
Cell adhesion molecule activity Oxidoreductase activity
Chaperone activity Peptidase activity
Chemokine activity Peptide hormone
– Marketed # 54 Complement activity

Cysteine-type peptidase activity
Peroxidase activity
Phosphoric diester hydrolase activity
Cytokine activity Protein binding
– Registered # 1 DNA binding
DNA repair protein
Protein serine/threonine kinase activity
Protein threonine/tyrosine kinase activity
– Pre-registration # 2 DNA topoisomerase activity

DNA-directed DNA polymerase activity
Protein-tyrosine kinase activity
Receptor activity
Extracellular ligand-gated ion channel activity Receptor binding
– Phase III # 23 Extracellular matrix structural constituent
G-protein coupled receptor activity
Receptor signaling complex scaffold activity
Receptor signaling protein serine/threonine kinase activity
– Phase II # 167 Glutathione transferase activity

Growth factor activity
RNA binding
RNA-directed DNA polymerase activity
Growth factor binding Serine-type peptidase activity
– Phase I # 94 Hormone activity
Intracellular ligand-gated ion channel activity
Structural constituent of cytoskeleton
Structural molecule activity
– Preclinical # 137 Ion channel activity

Isomerase activity
Superoxide dismutase activity
T cell receptor activity
Kinase activity Transcription factor activity
– No Data # 1 Kinase binding
Kinase regulator activity
Transcription regulator activity
Transferase activity
– Suspended # 7 Ligand-dependent nuclear receptor activity

Ligase activity
Translation regulator activity
Transmembrane receptor activity
Lipid kinase activity Transmembrane receptor protein tyrosine kinase activity
– Ceased # 185 Lipid phosphatase activity
Metallopeptidase activity
Transporter activity
Voltage-gated ion channel activity
Systemic therapy for breast cancer
Systemic therapy for breast cancer
P.A., female, aged 50, Iasi
 Presented for upper outer quadrant indolor mass in the right breast with
enlarged axillary lymph nodes, clinically apparent since December 2007.
 HISTORY
• no family history of cancers
• first period: age 12, last period: May 2008; pregnancies: 2 (age 28, 31),
abortions: 2
• no personal history of relevant diseases/ hospital admissions
 DIAGNOSIS
May 2008
• Surgery service admission/ clinical evaluation:
• 3.5/4 cm mass in the upper outer quadrant of the right breast, slightly
adherent to skin
• associated fixed, matted right axillary lymph nodes
• Fine-needle aspiration biopsy:
• malignant cytology (class V)
 TREATMENT (I)
August 2008
• Surgery – quadrantectomy + axillary clearance
Pathology report: invasive ductal carcinoma NOS, pT1 N1a M0 G2 L1 V1
• 1/1 cm tumor, negative resection limits
• 3 out of 10 axillary lymph nodes with large metastasis
• invasion of the subcutaneous tissue, vascular emboli, no perineural invasion
Immunohistochemistry report:
• ER positive (35%), PR positive (50%)
• c-ErbB2 negative (1+)
ER+
September 2008
• Oncology admission/ clinical evaluation:
• ECOG PS 0, no pain HER-2/neu 1+
• Biologic work-up – normal

• Postoperative thoracic scar – normal aspect
• Abdominal ultrasound, chest X-ray – no apparent secondary lesions
 QUESTION 1
HOW WOULD YOU TREAT?
A. Start adjuvant chemotherapy (anthracycline-based regimen) +

radiation therapy + hormone therapy
B. Start adjuvant chemotherapy (CMF regimen) + hormone therapy
C. Start adjuvant radiation therapy + hormone therapy
D. Start adjuvant hormone therapy: tamoxifen
E. Start adjuvant hormone therapy: aromatase inhibitors

 TREATMENT (II)
October-December 2008
• Adjuvant chemotherapy
• CA protocol – cyclophosphamide 600 mg/m2 + adriamycin 60
mg/m2, 3-weekly schedule, 4 cycles
January-March 2009
• Adjuvant radiation therapy
• conventional irradiation, TD 50 Gy/25 fr., breast + axillary field
March 2009
• Adjuvant hormone therapy
• tamoxifen 20 mg/day
2009-2011
• 3-6-monthly evaluations (clinical, biologic and imagistic)
• no signs of disease progression
February 2011
• Clinical evaluation:
• ECOG PS 1, progressively worsening low-back and right leg pain.
Denies incontinence of bowel or bladder.
• Lumbar spine X-ray:

• dorso-lumbar scoliosis
• reduction of the L3-L4 intervertebral space
• no aspects suggestive of bone metastases
 QUESTION 2
A. Order a bone scan
B. Recommend lumbar magnetic resonance imaging (MRI) to exclude

spinal cord compression
C. Prescribe nonsteroidal anti-inflammatory drugs (NSAIDs)
D. Evaluate serum and urine protein electrophoresis
E. Perform a CT-guided biopsy

February-March 2011
• NSAID treatment
• Pain diminished in intensity, still not controlled
March 2011
• Bone scan:
• Multiple sites of pathologic increased uptake:
skull, vertebral spine, bone pelvis, clavicle,
right humerus, left femur, left tibia
– bone metastases
 QUESTION 3
A. Start 2nd line hormone therapy (aromatase inhibitor) +

bisphosphonate + palliative radiation therapy
B. Initiate 2nd line chemotherapy (taxane) + bisphosphonate
C. Start 2nd line chemotherapy + 2nd line hormone therapy +

bisphosphonate + palliative radiation therapy
D. Recommend orthopedic surgery for internal fixation
E. Initiate palliative radiation therapy

 TREATMENT (III)
March 2011
• Palliative radiation therapy
• conventional irradiation, TD 20 Gy/5 fr., anterior femoral field
! during irradiation – pathologic fracture: left femur, medium third
• Orthopedic surgery – osteosynthesis by metallic rigid nail
• Starts 2nd line hormone therapy

• letrozole 2.5 mg/day
• Starts bisphosphonates
• pamidronate 90 mg/day I.V., on a monthly basis
• Continues pain therapy

• NSAIDs
• tramadol P.O. 50 mg tid
September 2011
• ECOG PS 1, pain controlled
• Liver work-up – modified:

• γGT = 204 UI/l
• Abdominal ultrasound:
• Liver – hipoechogenic nodules, segment 6 = 3.4 cm; segment 8 = 2
cm; segment 2 = 1.8 cm (metastases)
 QUESTION 4
A. Start 2nd line chemotherapy (capecitabine/ docetaxel/ liposomal

doxorubicin)
B. Start 3rd line hormone therapy
C. Consider transarterial hepatic chemoembolization (CHEAT)
D. Consider surgical resection of hepatic lesions
E. Best supportive care

 TREATMENT (IV)
October 2011
• Starts 2nd line chemotherapy
• capecitabine 1250 mg/m2 x 2 P.O., D1-14, 3-weekly schedule
• Continues 2nd line hormone therapy (letrozol) and
bisphosphonates (pamidronat), unchanged dosage and schedule.
December 2011
• ECOG PS 1, lumbar pain relatively controlled
• Liver work-up – normal:
• γGT = 33 UI/l
• Liver metastases – segment 6 = 2.7 cm, segment 8 = 2.9 cm, segment
2 = 2.0 cm (stable disease)
January 2012
• Left femur X-ray:
• Median osteoblastic cortical bone lesion (posttraumatic pathological
bone lesion?)
• Lumbar spine X-ray:

• Osteoblastic bone lesions of the L1 vertebral body (slightly
collapsed) and the L2 right vertebral pedicle
• Bone pelvis X-ray:

• Osteoblastic bone lesions of the right ramus ischium (2 cm) and of
the lateral aspect of the left sacro-iliac articulation (diffuse)
 QUESTION 5
A. Palliative radiotherapy
B. Start 3rd line chemotherapy
C. Consider an orthopedic intervention
D. Continue hormone therapy
E. Consider all the above mentioned options

 TREATMENT (V)
February 2012
• Palliative radiation therapy
• conventional irradiation, TD 20 Gy/5 fr., dorso-lumbar vertebral field
• Continues 2nd line chemotherapy (capecitabine), 2nd line

hormone therapy (letrozol) and bisphosphonates (pamidronat),
unchanged dosage and schedule

• NSAIDs
• tramadolum P.O. 50 mg tid
May 2012
• Liver metastases – segment 6 = 2.8 cm; segment 8 = 1.8 cm; segment
2 = 1.9 cm (stable disease)
September 2012
• Liver metastases – stable disease
• Dorso-lumbar spine X-ray:
• Multiple osteoblastic bone lesions (D7-D12, L1-L2, iliac bones,
sacrum)
• Left femur X-ray:
• Osteosynthesis nail overpasses the femoral head by approximately 2
cm
January 2013
• Liver – stable disease
• Bone X-rays:
• stable disease
 TREATMENT (present)
• Continues 2nd line chemotherapy (capecitabine), 2nd line
hormone therapy (letrozol) and bisphosphonates (pamidronat),
unchanged dosage and schedule
• NSAIDs
• tramadolum 100 mg bid

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Systemic therapies for breast cancer

March 21, 2013 Iasi, Romania

Any of a group of more than 100 distinct

Hanahan D & Coussens LM, Cancer Cell 2012

Ausprunk DH, Folkman J. Paku S, Paweletz N.

Podsypanina K. et al. Science 2008.

Cytoplasm Akt p90RSK MEK

Proliferation genes ER signalling

Hanahan D & Weinberg R, Cell 2000

Hanahan D & Weinberg R, Cell 2011

Hanahan D & Weinberg R, Cell 2011

 Prognostic factor = measurement taken at time of diagnosis or

Patient Disease Tumor

Patient Disease Tumor

 Patient’s age (< 35 years vs. > 65 years)

PNAS vol 98, no 19, 10869-10874, 2001

Genomic profiling (gene signatures)

 BC – largely curable in initial stages

 Therapeutic conduct – conditioned by:

 Operable breast cancer

inoperable breast cancer

 Operable breast cancer

 Metastatic or relapsed breast cancer

Theoretical model Decision-making process

Paternalism Physician makes decision

Physician as agent Physician makes decision after

Shared decision-making Physician and patient make

Informed Patient makes decision after

Consumerism Patient makes decision

Theoretical model Decision-making process Preference

Paternalism Physician makes decision 18%

Shared decision-making Physician and patient make 44%

Informed Patient makes decision after 22%

Consumerism Patient makes decision 9%

 Indications and advantages:

 Contraindications for neoadjuvant therapy and/or BCS:

 Prospective RCTs of neoadjuvant chemotherapy (NACT)

van der Hage JA, et al. J Clin Oncol 2001 ;19(22):4224.

 Meta-analysis of 9 RCTs of NACT compared with postoperative CTx

 Increased rates of local recurrence after NACT may reflect

 HER2 overexpression: trastuzumab (H) + NACT

– Higher pCR rates confirmed in subsequent clinical trials

 IMPACT: ANA 1mg daily, TMX 20mg daily, or ANA+TAM, 3 mos

 Goal: to prevent BC recurrence by eradicating micrometastatic

 3 systemic treatment modalities widely used as adjuvant therapy in

 Tamoxifen (TAM) – historic standard

– Shorter durations – also beneficial, but with less impact

– Not effective in preventing recurrence of HR– BC

 Aromatase inhibitors (AI) – clinical studies

HR for Absolute Difference

Timing/Setting Trial AI n DFS in DFS (%)

Upfront; y 0 ATAC ANA 9,366 0.87a 2.8 @ 5 y

BIG 1–98 LET 8,010 0.81 2.6 @ 5 y

Sequential; after 2–3 y of TAM IES EXE 4,742 0.68 4.7 @ 3 y

ARNO/ABCSG ANA 3,224 0.60 3.1 @ 3 y

Extended; after 5 y of TAM MA17 LET 5,187 0.58 4.6 @ 4 y

NSABP B-33 EXE 1,598 0.68 2.0 @ 4 y

Howell A, et al. Lancet 2005;365(9453):60.

 AI to be used in most postmenopausal women with early-stage HR+

 Differences in side effect profiles between tamoxifen and AI therapy

 Role of ovarian suppression (OvS) plus TAM or CTx – still unclear

 Multiple cycles of polychemotherapy – well established strategy for

 Introduction of taxanes into early-stage BC treatment – important