This document discusses chemotherapy for early breast cancer. It begins with background on breast cancer prevalence and stages. It then reviews the history of theories about breast cancer spread and the development of adjuvant systemic therapy. Current guidelines recommend an individualized approach considering prognostic factors. For HER2-negative disease, preferred regimens include dose-dense doxorubicin and cyclophosphamide followed by paclitaxel or docetaxel and cyclophosphamide. For HER2-positive disease, preferred regimens include the same chemotherapy plus trastuzumab with or without pertuzumab. The document discusses other regimens and toxicities to consider when determining chemotherapy for early breast cancer patients.

1. Where , When and How to give
chemotherapy in Early Breast Cancer.
Dr Deepika Malik
JR II, Department of Radiotherapy

2. Breast cancer –
 second most common cancer in the world ,
 most frequent cancer among women with an estimated
1.67 million new cancer cases diagnosed in 2012 (25%
of all cancers).
 It is the most common cancer in women both in more
and less developed regions with slightly more cases in
less developed (883,000 cases) than in more developed
(794,000) regions

3. Early stage breast cancer

4. Introduction
 Breast cancer is most often curable when
detected in early stages
 Micrometastases exist at the time of
diagnosis in most of the patients, leading
to spread of disease , locoregionally and
distant.
 Adjuvant systemic therapy has been found
to prolong both overall and disease-free
survival in breast cancer patients

5. History
 Henri Francois Le Dran (1685-
1770), a French surgeon
 proposed that breast cancer was
a localized disease that spread to
regional lymph nodes (RLNs) and
that the only hope for cure was
early surgery

6.  Le Dran’s proposal was further taken to
its logical conclusion by Halstead.
 The Halstedian theory was based upon:
 Local and regional nodes were the first
level of metastatic spread
 They were effective barriers against
further spread

7.  This concept , that breast cancer was a
localized disease that spread in an orderly
manner dominated cancer theory for the
next 200 years.

8.  The concept was challenged by the Fisher
brothers (Edward and Bernard), who
showed in a series of trials conducted by
the NSABP that:
 Lymph nodes were not effective as
barriers against systemic spread
 Hematogenous dissemination was as
important as lymphatic dissemination

9.  Systemic therapy is therefore effective in
Breast cancer.

10. Timeline!!!!

12. THE PAST
 2 Because adjuvant polychemotherapy improves
survival, it should be recommended to the majority of
women with localized breast cancer regardless of
lymph node, menopausal, or hormone receptor status.
 The inclusion of anthracyclines in adjuvant
chemotherapy regimens produces a small but
statistically significant improvement in survival over
non-anthracycline-containing regimens. 00 (2000 NCI
Consensus Development Conference on Adjuvant Breast
Cancer 0 NCI Consensus
National Institutes of Health Consensus Development Conference
Statement: Adjuvant Therapy for Breast Cancer, November 1–3, 2000
Adjuvant Breast Cancer)

13. THE PRESENT AND FUTURE
 We are moving towards a more indivisualistic approach in giving
chemotherapy to early stage breast cancer patients!!!!!!!!!

14. What does NCCN panel
say?

15. NCCN Version 3.2015
 After surgical treatment , adjuvant systemic
therapy should be considered.
 The decision to use systemic adjuvant
chemotherapy requires considering and balancing
risk for
-disease recurrence alone
-magnitude of benefit from applying
adjuvant therapy
-toxicity of therapy
-comorbidity.

16. Adjuvant!Online
 Validated computer based model
 Algorithm which estimates rates of
recurrence
 estimates 10 year DFS and OS
 Making use of all prognostic factors for
breast cancer ( except HER2 tumor status) ie
patient age, comorbidity , tumor size, tumor
grade, number of LN’s involved, LVE, PNI.

17. Adjuvant online contd..
 Aids clinician in objectively estimating
- outcome with local treatment only
- absolute benefits expected from
systemic adjuvant therapy
 These estimates are utilised by clinician for
patient to decide regarding toxicities and
benefits of systemic therapy.

18. HER2 Status
 HER2 tumor status provides predictive information
in selecting optimal adjuvant therapy and in the
selection of therapy for recurrent or metastatic
disease

19.  For example, retrospective analyses have
demonstrated that
-anthracycline-based adjuvant therapy
is superior to non-anthracycline
based adjuvant chemotherapy in
patients with HER2-positive disease

20. Five major subtypes of breast cancer have
been identified

22. DNA microarray assays
 Characterize breast cancer
 Allow for classification of breast cancer
by gene expression profile.
 In retrospective analyses, these gene
expression subtypes are associated with
differing relapse-free survival and OS.

23. Oncotype DX
 The 21-gene assay using reverse
transcription polymerase chain reaction
(RT-PCR) on RNA isolated from paraffin-
embedded breast cancer tissue (Oncotype
DX)
 among the best-validated prognostic
assays
And can predict who is most likely to
respond to systemic chemotherapy.

24.  Patients with a high score benefited from
chemotherapy
 patients with a low score did not appear to
benefit from the addition of chemotherapy
regardless of the number of positive lymph nodes.
 (clinical practice)

25. Mamma print Assay
 uses microarray technology
 to analyze a 70-gene expression profile from
breast tumor
 to help identify patients with early-stage
breast cancer likely to develop distant
metastases.
 approved by the FDA and assigns women of all
ages with ER-positive or ER-negative breast
cancer as having high versus low risk for
recurrence.
 but it does not predict benefit from adjuvant
systemic therapy.

26.  the prospective RASTER study reported
that breast cancer patients classified by
MammaPrint as low risk (of whom 85% did
not receive adjuvant chemotherapy) had
an overall 97% distant recurrence-free
interval at five years.

27. PAM 50
 The Prediction Analysis of Microarray 50
(PAM50)
 50-gene test
 identifies intrinsic breast cancer subtypes
(luminal A, luminal B, HER2 enriched and
basal-like) in addition to generating a risk
of recurrence (ROR) score that can be
used to predict prognosis among
postmenopausal women with hormone-
positive breast cancer

28.  The NCCN Panel members acknowledge
that many assays, including PAM50 and
MammaPrint, have been clinically
validated for prediction of prognosis.
 However, based on the currently available
data, the panel believes that the 21-
gene assay has been best-validated for its
use as a prognostic test as well as in
predicting who is most likely to respond
to systemic chemotherapy

29. Chemotherapy regimens

30.  Cyclophosphamide+methotrexate+5-
fluorouracil (CMF) – the first effective
chemotherapy regimen for breast cancer
(Bonadonna et al, 1976).
 2 weeks of oral cyclophosphamide for
each cycle, and produced significant and
long-lasting nausea

31.  the first anthracycline-containing regimen to
become a ‘gold standard' was
doxorubicin+cyclophosphamide (AC), investigated
initially by the NSABP in the 1990s (Fisher et al,
1990)
 The rationale for including anthracycline was to
reduce the duration of treatment, the number of
hospital visits and the need for antiemetic.

32.  Over the ensuing 30 years, CMF and AC became
references for the development of newer, more
effective chemotherapy regimens.

33.  Owing to potential cardiotoxicity of
doxorubicin, epirubicin was introduced .
 (French Adjuvant Study Group, 2001)

34.  In the 1970s, the development of the taxanes,
the first new cytotoxic drugs after several
decades with activity in metastatic breast cancer
(Wani et al, 1971)
 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).

35.  AC followed by paclitaxel was shown to be
more effective than AC alone (Henderson et al,
2003).
 subsequently ‘accelerated' – given every 2
weeks rather than every 3 weeks (an
adaptation made possible through the use of
granulocyte colony-stimulating factor),

36. Chemotherapy regimens
NCCN Version 3.2015

37. HER 2 negative disease
Preferred regimens:
 • Dose-dense AC (doxorubicin/cyclophosphamide)
followed by paclitaxel every 2 weeks
 • Dose-dense AC (doxorubicin/cyclophosphamide)
followed by weekly paclitaxel
 • TC (docetaxel and cyclophosphamide)

38.  Dose-dense AC followed by paclitaxel chemotherapy
• Doxorubicin 60 mg/m2 IV day 1
• Cyclophosphamide 600 mg/m2 IV day 1
Cycled every 14 days for 4 cycles.
(All cycles are with myeloid growth factor support)
Followed by:
• Paclitaxel 175 mg/m2 by 3 h IV infusion day 1 Cycled every
14 days for 4 cycles.

39.  Dose-dense AC followed by weekly paclitaxel
chemotherapy1
 • Doxorubicin 60 mg/m2 IV day 1
 • Cyclophosphamide 600 mg/m2 IV day 1
Cycled every 14 days for 4 cycles.
(All cycles are with myeloid growth factor support)
Followed by:
 • Paclitaxel 80 mg/m2 by 1 h IV infusion weekly
for 12 wks.

40.  TC chemotherapy
 • Docetaxel 75 mg/m2 IV day 1
 • Cyclophosphamide 600 mg/m2 IV day 1
Cycled every 21 days for 4 cycles.
 (All cycles are with myeloid growth factor
support)

41. HER2 negative disease
 Other regimens
 • Dose-dense AC
(doxorubicin/cyclophosphamide)(60,600), every
14 days , 4 cycles
 • AC (doxorubicin/cyclophosphamide)
(60,600)every 3 weeks ,4 cycles
 •FAC(fluorouracil/doxorubicin/cyclophosphamide
) 500 mg/m2i/v day 1 and day 8 or day 1 nd day
4; 50mg/m2; 500 mg/m2) every 3 weeks, 6
cycles

42.  • FEC
(cyclophosphamide/epirubicin/fluorouracil)
 (75 mg/m2 p/o d1-d14; 60 mg/m2 i/v
d1,d8;500mg/m2 i/v d1,d8) every 28 days,
6cycles
 • CMF
(cyclophosphamide/methotrexate/fluorouracil) (
100 mg/m2 p/o d1-14; 40 mg/m2 d1,d8; 600
mg/m2 d1,d8) every 28 days, 6 cycles

43.  • AC followed by docetaxel every 3 weeks
 • AC followed by weekly paclitaxel
 • EC (epirubicin/cyclophosphamide)
 • FEC/CEF followed by T
(fluorouracil/epirubicin/cyclophosphamide followed
by docetaxel) or
(fluorouracil/epirubicin/cyclophosphamide followed
by weekly paclitaxel)
 • FAC followed by T
 (fluorouracil/doxorubicin/cyclophosphamide followed
by weekly paclitaxel)
 • TAC (docetaxel/doxorubicin/cyclophosphamide)

44. HER 2 positive disease
Preferred regimens
 AC followed by T + trastuzumab ± pertuzumab
Doxorubicin 60 mg/m2 IV day 1
Cyclophosphamide 600 mg/m2 IV day 1
Cycled every 21 days for 4 cycles.
Followed by:
Paclitaxel 80 mg/m2 by 1 h IV weekly for 12 wks
With:
• Trastuzumab 4 mg/kg IV with first dose of paclitaxel
Followed by:
• Trastuzumab 2 mg/kg IV weekly to complete 1 y of treatment.
As an alternative, trastuzumab 6 mg/kg IV every 21 days may be used following the
completion of paclitaxel, and given to complete 1 y of trastuzumab treatment.
 Cardiac monitoring at baseline, 3, 6, and 9 mo.

45.  TCH
Docetaxel 75 mg/m2 IV day 1
Carboplatin AUC 6 IV day 1
Cycled every 21 days for 6 cycles
With:
• Trastuzumab 4 mg/kg IV wk 1
Followed by:
• Trastuzumab 2 mg/kg IV for 17 wks
Followed by:
• Trastuzumab 6 mg/kg IV every 21 days to complete 1 year of trastuzumab therapy
Cardiac monitoring at baseline, 3, 6, and 9 months.

46. Her 2 positive disease
 Other regimens
 • AC followed by docetaxel + trastuzumab ± pertuzumab
 • Docetaxel + cyclophosphamide + trastuzumab
 • FEC followed by docetaxel + trastuzumab + pertuzumab9
 • FEC followed by paclitaxel + trastuzumab + pertuzumab
 • Paclitaxel + trastuzumab
 • Pertuzumab + trastuzumab + docetaxel followed by FEC
 • Pertuzumab + trastuzumab + paclitaxel followed by FEC9

47. The biggest concern- toxicities!!!

48. Chemotherapy toxicities!!!!

49. Specific drug considerations

50. Anthracyclines
Very strong vesicants!!!!
- dilute with NS to yield a final
concentration of 2mg/ml
- reconstituted solution stable for 7 days at
room temperature;15 days under refrigeration

51. Anthracyclines..
• administered slowly with a
rapidly flowing IV
• if extravasation suspected ,
immediately stop infusion,
withdraw fluid, elevate
extremity , apply ice to involved
site.
• if severe, may consult a plastic
surgeon

52. 5- fluoro uracil.
“Hand –foot syndrome”
(palmar- plantar erythrodysestheia)--- tingling
numbness,pain, erythema, dryness, rash, pruritis
and/or desquamation of hands and feet

53. Paclitaxel
Administration
-dilute in 5%D or NS to a final
concentration of 0.3-1.2 mg/ml
-administer in either glass or polyolefin
containers using 0.22 micrometer filter
and polyethylene lined i/v sets
- do not use PVC i/v sets since
cremaphor EL causes leaching into
infusion fluid.
Toxicities- severe myelosuppression, hypersensitivity
reactions, neurotoxicity.

55.  Chemotherapy is an integral part of mutidisciplinary
management of early breast cancer
 From giving chemotherapy to all Breast cancer patients
after surgery , we are now moving towards a more
indivisualistic approach
TAKE HOME

56.  Her 2 neg disease
 • AC ( 4)followed by paclitaxel(4).. every 2
weeks , 4 cycles
 • AC( 4) every 2 weeks followed by weekly
paclitaxel (12)
 • TC , every 21 days, 4 cycles

57.  HER 2 positive disease
AC followed by T + trastuzumab
TCH

58. Thank you.
Have a good day 