1) Breast cancer is the most common malignancy among females worldwide. Survival rates vary significantly based on cancer stage, with metastatic breast cancer having only a 26% 5-year survival rate. 2) Hormonal therapy is first-line treatment for hormone receptor-positive metastatic breast cancer. Tamoxifen and aromatase inhibitors are commonly used, with aromatase inhibitors showing improved outcomes compared to tamoxifen. Fulvestrant and newer targeted agents are options for progressed disease. 3) Chemotherapy is also used to treat metastatic breast cancer. Commonly used agents include taxanes like paclitaxel and docetaxel, anthracyclines like doxorubicin, and newer options

1. SYSTEMIC THERAPY OF
METASTATIC BREAST
CARCINOMA
DR SADIA SADIQ
PGR,RADIATION ONCOLOGY,INMOL

2. Breast cancer is the most common malignancy
among females all over the world

3. 5 YEAR SURVIVAL RATES
 The overall 5-year survival for all stages combined is 89%
[http://seer.cancer.gov/statfacts/html/breast.html].
 However, survival rates vary by stage. 5 year survivals:
[http://seer.cancer.gov/statfacts/html/breast.html].
LOCALIZED DISEASE 99%
REGIONAL DISEASE 85%
METASTATIC DISEASE 26%

4. Clinical Challenges
in the Management of MBC
 Individualizing treatment to specific cancer biology
 Reducing and managing toxicity of chemotherapies
 Understanding and then overcoming resistance to
chemotherapy and hormone therapy
 Impact in metastatic and adjuvant settings
 Increasing disease control and survival

5. METASTATIC DISEASE
 Patients with metastatic cancer can be divided into two
groups:
1. those with stage IV disease at presentation and
2. those who develop metastases after primary treatment.
 Biopsy is highly recommended for pathologic
confirmation of presumed metastatic breast cancer and
for marker investigations.

6.  The management of stage IV disease depends on the
site and extent of metastases, comorbid conditions, and
clinical tumor characteristics.
 Patients with delayed metastatic disease can be divided
into two groups, that is, so-called low-risk
 and/or high-risk patients,

7.  The low-risk group includes patients
1. who develop metastatic disease after a long
disease-free interval
2. those whose tumors are positive for hormone
receptors
3. those with bone-only disease, and
4. those without extensive visceral organ
involvement.

8.  Intermediate-risk or high-risk patients include
those
1. with rapidly progressive disease or
2. visceral involvement and
3. those with disease shown to be refractory to
hormonal manipulation by a prior therapeutic
trial.

9.  Low-risk patients who have hormone receptor–positive tumors
should be treated with a trial of hormone therapy.
 First-line hormonal therapy consists of an aromatase inhibitor or
 tamoxifen, with careful serial assessment of clinical and disease
responses.

10. • Second-line hormonal
agents
 The choice of second-line endocrine therapy depends on
the
 front-line endocrine agent used. Typically, if tamoxifen was used, the second-
line agent includes an aromatase inhibitor or fulvestrant (Faslodex) for
postmenopausal women.
 For premenopausal women, the choice may be megestrol (Megace) or induction
of menopause with an LHRH (luteinizing hormone–releasing hormone) agonist
with or without an aromatase inhibitor.
 If aromatase inhibitors were used as front-line agents for postmenopausal
women, second-line options can be to change treatment to include another
class of aromatase inhibitor, or fulvestrant, or tamoxifen.

12. TIMELINE OF DEVELOPMENT OF HORMONAL
AGENTS IN BREAST CANCER

13. AGENTS USED IN HORMONAL
THERAPY
 Selective Estrogen Receptor
Modulators (SERM)
 Tamoxifen
 Raloxifen
 Torimefene
 Anti Estrogens
 Fulvestrant
 Aromatase Inhibitors
 Letrozole
 Anastrazole
 Exemestane
 LHRH Agonists
 Leuprolide
 Goserlin
 Progestins
 Megestrol acetate
 Medroxyprogesterone acetate

14. HORMONAL THERAPY IN
METASTATIC SETTING
 Pre menopausal :
 Tamoxifen is the drug of choice
 Response rates range from 16% to 56% (Median 30%) – same as
ovarian ablative techniques.
 Overall mean Time to progression for patients with metastatic
disease treated with Tamoxifen is about 6 months
 Duration of response is between 12 and 18 months
 Tamoxifen plus castration has been shown to have better results
in a meta analysis

15. Ref : Facts and Controversies in Systemic Treatment of Metastatic Breast
Cancer ; CHANTAL BERNARD-MARTY, FATIMA CARDOSO, MARTINE J.
PICCART ; The Oncologist 2004;9:617-632

16. Ref : New directions in hormone therapy for metastatic breast cancer ; M. Namer ;
European Society for Medical Oncology
TAMOXIFEN + OVARIAN SUPRESSION

17. HORMONAL THERAPY IN
METASTATIC SETTING
 Post Menopausal
4 major phase III trials have directly compared
Tamoxifen against Aromatase Inhibitors (AI)
All have shown an improvement in time to
progression
The impact on Overall survival not clear however.
In the trial comparing Letrozole to Tamoxifen it was
shown that OS improved in the first 2 yrs.
However no benefit exists at 5yrs.

18. Ref : New directions in hormone therapy for metastatic breast cancer ; M. Namer ;
European Society for Medical Oncology

19. HORMONAL THERAPY IN
METASTATIC SETTING
 In case of progression on Tamoxifen /
Aromatase Inhibitors
Anti androgens – FULVESTRANT
Progestins
Other methods
Ovarian Suppression/Ablation :
Medical/Surgical/Radiation Therapy

20. EFFECT TRIAL..Fulvestrant in 2nd Line

21. Fulvestrant..1st Line
FACT TRIAL..-VE
SWOG S0226 TRIAL

22. MEGESTROL
 The most commonly used second-line hormonal
agents had been progestational drugs, such as
megestrol.
 Recent randomized trials have indicated that
fulvestrant or the aromatase inhibitors are equally
effective for palliation of metastatic disease, have less
toxicity, and may provide a survival advantage
compared with megestrol.

23. HORMONAL THERAPY IN
METASTATIC SETTING
 BOLERO 2 Trial :
 Randomized controlled Phase III trial
 Compared everolimus and exemestane versus exemestane and placebo in
hormone-receptor–positive advanced breast cancer who had recurrence or
progression while receiving previous therapy with a nonsteroidal aromatase
inhibitor in the adjuvant setting or to treat advanced disease (or both)

24. Despite the significant improvement seen in progression-free
survival, the addition of everolimus to exemestane did not confer a
statistically significant improvement in overall survvial.
Median overall survival in patients receiving everolimus plus
exemestane was 31.0 months compared to 26.6 months in patients
receiving placebo plus exemestane (HR = 0.89; 95% CI, 0.73–1.10;
log-rank P = .14)
BOLERO 2 TRIAL

25. CIRCULATING TUMOR CELLS
 A prospective, multicenter study assessed the role of circulating
tumor cells (CTCs) in predicting survival in 177 patients with
metastatic breast cancer before the start of a new treatment.
 Patients with CTC levels greater than five per 7.5 mL of whole blood
had a shorter median progression-free survival time (2.7 vs 7
months; P < .001) and shorter overall survival (10.1 vs > 18
months; P < .001) than did those with fewer than 5 circulating
tumor cells per 7.5 mL of whole blood.
 Of all the variables in the statistical model, levels of CTCs at
baseline and at the first follow-up visit were the most significant
predictors of progression-free and overall survival in this group of
patients.

26. CHEMOTHERAPY IN CA BREAST

27. CHOICE OF CHEMOTHERAPEUTIC
AGENT
 Many patients with recurrent disease will already have had substantial
anthracycline exposure from adjuvant chemotherapy, and retreatment with
doxorubicin or epirubicin is generally avoided.
 Taxane-based therapy is often considered for patients with anthracycline-
pretreated breast cancer; however, it is becoming increasingly common for
patients to have received both an anthracycline and a taxane in the adjuvant
setting.
 Time to recurrence is also an important consideration. If time to recurrence is
several years following adjuvant therapy, retreatment with prior active agents
may be desirable. If progression or disease recurrence takes place in a
relatively short time (i.e., <12 months), the use of different classes of classes of
agents is generally preferable.

28. Cytotoxic Therapy: Metastatic Breast Cancer
FDA approved drugs before 1994
 Methotrexate 1953
 Cyclophosphamide 1959
 Thiotepa 1959
 Vinblastine 1961
 5-Fluorouracil 1962
 Doxorubicin 1974

29. First-Line MBC
Single-Agent Response Rates
Treatment ORR (%)
Docetaxel1 (75-100 mg/m2) 40-68
Paclitaxel1 (175-250 mg/m2 3-24 h) 32-62
Doxorubicin4 43
Capecitabine3 30
Vinorelbine2 35-53
Gemcitabine2 18-37
Cyclophosphamide4 36
Fluorouracil4 28
Methotrexate4 26
Mitoxantrone4 27
1. Seidman AD, Clin Cancer Res 2.Vogel and Nabholtz. The Oncologist. 1999;4:17.
3. O’Shaughnessy et al. Ann Oncol. 2001;12:1247.4. Sledge. Cancer Control. 1999;6:17.

31. PACLITAXEL IN METASTATIC BREAST CA:
CALGB protocol 9840
 577 patients with
 metastatic breast cancer who had received one or two prior
regimens were randomized to receive
 standard (175 mg/m2) or weekly (80 mg/m2) paclitaxel.
 Weekly paclitaxel was shown to be superior with respect to
response rate (40% vs 28%; P = .017), TTP (9 months vs 5 months;
P = .0008), and
 overall survival (24 months vs 16 months).
 The authors concluded that weekly paclitaxel is superior to
standard paclitaxel in the management of metastatic breast cancer.
 Weekly paclitaxel caused more grade 3 sensory/motor neuropathy
and less grade 3 granulocytopenia.

32. DOCETAXEL IN METASTATIC
BREAST CA
 Docetaxel has demonstrated overall response rates of
41% in patients with doxorubicin-resistant disease.
 It has been shown to be superior to
mitomycin/vinblastine in patients who experienced
disease progression after being treated with an
anthracycline-based chemotherapy regimen.
 Docetaxel as a single agent has been shown to produce
objective responses in up to 60% of patients with
metastatic breast cancer that had not previously been
treated with chemotherapy.

33. DOCETAXEL ..FDA AA IN
METASTATIC BREAST CA..1996

34. Doce..RA..TAX304 Study
392
Patients with
Prior anthracycline
regimens
Docetaxel
203
Myt
+Vinblastine
189
TTP (months) 4.3 2.5
Risk Ratio
95% CI (RR)
0.75
0.61-0.94
P-value (log
rank)
p=0.01
Survival (months) 11.4 8.7
Risk Ratio*
95% CI (RR)
0.73
0.58-0.93
P-value (log
rank)
p=0.01
Docetaxel 100mg/m2
Q 3w
Mytomicin 12 mg/m2
Q 6 week
Vinblastin 6 mg/m2
Q 3 weeks

35. NAB-PACLITAXEL
 The approval in MBC was based on a randomized phase III trial of nab-paclitaxel
260 mg/m2 vs paclitaxel 175 mg/m2 every 3 weeks (q3w).
 Significantly less grade 4 neutropenia (9 vs 22%; P < 0.001) and more grade 3
sensory neuropathy (10 vs 2%; P < 0.001) were reported with nab-paclitaxel . Grade 3
sensory neuropathy in patients who received nab-paclitaxel improved to a lower grade
after a median of 22 days of treatment interruption.
Nab-pacli pacli P value HR
ORR 33% 19% 0.001
TTP 23w 17w 0.006 0.75
Median OS 56w 47w 0.024 0.73

36. More 5-FU in the tumour than
healthy tissue with TP-activated
Capecitabine
Schüller J, et al. Cancer Chemother Pharmacol 2000;45:291–7
x3.2*
Tumour tissue
*Ratio of median values
Normal tissue Plasma
5-FU
x21.4*
5-FU
5-FU
5-FU
5-FU
5-FU
5-FU
5-FU
5-FU
5-FU
5-FU5-FU
5-FU 5-FU
5-FU

37. CAPECITABINE Trials in MBC
(Combination Therapy)
Superior survival with capecitabine plus docetaxel combination therapy in
anthracycline-pretreated patients with advanced breast cancer: phase III trial results.
JCO 2002 Jun 15;20(12):2812-23.
PURPOSE:
This international phase III trial compared efficacy and tolerability of capecitabine/docetaxel
therapy with single-agent docetaxel in anthracycline-pretreated patients with MBC.
PATIENTS AND METHODS:
Patients were randomized to 21-day cycles of oral capecitabine 1,250 mg/m(2) twice daily
on days 1 to 14 plus docetaxel 75 mg/m(2) on day 1 (n = 255) or to docetaxel 100 mg/m(2)
on day 1 (n = 256).

38. • Capecitabine + docetaxel reduced the risk of progression and death over
docetaxel alone.
• The overall response rate with Capecitabine plus docetaxel was 32% vs 22% with
docetaxel
alone (P=0.009)
35.7 % reduced risk of progression with
Capecitabine plus Docetaxel over
docetaxel alone.
22.5 % reduced risk of death with
Capecitabine plus Docetaxel over docetaxel
alone.
Capecitabine + Docetaxel (n=255) Capecitabine + Docetaxel (n=255)
CAPECITABINE Trials in MBC
(Combination Therapy)

39. Study design
Primary objective:
• To determine the time to progression
Secondary objective:
• To determine the overall response rate, the
duration of response, the clinical benefit rate
• To evaluate the safety + toxicity
• To assess the quality of life
• To determine the overall survival
Schedule:
Capecitabine 2000 mg/m², days 1 - 14 q 22
A prospective, open label, non randomised phase II trial
CAPECITABINE:MONOTHERAPY IN METASTATIC BREAST CA

40. Median OS, weeks 74.22
95% CIfor median OS (60.59, 87.85)
Median TTP, weeks 31.63
95% CIfor median TTP (26.93, 36.32)
The actual result was a
TTP of 31.63 weeks which
(p<0.05) excludes a TTP
lower than 25 weeks.
Time To Progression, Overall Survival and
Overall Response
Clinical Response N %
CR 13 8.1
PR 29 18
CR+PR 42 26.1

41. Phase III Trial of Ixabepilone + Capecitabine
in MBC Patients Previously Treated/Resistant
to Anthracyclines/Taxanes
Ixabepilone
(40 mg/m2 IV over 3 hr d1 q3wk)
+
Capecitabine
(2000 mg/m2/day PO 2 divided doses
d1-d14 q3wk)
Capecitabine
(2500 mg/m2/day PO 2 divided doses
d1-d14 q3wk)
Metastatic or locally
advanced breast cancer
RESISTANT
to anthracyclines
and taxanes
N = 752
Stratification
Visceral metastases Anthracycline resistance
Prior chemotherapy for MBC Study site

42. Median 95% CI
Ixabepilone +
Capecitabine
5.8 mo (5.5–7.0)
Capecitabine 4.2 mo (3.8–4.5)
Progression-free Survival
by Independent Radiologic Review
HR: 0.75 (0.64–0.88)
P = 0.0003
ProportionProgressionFree
1.0
0.8
0.6
0.4
0.2
0
0 4 8 12 16 20 24 28 32 36
Months
Thomas et al. J Clin Oncol. 2007;25:5210.

43. Response Rate
% Response
Investigator IRR
Ixabepilone +
Capecitabine
N = 375
Capecitabine
N = 377
Ixabepilone +
Capecitabine
N = 375
Capecitabine
N = 377
ORR (CR + PR) 42 23 35 14
P<0.0001 P<0.0001
Stable disease 36 38 41 46
Progressive
disease
14 29 15 27
Unable to
determine
8 10 9 12

44. Summary
 Ixabepilone plus capecitabine demonstrates superior efficacy to
capecitabine alone in metastatic breast cancer resistant to anthracyclines
and taxanes
 Improvement of PFS (HR 0.75)
 2.5-fold increase in ORR (35% vs 14%)
 Benefit was consistent across most subgroups
 Manageable safety profile (normal or Grade 1 LFTs)

45. GEMCITABINE
 In 2004, gemcitabine in combination with paclitaxel was granted RA for the initial
treatment of patients with MBC. The RCT that supported this approval enrolled 529
patients with locally advanced or MBC who had received prior adjuvant or
neoadjuvant anthracycline chemotherapy.17 Patients were randomly assigned to
receive gemcitabine 1,250 mg/m2 on days 1 and 8 with paclitaxel 175 mg/m2 on day
1 or to single-agent paclitaxel 175 mg/m2. Drugs were administered intravenously on
a 21-day cycle.
 Approval of gemcitabine was based on an improvement in TTP supported by a
numeric improvement in OS. Median TTP in patients treated with the gemcitabine
plus paclitaxel combination was 5.2 months compared with 2.9 months for paclitaxel
alone (HR, 0.65; 95% CI, 0.52 to 0.81; P < .001). In the final OS analysis, median
survival was 18.6 months in the gemcitabine plus paclitaxel arm and 15.8 months in
the paclitaxel monotherapy arm (HR, 0.86; 95% CI, 0.71 to 1.04).

46. ERIBULIN
 In 2010, eribulin was granted RA for the treatment of patients with MBC who have received an
anthracycline, taxane, and at least two chemotherapeutic regimens.
 Safety and efficacy were evaluated in an RCT of 762 patients with MBC who had received at least two
chemotherapeutic regimens for the treatment of metastatic disease and experienced disease progression
within 6 months of the last chemotherapeutic regimen.
 Patients were randomly assigned in a ratio of two to one to receive eribulin (n = 508) 1.4
mg/m2 intravenously on days 1 and 8 of a 21-day cycle or the physician's choice of a single-agent
therapy selected before randomization (n = 254). Patients had received a median of four prior
chemotherapy regimens in both arms.
 Eribulin approval was based on an improvement in OS, with median OS of 13.1 months for eribulin-
treated patients compared with 10.6 months for patients treated in the control arm (HR, 0.81; 95% CI,
0.660 to 0.991; P = .041). The application was also supported by higher ORR in the eribulin treatment
arm (11.2%) compared with the control arm (3.9%) and a consistent, but nonsignificant, effect on PFS
as determined by independent review (median PFS, 113 v 68 days; HR, 0.87; 95% CI, 0.71 to 1.05; P =
.14).

47.  The use of combination therapy versus monotherapy or sequential
single agents remains a controversial issue.
 Depending on the individual patient and specific treatment goals,
either can be appropriate.
 Combination therapies generally result in higher overall
response rates and times to disease progression than with
sequential single agents, but usually at a cost of greater toxicity.
In addition, the higher overall response rates with combination
therapy versus sequential single agents may not necessarily translate
into superior survival outcomes.
COMBINATION VS SEQUENTIAL MONOTHERAPY

49. PARP INHIBITORS
 In a randomized phase II study in patients with metastatic triple-
negative breast cancer, O’Shaughnessy et al suggested that iniparib
added to gemcitabine/carboplatin (GC) improved overall survival
without potentiating GC toxicity.
 Unfortunately, a subsequent phase III study reported at ASCO in
2011, evaluating the safety and efficacy of GC with or without I in a
 similar population with metastatic triple-negative breast cancer,
failed to demostrate a significant improvement in overall survival or
progression-free survival

50. TARGETED THERAPY IN CA BREAST

51. Milestones of HER2/anti-HER2 therapies in BC
EGFR discovery
Cohen
neu oncogene
discovery
Weinberg
EGFR MoAb
inhibited
growth
Mendelsohn
FDA approves
trastuzumab in
adjuvant
setting
1982 19851978 1984 1998 2006 2007 2010
Her2
amplification in
breast cancer
Aaronson
FDA approves
trastuzumab
alone for 2nd
line and in with
paclitaxel for 1st
line MBC
FDA approves
lapatinib +
letrozole for
MBC
FDA approves
lapatinib +
capecitabine
for MBC
1987
Her2/neu
amplification
correlates with
shorter survival
Slamon
MBC : metastatic breast cancer; MoAb : monoclonal antibody
Her2 cloned
Ullrich and
Coussens
1983 2012
FDA approves
pertuzumab +
trastuzumab +
docetaxel for
MBC
2013
FDA approves
trastuzumab
emtansine for
MBC
Accelerated
approval of
pertuuzmab/
trastzumab as
neoadjuvant
therapy

52. TRASTUZUMAB
 Trastuzumab received RA in 1998 as a single agent for the
treatment of MBC overexpressing the human epidermal
growth factor receptor 2 (HER2) protein in patients who
have received one or more chemotherapy regimens for
metastatic disease.
 The trial supporting the approval was a single-agent SAT
in 222 patients with HER2-overexpressing MBC. Patients
had progressive disease after one (32%) or two (68%)
prior chemotherapy regimens for metastatic

53. Herceptin (Trastuzumab) Study Design
Chemotherapy (AC or Paclitaxel)
Herceptin loading: 4 mg/kg
weekly: 2 mg/kg469
Chemotherapy Alone
Patients with untreated MBC HER2
overexpression 2+ 3+
Slamon et al. N Engl J Med. 2001;344:783.

54. Herceptin :Overall Survival & Progression free
Survival All Patients
PFS 7.4 VS 4.6 m Median OS 25.1 vs 20.3 m

55. CLEOPATRA: Trastuzumab + Docetaxel +
Pertuzumab or Placebo
Baselga J, et al. N Engl J Med. 2012;366(2):109-119.
808 patients
with centrally
confirmed
HER2+ MBC
≥ 6 cycles of docetaxel
recommended
R
A
N
D
O
M
I
Z
E
1:1
Trastuzumab + pertuzumab until
progressive disease
Study dosing every 3 weeks
• Pertuzumab/Placebo: 840 mg loading dose, 420 mg maintenance
• Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance
• Docetaxel: 75 mg/m2, escalating to 100 mg/m2 if tolerated
≥ 6 cycles of docetaxel
recommended
Trastuzumab + placebo until
progressive disease

56. CLEOPATRA: Updated Survival Results
Swain SJ, et al. ESMO 2014. Abstract 350O_PR.
Pertuzumab +
Trastuzumab +
Docetaxel
(n=402)
Placebo +
Trastuzumab +
Docetaxel
(n=406)
P value
Median PFS 18.7 months 12.4 months HR=0.68
P<.0001Improvement: 6.3 months
Median OS 56.5 months 40.8 months HR=0.68
P<.0002Improvement: 15.7 months
PFS = progression-free survival

60. EMILIA: T-DM1 vs Lapatinib + Capecitabine
Verma S, et al. N Engl J Med. 2012;367(19):1783-1791.
T-DM1
Lapatinib +
Capecitabine
P value
Median PFS 9.4 months 6.4 month
HR=.65
P<.0001
Median OS 30.9 months 25.1 months
HR=.682
P=.0006
12-month
survival rate
85.2% 78.4%
24-month
survival rate
64.7% 51.8%
• 991 patients previously treated with trastuzumab and a
taxane

61. LAPATINIB
 Lapatinib was granted RA for use in combination with capecitabine for the
treatment of patients with HER2-overexpressing locally advanced or MBC who
have received prior therapy, including anthracyclines, taxanes, and trastuzumab.
 An RCT of 399 patients overexpressing HER2 3+ or 2+ supported this approval.
Patients were randomly assigned to receive lapatinib 1,250 mg/m2 orally daily plus
capecitabine 2,000 mg/m2 orally daily for 14 days or single-agent capecitabine
2,500 mg/m2 orally daily for 14 days.
 The study was stopped early for efficacy based on a planned interim analysis of
TTP, the primary end point. TTP improvement was statistically significant; median
difference in TTP was 8.5 weeks (HR, 0.57; 95% CI, 0.43 to 0.77; P < .001
 At the time of approval, the survival data were not mature, with only 32% of the
planned mortality events. An updated survival analysis after 2 additional years of
follow-up showed no difference in OS (HR, 0.89; 95% CI, 0.71 to 1.10; P = .276).

62. Targeted Therapies for ER+ MBC
 CDK 4/6 regulates
cell cycle progression
• Palbociclib is an oral,
potent inhibitor of CDK4/6
• PALOMA-1:
– Palbo + Letrozole is superior
to Letrozole in 1st line ER+
MBC (median PFS 20.2 vs. 10.2
mo, HR 0.49, p=0.0004)

63. BEVACIZUMAB
 The initial promising results of a 5-month improvement in
progression-free survival time from the ECOG 2100 trial provided
the basis for the “accelerated approval” of bevacizumab in
metastatic breast cancer by the FDA.
 However, given the only modest improverment in progression-
free survival in subsequent trials of bevacizumab and the lack of
improvement in overall survival, coupled with the severe to life-
threatening side effects of bevacizumab, such as gastrointestinal
perforation and severe bleeding, enthusiasm for this agent waned,
and in November 2011 the FDA revoked its accelerated approval
of the breast cancer indication for bevacizumab.

64. BISPHOSPHONATES
Zoledronic acid is an intravenously administered bisphosphonate that reduces
skeletal-related events (SREs) including pain and risk of fracture in women with
breast cancer metastatic to bone. In addition, zoledronic acid treats
hypercalcemia of malignancy.
 Multiple published reports have now confirmed the benefit of bisphosphonates
as an adjunct to treatment of patients with bone metastasis. Use of these
agents results in a significant reduction in SREs, including pathologic fracture,
bone pain, and the need for radiation therapy to bone.
 Patients with breast carcinoma who had all types of bone were randomized to
receive treatment with either 4 or 8 mg of zoledronic acid as a 15-minute
infusion or 90 mg of pamidronate as a 2-hour infusion every 3 to 4 weeks for
12 months.
 The proportion of patients who had an SRE was comparable between treatment
groups (approximately 45%).
 However, among patients who had breast carcinoma with at least one
osteolytic lesion, treatment with 4 mg of zoledronic acid was more effective in
reducing skeletal complications than was 90 mg of pamidronate.

65. DENOSUMAB
 Denosumab is a fully human monoclonal antibody against receptor
activator of nuclear factor κ B ligand (RANKL), a key mediator of
osteoclast activity.
 Results from a phase III pivotal study demonstrated that
denosumab was superior to zoledronic acid in delaying or
preventing SREs in breast cancer patients with bone metastases.
Patients with breast cancer and

66. Systemic Treatment Approach
for Metastatic Breast Cancer
Metastatic Breast Cancer
• Limited metastases (bone & soft tissue)
• Positive hormone receptors
• Hormone responsive
• Disease-free interval 2 years
• Extensive disease or visceral crisis
• Negative hormone receptors
• No response to hormones
Hormonal Therapy Chemotherapy
Response No response No progression Progression of disease
If disease progresses,
second-line hormonal therapy
Second-line chemotherapy