1) Chemotherapy for breast cancer evolved from the 1940s when nitrogen mustards and antifolates were found to have anticancer effects, leading to the development of CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy. 2) Over subsequent decades, regimens incorporating anthracyclines like doxorubicin (AC) or taxanes like paclitaxel were found to improve survival outcomes compared to CMF or AC alone. 3) Current standard regimens include dose-dense AC followed by paclitaxel, or TAC (docetaxel, doxorubicin, cyclophosphamide) based on evidence they provide

1. Evolution and role of
Chemotherapy in CA Breast
Dr. Kartik Kadia

2. • Breast cancer has been recognized since at least 1600 BC, when an
ancient Egyptian medical text described eight cases of a tumor or
ulcer of the breast that were treated by cauterization
• There followed many historical reports of the disease, all
concluding that there was no cure
Introduction

3. • In the seventeenth century, an understanding of the lymphatic
circulation enabled the link to be made between the breast and the
axillary lymph nodes, and led to the first lymph node surgery in
women with breast cancer.
• Radical surgery for breast cancer reached its zenith in the
nineteenth century, at the hands of the US surgeon William Halsted

4. • Breast cancer is a Systemic disease
• Chemotherapy is an integral part of treatment
Adjuvant Neoadjuvant

5. Indications of chemotherapy
• Generally recommended for >1cm tumors
• Node positive diseases
• To be considered for all Triple negative tumors
• Given high rate of recurrence and lack of options – (for hormonal
and endocrine therapies)

6. • Risk stratification of adjuvant therapy based on –
 Oncotype DX and
 MammaPrint
Indications of chemotherapy

7. Adjuvant chemotherapy

8. William Halsted’ old concept
• Introduced Halsted’s radical mastectomy
• Breast cancer arose in one location – then spread to
nearby lymph nodes and then throughout body
• So removal of breast, chest wall muscle and lymph
nodes was a logical treatment

9. Rationale for Adjuvant chemotherapy
• Fisher Hypothesis
• Gompertzian model

10. Bernard Fisher’s Hypothesis
• Breast cancer is a systemic disease in which, tumor cells
were likely to have disseminated throughout the body by the
time of diagnosis
• Locoregional therapy is hence unlikely to improve survival

11. Benjamin Gompertzian’s –
Law of Mortality
• Growth rate of tumor cells are –
 exponential at early stages of development and
 slower at later stage

12. Norton-Simon Hypothesis
• The Norton–Simon hypothesis states that
- the rate of cancer cell death in response
to treatment is directly proportional to the
tumor growth rate at the time of
treatment

13. Evolution of chemotherapy for Breast carcinoma

14. BIRTH OF CHEMOTHERAPY
• After the Second World War, the observation by Goodman and
Gilman that nitrogen mustards had the potential for anticancer
effects
• And parallel work on antifolates by Farber et al (1948), led to the
successful drug treatment for cancer.
• Subsequently, observations of uracil uptake by normal rat mucosa
and tumours led to the development of 5-fluorouracil
• Thus, cyclophosphamide+methotrexate+5-fluorouracil (CMF) – the
first effective chemotherapy regimen for breast cancer was formed
M
C
F

15. Cyclophosphamide
• Comes under class of - NITROGEN MUSTARDS
• METABOLISM  in liver by cytP450
• elimination half life 4 – 6 hrs
• BREAST CANCER: orally – 100 mg/m2 PO D1-14 every 28 days,
IV- 600 mg/m2 every 28 days as a part of
CMF regimen

16. Cyclophosphamide - Side effects
• Hemorrhagic cystitis
• Dysuria
• Increased urinary frequency, myelosuppression, mainly
neutropenia  may be dose limiting
• Hyperpigmentation of skin and nails, sterility, cardiotoxicity with
high doses

17. Cyclophosphamide - Cost

18. Methotraxate
• Comes under class of - FOLATE ANTAGONIST
• Cell cycle–specific, active in S-phase of the cell cycle
• Dose in CMF regimen – 40 mg/m2 i.v.
• Side effects –
 Mucositis
 Acute renal failure

19. Methotraxate - Cost

20. 5-Fluorouracil
• Comes under class of - PYRIMIDINE ANTAGONIST
• 5-FU and its derivatives are an integral part of treatment for a
broad range of solid tumors
• It is a S phase specific drug
• Dose in CMF regimen – 600 mg/m2

21. • Common side effects includes –
• Myelosuppression
• Mucosistis
• GI toxicity
• Hand foot syndrome
• Blepharitis
• Conjuctivitis
5-Fluorouracil
Hand foot syndrome

22. 5-Fluorouracil - Cost

23. Contd.
• CMF was tested in the 1970s by Bonadonna et al at Milan, Italy
• They demonstrated - that the risk of breast cancer recurrence after surgery could be
reduced with the addition of adjuvant chemotherapy –
and it paved the way for the development of surgical procedures less morbid than
those pioneered by Halsted.

24. Through the years..
• Although the Milan group was the first to describe the use of an
anthracycline (doxorubicin) in metastatic breast cancer (Bonadonna
et al, 1969),
the first anthracycline-containing regimen to become a ‘gold
standard’ was Doxorubicin and Cyclophosphamide (AC), investigated
initially by the NSABP in the 1990s (Fisher et al, 1990).

25. Adriamycin (Doxorubicin)

26. • Comes under class of ANTHRACYCLINES
• Antracyclins are - TOP2 inhibitors with additional effect of DNA
INTERCALATOR i.e. at higher concentrations bind to top2 cleavage
complex and inhibit binding of TOP2 to DNA
• Metabolised in liver to active form  Doxorubicinol
Adriamycin

27. • Highly Cardiotoxic drug
• Acute form presents within the first 2–3 days as arrhythmias and/or
conduction abnormalities, ECG changes, pericarditis, and/or myocarditis
• Chronic form results in a dose-dependent, dilated cardiomyopathy
associated with congestive heart failure
• Risk increases when cumulative doses are greater than 450 mg/m2
Adriamycin – Side effects

28. Adriamycin - Cost

29. • There was no efficacy advantage of AC over CMF,
possibly because of the shorter duration of treatment and the
elimination of both 5-fluorouracil and methotrexate from the
combination.
• Over the ensuing 30 years, CMF and AC became references for the
development of newer, more effective chemotherapy regimens

30. • In early attempts to improve the efficacy of CMF, a number of
investigators tested regimens where, in a 6-cycle regimen –
an anthracycline (doxorubicin or epirubicin) was substituted for
methotrexate to make either –
FAC (5-FU 500 mg/m2, Doxorubicin 50 mg/m2 & Cyclophosphamide 500 mg/m2) or
FEC (5-FU 500 mg/m2, Epirubicin 100 mg/m2 & Cyclophosphamide 500 mg/m2)

31. • Various doses of the drugs have been tested using either the classic
4-weekly schedule or a shortened 3-weekly regimen, which has
often been compared with 3-weekly CMF.
• The FAC regimen is most commonly used of those –
 5-FU 500 mg m/2
 Doxorubicin 50 mg m/2 and
 Cyclophosphamide 500 mg m/2
all drugs to be given 3 weekly (Martin et al, 2003)*
*Martin M, Villar A, Sole-Calvo A, Gonzalez R, Massuti B, Lizon J, Camps C, Carrato A, Casado A, Candel MT, Albanell J. Doxorubicin in
combination with fluorouracil and cyclophosphamide (iv FAC regimen, day 1, 21) versus methotrexate in combination with fluorouracil and
cyclophosphamide (iv CMF regimen, day 1, 21) as adjuvant chemotherapy for operable breast cancer: a study by the GEICAM group. Annals
of Oncology. 2003 Jun 1;14(6):833-42.

32. • An alternative to the substitution of methotrexate is the addition of
an anthracycline to CMF, in what is known as a block-sequential
design
• In the National Epirubicin Adjuvant Trial, four cycles of Epirubicin
were followed by four cycles of CMF, resulting in significantly
improved efficacy compared with six cycles of CMF alone (Poole et
al, 2006).

33. Addition of Taxanes
• In the 1970s, the development of the taxanes, the first new
cytotoxic drugs for several decades with activity in metastatic
breast cancer (Wani et al, 1971), was soon followed by the inclusion
of paclitaxel or docetaxel in various adjuvant chemotherapy trial
regimens –
(Henderson et al, 2003; Mamounas et al, 2005; Martin et al, 2005;
Bear et al, 2006).

34. Paclitaxel
• Taxanes were the first-in-class microtubule stabilizing drugs
• Identified in 1963  from the bark extract of the Pacific yew tree,
Taxus brevifolia
• Cell cycle–specific, active in the mitosis (M) phase of the cell cycle
• Dose - Breast cancer – TAC/Paclitaxel alone Regimen: 175 mg/m2 IV
as a 3-hour infusion every 3 weeks

35. Paclitaxel – side effects
• Myelosuppression
• Infusion reactions - Monitor patient’s vital signs every 15 minutes
during the first hour of drug administration  hypersensitivity
reactions are common
• Sensory neuropathy, numbness, paresthesias
• Transient asymptomatic sinus bradycardia is most commonly
observed cardiotoxicity
• Mucositis, diarrhoea

36. Paclitaxel - Cost

37. Docetaxel
• Semisynthetic taxane
• Metabolised by hepatic microsomal p450 system
• Commonly used at dose of 75 mg/m2 in TAC Regimen of CA Breast
• Hypersensitivity reactions and neurotoxicity are described more
common with Paclitaxel,
whereas fluid retention and fatigue are seen
with Docetaxel administration

38. Docetaxel – Cost

39. • AC (A – 50 mg/m2, C – 500 mg/m2) followed by Paclitaxel (175
mg/m2) in a block-sequential design was shown to be more
effective than AC alone (Henderson et al, 2003)*
• This regimen was subsequently ‘accelerated’ – given every 2 weeks
rather than every 3 weeks
*Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, Ingle JN, Cooper MR, Hayes DF, Tkaczuk KH,
Fleming G. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant
chemotherapy regimen for patients with node-positive primary breast cancer. Journal of clinical oncology. 2003 Mar
15;21(6):976-83.

40. The TAC regimen
• Another major development was marked by the Breast Cancer
International Research Group (BCIRG)-001 trial, in which –
• 5-fluorouracil component of FAC was replaced by docetaxel, that is,
the TAC regimen [T-75mg/m2, A-50 mg/m2, C-500mg/m2](Martin et
al, 2005)*
• The trial showed that TAC provided a significant improvement in
efficacy compared with FAC.
*Martin M, Lluch A, Segui MA, Ruiz A, Ramos M, Adrover E, Rodriguez-Lescure A, Grosse R, Calvo L,
Fernandez-Chacón C, Roset M. Toxicity and health-related quality of life in breast cancer patients
receiving adjuvant docetaxel, doxorubicin, cyclophosphamide (TAC) or 5-fluorouracil, doxorubicin
and cyclophosphamide (FAC): impact of adding primary prophylactic granulocyte-colony stimulating
factor to the TAC regimen. Annals of oncology. 2006 Aug 1;17(8):1205-12.

41. EVOLUTION OF CHEMOTHERAPY
• Primary chemotherapy may be thought of as having evolved over three
generations.
• First-generation primary chemotherapy
• Second generation primary chemotherapy
• Third-generation primary chemotherapy

42. • First-generation primary chemotherapy followed trials which proved that the
prognosis of breast cancer patients is better in patients receiving post-operative
chemotherapy.
• Second generation primary chemotherapy followed trials which demonstrated that
regimens containing anthracyclines and taxanes yielded complete pathological
response rates (pCR) of over 20%.
• Third-generation primary chemotherapy followed trials which demonstrated that
inclusion of newer agents, such as trastuzumab and capecitabine, in combination
with taxanes could yield pathological CR rates of over 30%.

44. 1st GENERATION CHEMOTHERAPY
• The 1st trials of adjuvant chemotherapy in the treatment
of breast cancer were launched in the 1950s, but it was
not until the late 1960s that the 1st modern trials of
combination chemotherapy were initiated.
• MELPHALAN was the first single agent utilized in early
1970 other single agents used after that were
cyclophosphamide, methotrexate, 5FU, Adriamycin, Mito-
c, Prednisolone etc.

45. • In May 1972, Paul P. Carbone of the National Cancer
Institute (NCI) showed Bonadonna the Medicine Branch
Annual Report, including the initial NCI data on a
quadruple drug regimen, cyclophosphamide,
methotrexate, fluorouracil and prednisone (CMFP).
• The result of study showed a remarkable response
(CR-20%) with a median duration of response of 8
months.

46. Contd.
• In 1976, Bonadonna et al. presented the 1st report on the efficacy of
CMF as adjuvant treatment for node-positive breast cancer.
• These results, along with those reported in a similar population of
patients by the National Surgical Adjuvant Breast Project (NSABP) ,
raised hopes that chemotherapy could have a more central role in the
primary management of breast cancer.

47. Bonadonna et al (1976)
Aim of the study was To assess the long term effectiveness of adjuvant treatment with
cyclophosphamide, methotrexate, and fluorouracil (CMF) in patients with operable breast cancer at
risk of relapse, on the basis of three successive randomised trials.

49. CONCLUSION (Bonadonna et al - 1976)
• After a median follow up of 28.5 years for the initial study, adjuvant CMF was found to
reduce the relative risk of relapse significantly (p = 0.005) and death (p= 0.04).
• Administration of CMF for 12 cycles does not seem superior to a shorter administration of
six cycles.

50. STUDY COMPARING
L-PAM WITH CMF
• A prospective randomized clinical trial was undertaken in 184 patients with
metastatic breast carcinoma to compare single drug chemotherapy with L-PAM
and intermittent combination chemotherapy with CMF

51. R
A
N
D
O
M
REST
PERIOD
5 FU 600
mg/M2/i.v.
1 8 14 15 - 28
DAY
MTX 60
mg/M2/i.v.
Cytoxan 100
mg/M2/p.o
L-PAM 6.0
mg/M2/p.o
1 5 6 - 42
DAY
NO
TREATMENT
THERAPY A CYCLE
THERAPY B CYCLE
Randomization
scheme
90 patients were
Treated with
multiple drug
therapy (CMF)
and 91 patients
received L -PAM

52. METASTATIC BREAST CANCER (RESPONSE TO THERAPY)
L PAM CMF
RESPONDERS 18 (20%) 49 (53%)
COMPLETE 5 14
PARTIAL 13 35
NONE 73 44
TOTAL 91 93
• This difference in response rates is highly significant (p <.001)
• The overall survival of CMF-treated patients was superior to that of the single
drug L PAM group

53. CONTD.
• Subsequently the ease of administration and the virtual absence of
severe acute toxicity made CMF the most frequently used
combination of drugs in clinical practice in oncology, as well as the
regimen against which all new systemic adjuvant treatments were
tested.

54. CONTD.
• After 20 years the patients given adjuvant combination
chemotherapy with CMF had significantly better rates of
relapse-free survival (p<0.001) and overall survival
(p=0.03) compared with no chemotherapy*
• 6 cycles of CMF was the gold standard of adjuvant
chemotherapy in breast cancer for decades.
*Bonadonna et al - 1976

56. NSABP B-13 and NSABP B-19
• STUDY to compare sequential methotrexate (M) and fluorouracil (F) (M-->F) with
surgery (National Surgical Adjuvant Breast and Bowel Project [NSABP] B-13)
• and cyclophosphamide (C), M, and F with M-->F (NSABP B-19), in patients with
estrogen receptor (ER)-negative tumors and negative axillary nodes
• A total of 760 patients were randomized to B-13; 1,095 patients were randomized
to B-19.

57.  A significant benefit in overall DFS (74% v 59%; P < .001) was
demonstrated at 8 years in all B-13 patients who received M-->F 69%
v 56% [P = .006]
 In B-19, through 5 years, an overall DFS advantage (82% v 73%; P <
.001) and a borderline survival advantage (88% v 85%; P = .06) were
evident with CMF.

58.  M-->F or CMF after lumpectomy and breast irradiation resulted in a
low probability of ipsilateral breast tumor recurrence (IBTR).
 In B-13, the frequency of IBTR was 2.6% following M-->F versus 13.4%
in women treated by lumpectomy; it was 0.6% following CMF in B-19
• In B-19, benefit from either therapy was evident in all patients, but
the CMF advantage was greater

59. 2nd GENERATION CHEMOTHERAPY
• The Milan research group decided in the early 1980s to challenge the popular
CMF combination by introducing doxorubicin within the adjuvant program
• Compared with standard CMF, anthracyclin-containing regimens reduced the
annual risk of recurrence by 12% and the annual risk of death by 11%, equating
to absolute reduction in mortality at 5 years.

60. ANTHRACYCLINES
• The first anthracycline-containing regimen to become a ‘gold standard’ was doxorubicin &
cyclophosphamide (AC) investigated initially by the NSABP in the 1990s
• The rationale for including the anthracycline was to –
 reduce the duration of treatment,
 the number of hospital visits and
 the need for antiemetic medication (classical CMF produces significant and long-lasting nausea).

61. EPIRUBICIN TRIALS
• ICCG 1996 SHOWED THAT FEC 50 AND CMF HAD SIMILAR EFFICACY IN
NODE POSITIVE PATIENTS
• FASG 1998 COMPARED FEC 100 VS FEC 50 AS ADJUVANT TREATMENT FOR
PATIENTS WITH NODE POSITIVE BREAST CANCER
5 YR OS 76% VS 65% AND DFS WAS 65% VS 52%

64. TAXANES
• In the 1970s, the development of the taxanes, the first new cytotoxic drugs for
several decades with activity in metastatic breast cancer, was soon followed by the
inclusion of paclitaxel or docetaxel in various adjuvant chemotherapy trial
regimens.
• Three of the most important trials that have shown a benefit for adjuvant taxanes
after anthracycline chemotherapy –
 CALGB 9344/Intergroup 0148 trial
 NSABP B-28 trial
 BCIRG 001 trial

65. CALGB 9344/INTERGROUP 0148 TRIAL
• 2 Arms –
 AC (A- 50 mg/m2, C – 500 mg/m2) alone
 AC (A- 50 mg/m2, C – 500 mg/m2) f/b Paclitaxel (175 mg/m2)

66. Contd.
• Conclusion: The addition of four cycles of paclitaxel after the
completion of a standard course of AC improved the disease-free and
overall survival of patients with early breast cancer
• The paclitaxel arms had a decrease in the hazard of recurrence by
17% (hazard ratio 0.83, P .0023) and the hazard of death by 18%
(hazard ratio 0.82, adjusted P .0064).
• At 5 years,
Overall survival was 77% and 80% after AC alone or AC plus
paclitaxel, respectively

67. NSABP B-28 trial
• TOTAL 3060 PATIENTS WERE RANDOMISED TO AC 1529 AND AC FOLLOWED BY PACLITAXEL 1531
• Patients 50 years and those younger than 50 years with estrogen receptor (ER) or progesterone
receptor (PR) -positive tumors also received tamoxifen for 5 years, starting with the first dose of
AC.
• Median follow-up was 64.6 months.

68. Results - NSABP B-28 trial
 The addition of PTX to AC significantly reduced the hazard for DFS
event by 17% (P .006).
 Five-year DFS was 76% for patients randomly assigned to AC 4 PTX
compared with 72% for those randomly assigned to AC.
 Toxicity with the AC 4 PTX regimen was acceptable for the adjuvant
setting.

69. • The addition of PTX to AC resulted in significant improvement in DFS but no significant
improvement in OS with acceptable toxicity.
• No significant interaction between treatment effect and receptor status or tamoxifen
administration was observed

70. BCIRG 001 trial
 1491 women with axillary node-positive breast cancer
 Median follow-up of 55 months
• TAC vs FAC in Breast Cancer
 F 500 mg/m2
 A 50 mg/m2
 C 500 mg/m2 q3 wks x 6
 T (Docetaxel) 75 mg/m2
 A 50 mg/m2
 C 500 mg/m2 q3 wks x 6
55 MONTHS
DFS
TAC
75%
FAC
68%
P=.0001
OS 87% 81% P=.008

71. REVIEW OF ADJUVANT TAXANE CHEMOTHERAPY TRIALS

72. Conclusion of these 3 trials
• In aggregate, these trials have indicated that –
the addition of taxanes to anthracycline chemotherapy provides an
additional reduction in the risk of recurrence in the adjuvant
treatment of breast cancer.

73. CONTD.
• AC followed by Paclitaxel in a block-sequential design was shown to be
more effective than AC alone
• This regimen was subsequently ‘accelerated’ – given every 2 weeks
rather than every 3 weeks – an adaptation made possible through the
use of granulocyte colony-stimulating factor, which helped to prevent
chemotherapy-associated neutropenia
• The accelerated approach resulted in a further increment in antitumor
activity

74. 2 Weekly
Dose dense

75. NODE NEGATIVE BREAST CANCER
• GIECAM 9805 (FAC VS TAC)
• GIECAM / 2003-02 (FAC VS FAC WITH PACLITAXEL)

76. GIECAM 9805 (FAC VS TAC) in Node negative disease
• A regimen of docetaxel, doxorubicin, and cyclophosphamide (TAC) was
superior as compared with regimen of fluorouracil, doxorubicin, and
cyclophosphamide (FAC) when used as adjuvant therapy in women with
node-positive breast cancer.
• The value of taxanes in the treatment of node-negative disease was not
determined. 1060 women were randomly assigned to treatment with TAC
or FAC every 3 weeks for six cycles after surgery
• In women with high risk, node negative breast cancer;
• TAC significantly improved DFS (32% reduction in risk of recurrence at 77
months; P<0.01 )

77. GIECAM / 2003-02 (FAC VS FAC WITH PACLITAXEL)
• After primary surgery, 1,925 patients were randomly assigned to
receive fluorouracil, doxorubicin, and cyclophosphamide (FAC) × 6 or
FAC × 4 followed by wP × 8 (FAC-wP)
• Results:
• At a median follow-up of 63.3 months:
• 5Y-DFS: 93% in FAC-wP vs 90.3% in FAC
• FAC-wP reduced the risk of relapse by 26.7% compared with FAC
(statistically sig.)

78. Neo-adjuvant Chemotherapy

79. Benefits of pre-operative systemic
chemotherapy
• Can render inoperable tumors operable
• Allows time for Genetic testing

80. • Inflammatory breast disease
• Bulky or matted axillary nodes
• N3 Nodal disease
• T4 disease
• In operable breast cancer – NACT can be given to large primary
tumor in a patient who desires breast conservation
Candidates of pre-operative systemic
chemotherapy

85. 3rd GENERATION CHEMOTHERAPY
• 3rd gen chemotherapy brings forward an age of Targeted
Chemotherapy.
• Up to 25% of women with early breast cancer (EBC) have
human epidermal growth factor receptor 2 (HER-2)-positive disease,
which is associated with –
aggressive disease, a
 higher likelihood of recurrence after initial treatment, and
 a poor prognosis

86. TRASTUZUMAB
• Trastuzumab is a recombinant humanized monoclonal antibody that –
 binds with high affinity to the extracellular domain of HER 2 and
 inhibits proliferation in human tumour cells that over express HER 2
• Trastuzumab was the first HER2-targeted therapy approved by the US
FDA in 1998 for the treatment

87. Trastuzumab based Chemotherapy Regimens
*Within 3 weeks after completing all chemotherapy.
TCH=docetaxel and carboplatin plus Herceptin.
AC➝TH=doxorubicin and cyclophosphamide followed by paclitaxel or docetaxel plus Herceptin.

88. Trastuzumab - Cost

89. • Several clinical trials subsequently established the fact that the addition
of Trastuzumab to adjuvant chemotherapy (either in sequence or in
combination) resulted in significant improvement in disease-free and OS
rates in patients with early-stage HER2-overexpression MBC
• These trials included –
NSABP B 31
NCCTG N9831
HERA Trial
FinHer study and
BCIRG 006

90. Trastuzumab in early breast cancer: study designs of the adjuvant trials

91. RESULTS
1. HERA Trial :- Trastuzumab — 1 year reduced the relative risk of
recurrence over chemotherapy alone by 46% (8.4% absolute
reduction of the risk at 3 years), there was insufficient follow-up to
assess the trastuzumab—2 years arm
2. NSABP B31 & NCCTG N9831 :-Trastuzumab reduced the relative risk
of recurrence over chemotherapy alone by 52% (12% absolute
reduction of the risk at 3 years), there was a 33% proportional
reduction in the risk of death

92. RESULTS
3. BCIRG 006 :-Trastuzumab reduced the relative risk of recurrence or
death over chemotherapy alone by 39%
4. FinHer :-Trastuzumab reduced the relative risk of recurrence or
death over chemotherapy alone by 58% (11% absolute reduction of
the risk at 3 years

93. Progressive disease during trastuzumab treatment
• Two randomized trials have now evaluated the role of continuing
trastuzumab treatment beyond tumor progression.
• Von Minckwitz et al. compared capecitabine alone or with trastuzumab
among women with HER-2/neu positive MBC progressing under
previous trastuzumab based therapy.
• The study demonstrated an improvement in recurrence rate but could
not demonstrate an OS benefit

94. • Another trial tested progressing disease under –
trastuzumab, anthracycline and taxanes and randomized between –
addition of Lapatinib to trastuzumab and Lapatinib only.
• This study showed a significant improvement in clinical benefit rate &
a trend favoring OS.
• These findings indicate that continuing trastuzumab may have
benefits, but the magnitude of such benefits is unknown

95. Chemotherapy after anthracycline & taxane pretreatment
• Current therapy of choice is anthracycline & taxane based chemotherapy.
• If patient fails to respond or relapse after receiving these agents then
Several agents, including –
• Capecitabine
• Vinorelbine
• Gemcitabine
• Epithilones
• Platinum salts
as well as combinations have been investigated.

96. Contd.
• Of those, CAPECITABINE has been the most frequently used agent,
given its efficacy, safety and ease of administration.
• More recently, IXABEPILONE (an analogue of epithilone B), has
emerged as an active agent
• A recent phase 3 trial demonstrated that addition of Ixabepilone to
Capecitabine is associated increased OS as compared with
capecitabine alone.

97. RECOMMENDATIONS
• Consecutive cytotoxic chemotherapy is worth considering
in women who have responded to previous regimens, but
no definitive guidance exists regarding –
the optimal agents or the order they should be
administered.

98. Metastatic breast cancer

99. Treatment goals in Metastatic Breast
Carcinoma
• Palliation of signs and symptoms
• Control of tumor burden
• Maintenance of quality of life and function

100. Prognostic Factors in Patients With Metastatic
Breast Cancer
Prognostic factor Favorable Unfavorable
Performance status Good Poor
Sites of disease Bone, soft tissue Viscera, CNS
No. of sites of disease Few Multiple
Hormone receptor status Positive Negative
Her-2/neu status Negative
Positive (significance
less clear in Her-2/neu
inhibitors era)
Disease-free interval >2 years <2 years

101. Systemic Treatment Approach for Metastatic Breast
Cancer
Metastatic Breast Cancer
• Limited metastases (bone & soft
tissue)
• Positive hormone receptors
• 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

102. Role of Chemotherapy in metastatic
breast cancer

103. NICE clinical guideline
• For patients with Metastatic breast cancer who are not suitable for
Anthracyclines (because they are contraindicated or because of prior
Anthracycline treatment either in the adjuvant or metastatic setting),
systemic chemotherapy should be offered in the following sequence:
First line: single-agent docetaxel
Second line: single-agent vinorelabine or capecitabine
Third line: single-agent capecitabine or vinorelabine (whichever was
not used as second-line treatment).

104. Single vs Combination chemotherapy
• In E 1193 trial
• 700 women were randomly assigned to
 doxorubicin plus paclitaxel (AP) (50 mg/m(2) and 150 mg/m(2))
 Doxorubicin (60 mg/m(2))
 or paclitaxel (175 mg/m(2))

105. • Treatment with AP resulted in:
 A higher overall response rate (ORR) compared with doxorubicin or
to paclitaxel (47 versus 36 and 34 percent)
 However, there was no difference in overall survival (OS; 22 versus
19 and 22 months)

106.  Patients were randomly assigned to
 GD (G 1,000 mg/m2 days 1 and 8; D 75 mg/m2 day 1) or
 CD (C 1,250 mg/m2 twice daily days 1 through 14; D 75 mg/m2 day 1)
every 21 days

107. GD vs CD
 No difference was observed between GD and CD arms in OS

108. 752 patients were randomly assigned to
 Ixabepilone 40 mg/m2 intravenously on day 1 of a 21-day cycle
plus capecitabine 2,000 mg/m2 orally on days 1 through 14 of a 21-day cycle, or
 capecitabine alone 2,500 mg/m2 on the same schedule,
The primary end point was progression-free survival

109. • Ixabepilone plus capecitabine demonstrated superior efficacy to
capecitabine alone in patients with metastatic breast cancer pretreated or
resistant to anthracyclines and resistant to taxanes.
• Ixabepilone plus capecitabine prolonged progression-free survival relative
to capecitabine (median,5.8 v 4.2 months), with a 25% reduction in the
estimated risk of disease progression (hazard ratio, 0.75; 95% CI, 0.64 to
0.88; P .0003)
• Grade 3/4 treatment-related sensory neuropathy (21% v 0%), fatigue (9% v
3%), and neutropenia (68% v 11%) were more frequent with combination
therapy

111. Conclusion regarding current chemotherapy regimens for
Breast Cancer
• There is currently no one gold standard chemotherapy regimen in
breast cancer.
• The proliferation and diversity of trials, with varying interpretations
of the standard of care, has led to endless conjecture on the best
treatment

112. • The latest guidelines on breast cancer management from the
National Institute for Health and Clinical Excellence (NICE)
emphasise the importance of chemotherapy for both –
 early (NICE, 2009a) and
 advanced disease (NICE, 2009b).
• More specifically, for lymph node-positive early or locally advanced
breast cancer, NICE states that docetaxel, not paclitaxel, should be
part of the chemotherapy regimen (NICE, 2009a).

114. • No gold standard regimens, however there is general agreement that –
• CMF-like regimens are better than nothing
• Anthracycline-containing regimens are better than CMF
• Taxanes further add to the benefit of anthracyclines

115. Thank you