management of advanced and metastatic breast cancer a lecture in ACOD in 2015 by dr mahran alnahmi Alexandria Egypt

1. BREAST CANCER
LOCALLY ADVANCED AND
METASTATIC DISEASE
Prepared by Mahran Alnahmi
Supervisor Prof.Dr. Abbas Omar

2. INTRODUCTION
 Breast cancer, the second-leading cause of cancer
deaths in women, is the disease women fear most.
 Breast cancer can also occur in men, but it's far less
common.
 Yet there's more reason for optimism than ever
before.

3. Most common Cancer in women in developed countries.
The lifetime risk (upto age 85)
1940 - 5% ---- ----one in 20.
2000- 12.6% -------- one in 8
Incidence worldwide incidence 1.2 million(WHO)
Death – 2nd
leading cause of cancer death. 40,000 in US per
year, worldwide much higher
STATISTICS

4. Hereditary (10% of pts have 1st
deg relatives)
Genetic mutations- BRCA 1, 2
Radiation- esp. during childhood- mantle RT upto 20%
incidence by 50 y.
Benign disease- proliferative, with atypia
Previous h/o breast ca
Diet- obesity; dietary fat, anti-ox.- inconclusive.
Hormonal factors- increased risk with excess exposure to
estrogens; Progesterone containing OCPs
ETIOLOGY

5. RISK FACTOR MODELS
Gail model: ( www.nci.nih.gov )
Uses the following criteria:
-current age
-age at menarche
-age at first child birth
-no. of first degree relatives with breast ca
-no. of previous benign biopsies
-atypical hyperplasia in a prev. biopsy
-race

6. PATHOLOGY
In-situ Carcinomas-
DCIS, LCIS; Paget’s disease of nipple
Invasive Cas-
Invasive Ductal Ca (80%)
Invasive lobular Ca (10%)
Other invasive Cas- Medullary, papillary, tubular,
cribriform, metaplastic, squamous, adenoid cystic,
mucinous, secretory, undifferentiated.

7. “Intrinsic” breast cancer subtypes
Basal-like ER- PR- HER2- ck5/6+ and /or HER1+
Luminal A ER+ and/or PR+ HER2-
Luminal B ER+ and/or PR+ HER2+
HER2+ / ER – ER- PR- HER2+
“Unclassified” Negative for all five markers

8. SPREAD OF BREAST CANCER

9. Direct invasion- into chest muscles, wall, skin/nipple-
areola.
Lymphatic- Locoregional - axilla, supraclavicular,
infraclavicular and Internal mammary
Blood- Bones, lungs, liver, brain– Distant metastasis-
stage IV
MODES OF SPREAD

10. Local- Lump, discharge, skin/nipple changes,
axillary, arm swelling, ulcer ,Pain, tenderness-
Inflammatory Ca
Distant- back ache, cough, breathlessness, headache,
vomiting, anorexia, etc.
O/E – lump-hard, irregular , nipple retraction, peau de
orange/puckering.
Nipple discharge, axillary nodes
CLINICAL SYMPTOMS-

11. History and physical Examination.
Mammography.
FNAC/biopsy of the lump/gland- histology and
receptor status studies
Her 2 /neu, prognostic indicator studies
Evaluation- CBC, RFT, LFT, ALP, S. Ca++, Cardiac
evaluation,
Metastatic work up- CXR, USG A+P, Bone scan, ?
PET. CT thorax, brain- only if symptoms suggestive.
DIAGNOSIS

12. American Joint Committee on Cancer
Staging System for Breast Cancer
(p)T (Primary Tumor)
Tis Carcinoma in situ (lobular or ductal)
T1 Tumor ≤2 cm
T1a Tumor ≥0.1 cm, ≤0.5 cm
T1b Tumor >0.5 cm, ≤1 cm
T1c Tumor >1 cm, ≤2 cm
T2 Tumor >2 cm, ≤5 cm
T3 Tumor >5 cm
T4 Tumor any size with extension to the chest wall or skin
T4a Tumor extending to the chest wall (excluding the pectoralis)
T4b Tumor extending to the skin with ulceration, edema,nodules
T4c Both T4a and T4b
T4d Inflammatory carcinoma

13. N0 No regional node involvement, no special studies
N0 (i-) No regional node involvement, negative IHC
N0 (i+) Node(s) with isolated tumor cells spanning <0.2 mm
N0 (mol-) Negative node(s) histologically, negative PCR
N0 (mol+) Negative node(s) histologically, positive PCR
N1 Metastasis to 1-3 axillary nodes and/or int.
mammary positive by biopsy
N1(mic) Micrometastasis (>0.2 mm, none >2.0 mm)
N1a Metastasis to 1-3 axillary nodes
N1b Metastasis in int. mammary by sentinel biopsy
N1c Metastasis to 1-3 axillary nodes and int. mammary
by biopsy
(P)N (NODES)

14. N2 Metastasis to 4-9 axillary nodes or int. mammary
clinically positive, without axillary metastasis
N2a Metastasis to 4-9 axillary nodes, at least 1 >2.0 mm
N2b Int. mammary clinically apparent, negative axillary nodes
N3 Metastasis to ≥10 axillary nodes or combination of
axillary and int. mammary metastasis
N3a ≥10 axillary nodes (>2.0 mm), or infraclavicular nodes
N3b Positive int. mammary clinically with ≥1 axillary nodes or
>3 positive axillary nodes with int. mammary positive
by biopsy
N3c Metastasis to ipsilateral supraclavicular nodes

15. M (Metastasis)
M0 No distant metastasis
M1 Distant metastasis

16. Tumor size less than 2 cm
STAGE 1

17. 2-5 cm with N1 or N0
More than 5cm but N0
Less than 2 cm or T0 but no more
than N2
STAGE 2

18. Larger than 5 cm with any N
Less than 5 cm with nodal matting
Less than 5 cm with supraclavicular
LN involvement
Stage 3

19. Inflammatory breast
STAGE 3

20. Metastatic breast cancer
STAGE 4

21. BREAST CANCER
Locally Advanced And
Metastatic Disease

22. Locally Advanced and Metastatic Breast Cancer
Overview:
Principles of neoadjuvant chemotherapy for locally
advanced and inflammatory breast cancer
Systemic therapy of metastatic breast cancer
Chemotherapy
Hormonal agents
Biologic agents
Bisphosphonates
Rationale for selection of treatment in metastatic
disease
chemotherapy vs. hormonal agents
Ideal first line agents?

23. Locally Advanced Breast Cancer
Definition: breast cancer, without distant metastatic
spread, which is unresectable due to
Satellite skin nodules
Extensive regional lymph node involvement
Fixation to skin or chest wall
Inflammatory breast cancer

26. Locally Advanced Breast Cancer
Combined modality treatment is the standard
of care for locally advanced breast cancer.
Neoadjuvant chemotherapy
Goals are to improve resectability of the tumour
and to increase rates of breast conserving
treatment and establish tumor sensitivity
Locoregional therapy
Surgery, or radiotherapy, or both.

27. Locally Advanced Breast Cancer
Response rates to neoadjuvant chemotherapy:
Major responders: 47-100%
Clinical complete responders: 8-63%
Pathologic complete responders: 3-30%
A major response to chemotherapy is associated
with improved disease-free and overall survival.

28. Locally Advanced Breast Cancer
Survival is related to axillary lymph node
status after neoadjuvant chemotherapy.
Positive nodes 5-year overall survival
0 75%
1-4 40-50%
5-10 30%
>10 20%

29. Locally Advanced Breast Cancer
Survival is related to response of primary tumour to neoadjuvant
chemotherapy.
Author Median
follow-up,
years
Survival,
patients with
complete
response
Survival,
patients with
partial
response
Method of
response
assessment
Eltahir,
1998
5 74%
overall
survival
36%
overall
survival
Clinical
response
Kuerer,
1999
5 89%
overall
survival
64%
overall
survival
Pathologic
response
Bonnadonn
a,1998
8 86%
disease-free
survival
56%
disease-free
survival
Clinical
response

30. Locally Advanced Breast
Cancer
Duration of neoadjuvant chemotherapy
Optimal duration of treatment is not known.
Rule of thumb: “treat until maximal response.”
May require from 2-8 treatments, depending on
rapidity of response.
Patients should be assessed by multidisciplinary
team after every 2 cycles of chemotherapy to
determine optimal timing of surgery.

31. DEFINITIONS FOR RESPONSE EVALUATION OF
PRIMARY SYSTEMIC THERAPY
CLINICAL DEFINITION
 Complete: no palpable mass detectable (cCR)
 Partial: reduction of tumour area to < 50% (cPR)
IMAGING DEFINITION
 No tumour visible by mammogram and/or ultrasound and/or MRI
PATHOLOGICAL DEFINITION
 Only focal invasive tumour residuals in the removed breast tissue
 Only in situ tumour residuals in the removed breast tissue (pCR inv)
 No invasive or in situ tumour cells (pCR)
 No malignant tumour cells in breast and lymph nodes (pCR breast
and nodes).

32. Locally Advanced Breast Cancer
Ideal neoadjuvant chemotherapy regimen has not
been identified.
Anthracycline based (epirubicin or adriamycin)
chemotherapy is often used at start (AC, CAF, FEC).
Taxanes (taxol, taxotere) are also extremely effective
and have been shown to increase the rate of
pathologic complete responses.

33. Locally Advanced Breast Cancer
Impact of Taxanes in NeoadjuvantChemotherapy.
TAX-301 trial
162 patients, randomly assigned to pre-operative
CAVP X 8 cycles vs CAVP x 4 then Taxotere X4
5 year overall survival:
CAVP X 8: 78%
CAVP X 4 + Taxotere X 4: 97%

34. Role Of Docetaxel In Neo-adjuvant
Therapy For Breast Cancer

35. Neoadjuvant Taxotere
The Aberdeen Trial
NSABP B27
GEPARDUO

36. 4 cycles of Taxotere
4 cycles of CVAP
No Response
Response
RandomiseAll Patients
4 cycles of CVAP
First Phase
Tax301 Study
Conducted by the Aberdeen Breast Group
Second phase
4 cycles of Taxotere
FinalAssessment/Surgery

37. Aberdeen Tax 301
Objective clinical response rates
1st phase: 4 cycles CVAP
Response % of patients
Complete 15
Partial 52
Stasis 33
Progression 1
ORR - 67%
N=162 patients; 4 cycles of CVAP given to all patients

38. Aberdeen Tax301
Objective clinical response rates
2nd phase: responding patients
CVAP
n=52
Taxotere
n=52
Response % %
Complete 33 56
Additional partial 31 29
Maintained partial 29 6
Progression 4 0
ORR 64 85*
* p=0.03

39. Aberdeen Tax 301
Objective clinical response rates
2nd phase: non-responding patients
Response % of patients
Complete 11
Partial 36
Stasis 31
Progression 9
ORR - 47%
N=55 patients; additional 4 cycles of Taxotere given

40. Aberdeen Tax301Aberdeen Tax301
Type of surgeryType of surgery undertaken
Breast conservation surgery
Taxotere 67%
CVAP 48%
Conservation Mastectomy
0
20
40
60
80
100
Taxotere
CVAP
Type of surgery
%ofpatients
(p<0.01)

41. Tax 301 Overall Survival
Time (months)
Median Follow - up: 60 months
Survivalprobability
1.0
0.9
0.8
0.7
20 40 60 80 100
Log rank p=0.04
Taxotere
CVAP
97%
78%

42. Neoadjuvant Taxotere
The Aberdeen Trial
NSABP B27
GEPAR-DUO

43. NSABP B-27
Operable Breast CancerOperable Breast Cancer
RandomizationRandomization
AC x 4AC x 4
Tam X 5 YrsTam X 5 Yrs
AC x 4AC x 4
Tam X 5 YrsTam X 5 Yrs
AC x 4AC x 4
Tam X 5 YrsTam X 5 Yrs
SurgerySurgery Taxotere x 4Taxotere x 4 SurgerySurgery
SurgerySurgery Taxotere x 4Taxotere x 4
( 2411 pts )

44. 40%
45%
100100
8080
6060
4040
2020
00
%%
p < 0.001p < 0.001
ACAC
N=1502N=1502
AC TaxotereAC Taxotere
N=687N=687
65%
26%
NSABP B-27 Clinical ResponseNSABP B-27 Clinical Response
cCRcCR
cPRcPR
cNRcNR
14% 9%

45. NSABP B-27
Pathological Response (pCR) in Breast
p < 0.001
AC Taxotere
N=786
AC
N=1567
3.9%
9.8%
7.2%
18.9%
20
10
0
30 No Tumour
Non-Invasive
26.1%
13.7%

46. NSABP B-27:
Proportion of Patients with negative axillary lymph
nodes
58.2
p < 0.001p < 0.001
ACAC
N=1534N=1534
AC TaxotereAC Taxotere
N=752N=752
8080
6060
4040
2020
00
%%
50.8

47. NSABP B-27: Breast Conservation: Breast Conservation
p = 0.70
61 63
8080
6060
4040
2020
00
%%
ACAC
(N=1492)(N=1492)
AC TaxotereAC Taxotere
N=718N=718

48. LOCALLY ADVANCED BREAST
CANCER
Role of Herceptin (trastuzumab):
Initial reports are encouraging, but use of herceptin cannot be
recommended outside of a clinical trial.
Role of High-dose chemotherapy with stem cell
support:
No improvement in DFS or OS, with significant increase in
toxicity and worsening of quality of life, therefore not
recommended.

49. LOCALLY ADVANCED BREAST
CANCER
Hormonal Management
Acceptable in Estrogen Receptor and/or
Progesterone Receptor positive cancers.
Best used in patients where chemotherapy is
relatively contraindicated
Elderly
Poor performance status
Comorbid illness
Patient reluctance to accept chemotherapy

50. LOCALLY ADVANCED BREAST
CANCER
Hormonal Management, continued:
Rate of pathologic complete response is greatly
diminished.
Rate of breast-conserving treatment is greatly
diminished.
Response to treatment is much slower, e.g. 3-9
months.

51. Multidisciplinary Cancer Breast Management

52. Multidisciplinary Cancer Breast Management

53. Multidisciplinary Cancer Breast Management

54. Multidisciplinary Cancer Breast Management
Trials of Neoadjuvant Trastuzumab:
Summary of Efficacy
•Preoperative clinical responses observed
– Overall response rate, 70% to 90%
– Clinical complete response, 15% to 30%
– Pathologic complete response, approximately 18%
•Responses higher for patients with 3+ expression of
HER2

55. The relative efficacy of neoadjuvant endocrine
therapy versus chemotherapy in postmenopausal
women with ER positive breast cancer
 Methods: 121 postmenopausal women with ER(+) and/or
PgR(+) breast cancer T2N1–2, T3N0–1, T4N0M0
assigned to NAT with either CT Dox 60 mg/m2 + Pac 200
mg/m2, every 3 weeks, 4 cycles, n=62 patients (pts), or HT
with aromatase inhibitors, anastrazole 1 mg, n = 30 pts, 3
months).
In CT arm the most frequent grade III/IV toxicity was alopecia ( 79.3 % ), neutropenia ( 43.1 %),
cardiotoxicity (6.8 %), diarrhea (1.7%). HT was well tolerated. The most commonly adverse events
were hot flushes (23.3%), vaginal discharge (6.6%), musculosskeletal disorders (1.7%).
Note this does not give the pathologic CR rate.

56. Multidisciplinary Cancer Breast Management

57. Multidisciplinary Cancer Breast Management

58. Multidisciplinary Cancer Breast Management

59. Letrozole Is More Effective Neoadjuvant Endocrine
Therapy Than Tamoxifen for ErbB-1– and/or
ErbB-2–Positive, Estrogen Receptor–Positive
Primary Breast Cancer: Evidence From a Phase III

60. LOCALLY ADVANCED BREAST CANCER
Summary:
Standard of care is multimodality treatment.
Chemotherapy: should contain anthracyclines and/or taxanes
and should begin before surgery.
Locoregional therapy: should be performed when a maximal
tumour response has been obtained.
Post-operative chemotherapy: should be performed if less
than 8 cycles were given pre-operatively, until a total of 8
cycles of chemotherapy have been given.
Hormonal management: is a slower option, and is restricted
to ER and/or PR positive tumours.

61. METASTATIC BREAST CANCER
Goals of treatment of metastatic breast cancer:
Cure: not a realistic goal
Few patients have complete responses, and disease free
intervals are short.
Prolongation of survival:
5-10% of patients will survive 5 years or more.
2-5% of patients are long-term survivors (>10 years).
Improvement of Quality of Life:
Most patients experience fewer disease symptoms, with
manageable treatment side effects.

62. METASTATIC BREAST CANCER
Numerous treatment options exist:
Chemotherapy: anthracyclines, taxanes,
vinorelbine, capecitabine
Hormonal therapies: tamoxifen (Nolvadex),
anastrozole (Arimidex), letrozole (Femara),
exemestane (Aromasin), megestrol acetate (Megace)
Biologic agents: trastuzumab (herceptin)
Bisphosphonates: pamidronate, zolendronate

63. METASTATIC BREAST CANCER
Different options can be combined.
Herceptin and chemotherapy.
Hormonal agents and bisphosphonates.
Herceptin, chemotherapy and bisphosphonates.

64. METASTATIC BREAST CANCER
How is initial therapy selected?
Patient factors: age, comorbid conditions,
willingness to accept side effects.
Tumour factors: ER, PR, her-2/neu status.
Course of illness: extent and location of metastases,
disease-free interval, pace of spread of metastases.
Treatment factors: adjuvant chemotherapy, adjuvant
hormonal agents, adjuvant radiotherapy.

65. METASTATIC BREAST CANCER
The use of hormonal agents is favoured if:
Tumour is ER and/or PR positive.
Disease-free interval is long.
Few sites of metastases.
Metastases do not involve visceral organs.
Pace of disease progression is slow.
Patient has responded to previous hormonal agents.

66. METASTATIC BREAST CANCER
Use of hormonal agents, continued
Hormonal agents require 8-12 weeks to determine
their efficacy, thus they are not recommended for
patients with extensive visceral metastases.
Initial response to hormonal agents is 50-60% in
ER/PR positive patients.

67. METASTATIC BREAST
CANCER
The use of chemotherapy is favoured if:
Tumour is negative for ER and PR.
Disease-free interval is short.
Extensive metastases are present, especially visceral
disease (liver, lung).
Disease is progressing rapidly.
Patient has not responded to previous hormonal
agents.
Initial response to chemotherapy is 50-75%.
No clear advantage of combination regimens over
use of sequential single agents.

68. METASTATIC BREAST CANCER
Hormonal agents:
Tamoxifen:
Mixed estrogen receptor agonist-antagonist.
Can be used in premenopausal and postmenopausal
women.
Response rates are 50-60%.
Duration of response may be years.
Toxicities: hot flashes, increased risks of DVT/
pulmonary embolism, endometrial cancer
May be associated with tumour reluctance in up to
13% of patients.

69. METASTATIC BREAST CANCER
Hormonal agents, continued:
Aromatase inhibitors:
Anastrozole (Arimidex), non-steroidal
Letrozole (Femara), non-steroidal
Exemestane (Aromasin), steroidal
Method of action: block conversion of adrenal androgens
to estrogen in adipose tissue and in the breast.
Use is restricted to postmenopausal women.
Side effects: hot flashes, myalgias/arthralgias, increased
risk of osteoporosis, altered lipid profiles.

70. METASTATIC BREAST CANCER
Hormonal agents, continued:
Aromatase inhibitors:
Anastrozole and Letrozole:
are non-steroidal aromatase inhibitors.
are both superior to Megace in tamoxifen refractory
patients.
Have similar efficacy to tamoxifen, with fewer
side effects.

71. METASTATIC BREAST CANCER
Hormonal agents, continued:
Aromatase inhibitors:
Exemestane:
is a steroidal aromatase inhibitor.
is superior to Megace, and at least as effective as
Tamoxifen.
can be effective in patients who have failed non-
steroidal aromatase inhibitors.

72. METASTATIC BREAST
CANCER
Hormonal agents, continued:
Megace (megestrol acetate)
Is a progestin
Before aromatase inhibitors, was considered
second-line therapy, after tamoxifen.
May still have activity in some patients who have
failed tamoxifen and/or aromatase inhibitors.
Side effects: increased appetite, weight gain,
increased risk of DVT/pulmonary embolism.

73. Sequencing of Hormonal agents in metastatic
breast cancer:
Postmenopausal patients:
Anastrozole or Letrozole as first line
Exemestane as second line
Tamoxifen and Megace remain options for third line
OR for patients who do not tolerate aromatase
inhibitors.
Premenopausal patients:
Tamoxifen as first line
Megace OR aromatase inhibitor with ovarian
ablation as second line.
METASTATIC BREAST
CANCER

74. Chemotherapy:
Numerous agents have activity in metastatic
breast cancer:
Anthracyclines
Taxanes
Fluoropyrimidines
Vinca alkaloids
Other drugs: cyclophosphamide, methotrexate,
gemcitabine
METASTATIC BREAST
CANCER

75. Anthracyclines
 doxorubicin (Adriamycin),epirubicin, mitoxantrone
liposomal-PEGylated doxorubicin (Doxil-Caelyx)
Are among the most active agents in breast cancer
(response rate at least 50%)
METASTATIC BREAST
CANCER

76. Taxanes
 Paclitaxel (Taxol)
 Docetaxel (Taxotere)
Nanoparticle albumin-bound paclitaxel (Abraxane)
Are the single most active drugs in breast cancer
and the most active in adriamycin-refractory
patients. (RR = 60%)
Common toxicities include peripheral neuropathy,
myalgias, arthralgias and alopecia.
METASTATIC BREAST
CANCER

77. Paclitaxel (taxol)
can induce anaphylactoid reactions, requiring
premedication with steroids and antihistamines.
Efficacy and toxicity profile can be improved by
weekly administration (as opposed to q3weeks).
Docetaxel (taxotere)
Can induce responses in 25% of patients who are
resistant to paclitaxel.
Cumulative toxicities include fluid retention,
sclerosis of tear ducts, loss of fingernails/toenails.
METASTATIC BREAST
CANCER

78. Nanoparticle albumin-bound paclitaxel
(Abraxane)
Novel formulation, does not require Cremophor.
No risk of anaphylactoid reaction, thus no need for
steroids.
Better tissue penetration.
Less toxic and more effective than paclitaxel.
Approved in the USA, not yet approved in Canada.
METASTATIC BREAST
CANCER

79. Fluoropyrimidines:
5-fluorouracil:
is commonly used in combinations, such as CMF,
CAF, FEC.
Has activity as a single agent, esp. in prolonged
infusions, but these regimens are not convenient.
Toxicities: mucositis (stomatitis, enteritis, colitis),
hand-foot syndrome, some myelosuppression
METASTATIC BREAST
CANCER

80. Fluoropyrimidines, cont’d
Capecitabine (Xeloda)
Oral 5-FU derivative, given BID X14 days
q21days.
Prodrug is activated to 5-FU in tumour cells,
mimics a prolonged 5-FU infusion.
Has activity even in patients who are refractory to
anthracyclines and taxanes!! (RR=25%)
Dose limiting toxicity is usually hand-foot
syndrome.
NOT HEPATICALLY METABOLIZED, thus ideal
agent in patients with severe liver dysfunction!
METASTATIC BREAST
CANCER

81. Vinca alkaloids:
Vinorelbine (Navelbine)
Semi-synthetic vinca alkaloid, related to VCR/VBL
Less neurotoxicity, due to diminished binding to
axonal microtubules.
Active even in heavily pretreated patients (response
rates = 25-50%).
Excellent toxicity profile: no nausea, no alopecia,
no mucositis
Well tolerated by elderly, frail patients
METASTATIC BREAST
CANCER

82. Other drugs:
Cyclophosphamide
Methotrexate
Gemcitabine
All have limited activity as single agents, but are
useful in combinations with other active drugs
e.g. CMF, CAF, Gemcitabine-Taxol
METASTATIC BREAST CANCER

83. Biologic agents
Herceptin (trastuzumab)
Humanized mouse monoclonal antibody directed
against the her-2/neu protein.
Has activity against breast cancers that strongly
overexpress her-2/neu (score= 3+/3).
Has activity as a single agent, even in heavily pre-
treated patients.
METASTATIC BREAST
CANCER

84. Herceptin, cont’d
Can be safely administered with taxanes and
vinorelbine, with increased response rates (compared
to chemotherapy alone).
Cannot be given with adriamycin; response rates
increase BUT rate of cardiomyopathy rises to 27%!!!
Patients on herceptin who have received anthracyclines
in the past need monitoring for cardiac toxicity.
METASTATIC BREAST
CANCER

85. Bisphosphonates:
Pamidronate (Aredia)
Zolendronate (Zometa)
Given monthly to patients with bone metastases.
Leads to decreased risk of skeletal complications
(pain, fractures, need for radiotherapy)
Few toxicities: fever and chills post-infusion,
muscle spasms (transient hypocalcemia)
Rare cumulative toxicity: osteonecrosis of the
mandible (!)
METASTATIC BREAST
CANCER

86. A rational approach to selecting therapy for patients with
metastatic breast cancer:
For patients with bone metastases:
monthly administration of Pamidronate or
Zolendronate (regardless of ER/PR/her-2 status)
For patients with ER and/or PR positive breast
cancer, with low burden of metastases and slow
pace of disease:
start with hormonal agents.
If patient was on a hormonal agent at time of relapse,
try to select a non cross-resistant agent.
METASTATIC BREAST
CANCER

87. A rational approach to selecting therapy for patients
with metastatic breast cancer:
For patients with ER-negative/PR-negative disease
OR for patients with high tumour burden OR with
rapid disease progression:
Start with chemotherapy
In anthracycline-naïve patients, use anthracyclines.
In patients who had adjuvant anthracyclines, use
taxanes.
METASTATIC BREAST
CANCER

88. A rational approach to selecting therapy for patients
with metastatic breast cancer:
For patients with ER-negative/PR-negative disease OR
for patients with high tumour burden OR with rapid
disease progression:
2nd
, 3rd
, 4th
lines of treatment depend on patient’s
previous side effects and current symptoms.
e.g. navelbine contraindicated in patient with
abnormal liver function tests; capecitabine would be
a safer choice.
METASTATIC BREAST CANCER

89. A rational approach to selecting therapy for
patients with metastatic breast cancer:
For patients with her-2/neu 3+ disease:
Herceptin should be given with taxane or
vinorelbine chemotherapy.
Herceptin can be given as a single agent even in
heavily pre-treated patients.
Herceptin as a single agent can be given as
“maintenance” therapy after “inducing” a major
reduction in tumour burden with herceptin-chemo
combination.
METASTATIC BREAST
CANCER

90. Hormone receptor
positive
Triple-negative
HER2-Positive
*Note, these are just examples. Each patient is different and treatment is tailored accordingly.
Treatment

91. HER2+ disease:
a paradigm for advances in
targeted therapy

92. Lapatinib
 Oral dual tyrosine kinase inhibitor
of HER2 and EGFR
 FDA approved in combination with
capecitabine for trastuzumab-
resistant disease
 May have CNS penetration
 Well tolerated; common toxicities
include rash and diarrhea

93. Pertuzumab with trastuzumab
HER2 receptor
Trastuzumab
Pertuzumab
Dimerisation domain
of HER2
• Inhibitor of HER dimerization: binds HER2 and prevents formation of homo- or heterodimers
• Suppresses activation of several intracellular signaling cascades driving cancer cell growth
• Synergistic with trastuzumab
• Approved for first-line treatment of metastatic Her2+ breast cancer in combination with trastuzumab
and taxane chemotherapy

94. CLEOPATRA: phase 3 study of
pertuzumab in untreated metastatic disease
1:1
HER2-positive
MBC
Docetaxel + trastuzumab
+ placebo
Docetaxel + trastuzumab
+ pertuzumab
N=808
Pertuzumab prolongs time until progression by
six months (from 12.5 to 18.5 months)

95. Trastuzumab Emtansine (T-DM1)
T-DM1 is an antibody
drug-conjugate
Trastuzumab linked to a
potent chemotherapy
(DM1)
Average of 3.5 DM1 per
antibody

96. T-DM1 selectively delivers DM1
to HER2+ cells
Receptor-T-DM1 complex is
internalized into HER2-
positive cancer cell
Potent antimicrotubule
agent is released once
inside the HER2-
positive
tumor cell
T-DM1 binds to the HER2
protein on cancer cells
HER2

97. EMILIA: randomized trial comparing T-
DM1 to capecitabine and lapatinib in
previously treated patients
1:1HER2+ MBC (N=980)
•Prior taxane and
trastuzumab
PD
T-DM1
3.6 mg/kg q3w IV
Capecitabine
1000 mg/m2
orally bid, days 1–14, q3w
+
Lapatinib
1250 mg/day orally qd
PD
T-DM1 prolongs time until progression by three
months (from 6.4 to 9.6 months)
R
E
S
U
L
T
E

98. Th3RESA: randomized trial comparing T-DM1
to physician’s choice
Study treatment
continues until disease
progression or
unmanageable toxicity
HER2 positive
Metastatic breast
cancer
Prior trastuzumab,
lapatinib and
chemotherapy
T-DM1 q3w
Treatment of
physician’s choice
N = 795
2:1 randomization
2
1
T-DM1 prolongs time until progression by three months
(from 3.3 to 6.2 months)

99. T-DM1 is well-tolerated
Common side effects:
Decreased platelet count
Elevated liver tests
Does not cause typical chemotherapy side effects
No hair loss
Significant nausea or diarrhea are not common
Does not cause immune suppression or significant
neuropathy

100. ER+ disease: improving
on already very effective
treatments

101. Endocrine therapy for metastatic disease
Premenopausal
Tamoxifen
Ovarian
suppression/ablation
Ovarian suppression +
aromatase inhibition
Megace
 Postmenopausal
Tamoxifen
Aromatase Inhibitor +/-
everolimus
Fulvestrant
Megace

102. New drug approval: everolimus
Approved by the FDA in 2012 for patients with metastatic, hormone-receptor positive,
HER2-negative breast cancer
*Median time from study entry until worsening of cancer

103. What’s next for everolimus?
Multiple studies underway
In HER2+ cancers
In triple negative cancers
Studying this drug in combination with other
therapies

104. Testing the addition of an
HSP90 inhibitor to hormonal therapy

105. Other agents of interest in ER+ disease
Endoxifen
CDK 4/6 inhibitors
PI3Kinase inhibitors
Anti-IGF-1R Ab
SRC/Abl tyrosine kinase inhibitors
Combination therapy with targeted agents that may
overcome endocrine resistance

106. Triple negative breast cancer:
still searching for a target

107. There are many chemotherapies that are
active against metastatic disease
Mitotic inhibitors
vinorelbine
paclitaxel
docetaxel
Antifolates
methotrexate
Topoisomerase inhibitors
doxorubicin

108. Platinums
Sledge reported 47% response rate in first line metastatic
disease
Abandoned for many years because of concerns about
toxicity—largely replaced by taxanes
 Recent interest in patients with triple negative breast cancer
DNA crosslinking mechanism of action
 New data from a series of neoadjuvant studies supports activity in
TNBC

109. New chemotherapy: eribulin
Halichondria okadai•Metastatic breast cancer
•At least 2 prior
chemotherapies

110. PARP inhibitors
PARP1 is a protein that is important for repairing
single-strand DNA breaks
PARP inhibitors prevent DNA repair, leading to cell
death
Fast-dividing tumors and tumors containing BRCA
mutations, which also impair DNA repair, may be most
sensitive to PARP inhibitors
Ongoing trials are investigating the efficacy of PARP
inhibitors in breast cancer, particularly triple negative
breast cancer and BRCA-associated breast cancer

111. Inhibit binding to receptor (AR)
T
AR
T
Cell nucleus AR
Cell cytoplasm
Inhibit nuclear translocation of AR
Inhibit AR-mediated DNA binding
Targeting the androgen receptor in
triple negative breast cancer

112. Other agents of interest in triple
negative disease
PI3Kinase inhibitors
SRC/Abl tyrosine kinase inhibitors
HSP90 inhibitors
More to come…