This document summarizes the presentation of Dr. Sadia Sadiq on locally advanced breast cancer and chemotherapy. The presentation covers staging of breast cancer, local surgical treatments, management of the axilla, adjuvant and neoadjuvant chemotherapy. It discusses the evolution of surgical treatments from radical mastectomy to breast-conserving surgery plus radiation. It also summarizes landmark trials comparing different chemotherapy regimens and the addition of taxanes to anthracycline-based regimens. Finally, it notes that sequential therapy with anthracyclines/alkylators followed by taxanes was proven superior to concurrent taxane-anthracycline-alkylator treatments.

1. DR SADIA SADIQ
PGR 4,INMOL
LOCALLYLOCALLY
ADVANCED CAADVANCED CA
BREAST &BREAST &
CHEMOTHERAPYCHEMOTHERAPY

2. PRESENTATION OUTLINEPRESENTATION OUTLINE
 STAGING
 LOCAL SURGICAL
TREATMENT
 MANAGEMENT OF
AXILLA
 ADJUVANT
CHEMOTHERAPY
 NEO-ADJUVANT
CHEMO THERAPY
 TOPICS NOT
COVERED
 Genetics
 Workup
 Noninvasive Breast
Cancer
 Metastatic Breast
Cancer
 Hormonal Therapy
 Targetted Therapy
 Radiation Therapy

4. LOCAL MANAGEMENT OFLOCAL MANAGEMENT OF
INVASIVE CANCERINVASIVE CANCER
 Theevaluation of the patient newly
diagnosed with breast cancer begins
witha determination of operability.
 In the patient with clinicalstage I, II, and
T3N1 disease, the initial management is
usually surgical
 Patients with T4 tumors and those with N2 or
N3 nodal disease are not candidates for surgery as
the first therapeutic approach and should
be treated with systemic therapy initially

5. SURGICAL TREATMENTSURGICAL TREATMENT
HALSTEDIAN ERAHALSTEDIAN ERA
 WILLIAM HALSTED(1894) popularised radical
mastectomy as the treatment of choice for breast
cancer ,considered breast cancer strictly as a
locoregional disease.

6. HALSTEDIAN PRINCIPLEHALSTEDIAN PRINCIPLE
 Tumor spreads in an orderdly pattern
 Lymphnodes acts as barrier to spread, blood stream
is of little significance
 More radical the surgery , more the chance of cure
 Recurrance & death are due to inadequacy of
surgery

7. FISHER CONCEPTFISHER CONCEPT
 During the second half of 19th
century
alternate hypothesis (Fisher
Concept)emerged which stressed breast
cancer as a systemic disease.
 Operable breast cancer is a systemic disease
 Blood stream is of considerable importance
for tumour dissemination
 No orderly spread
 Regional lymph nodes are of biological
importance

8. NSABP B-04NSABP B-04
 Between 1971-74, 1765 patients from 34 institutions
across USA and Canada participated.
 Objective was to find whether reducing the extent of
surgery might not compromise outcome.
 Two companion trials conducted in parallel –one for
those with clincally node negative patients and other
for clinically node positive patients.
 Radical Mastectomy served as control arm for both.

9. SCHEMASCHEMA
 No difference in overall survival
among 3 arms in clinically node
negative patient.25% for RM arm,
19% for TM/radiation arm, 26%
for TM.
 P=0.38, Confidence Interval:0.91
to 1.28
 In node positive patients overall
survival 14% in each arm.
 P=0.72,Confidece Interval :0.87-
1.23
CONCLUSION :
MRM = RM
(OS,DFS)

10. MODIFIED RADICALMODIFIED RADICAL
MASTECTOMY VSMASTECTOMY VS
BREASTBREAST
CONSERVATIVECONSERVATIVE
SURGERYSURGERY

11. MRM vs BCS+RTMRM vs BCS+RT
 The NSABP B-06 trial, along with other trials
conducted by the Milan group to evaluate
quadrantectomy, was instrumental in the
establishment of breast conserving surgery plus
radiotherapy as the preferred method of local
treatment for patients with operable breast cancer.
 OBJECTIVE : To find whether LUMPECTOMY &
AXILLARY DISSECTION with or without
RADIOTHERAPHY is better than TOTAL
MASTECTOMY with AXILLARY DISSECTION in
early stage breast cancer (stage I & IIwith tumour
size < 4 cm,N0/N1)

12. NSABP B-06 :SCHEMA & RESULTSNSABP B-06 :SCHEMA & RESULTS
MRM=BCS+RT

13. NSABP 6: BCS +RT BETTER THANNSABP 6: BCS +RT BETTER THAN
BCS ALONEBCS ALONE
 After 25 years of follow-
up, the cumulative
incidence of a
recurrence of tumor in
the ipsilateral breast
was 39 percent in the
group treated with
lumpectomy alone and
14 percent in the group
treated with
lumpectomy and breast
irradiation (P<0.001)

14. RISK FACTORS FOR LOCALRISK FACTORS FOR LOCAL
RECURRENCR AFTER BCS+RTRECURRENCR AFTER BCS+RT

15. LOCAL RECURRENCE AFTERLOCAL RECURRENCE AFTER
BCS…INCREASED?BCS…INCREASED?
The incidence of LR after BCT has
Declined over time,from 10-year rates
of 8% to 19% seen in retrospective
studies and the initial Randomized
trials of BCT,to 2% to 7% in patients
excised to negative margins in more
recent studies.

16. TYPES OF MRMTYPES OF MRM

17. Importance of Axillary Lymph NodeImportance of Axillary Lymph Node
StatusStatus
 Nodal status determines stage, predicts outcome
 Nodal status influences adjuvant therapy
decisions:
- Chemotherapy, anti-estrogen therapy
- Drug choice, dose, combination
- Radiation therapy
 ALND provides excellent long term control with only
1.4% of pts in NSABP B-04 trial,treated with radical
mastectomy had isolated axillary recurrences at 10
year follow up.

18. SSlnb after neoadjuvantlnb after neoadjuvant
chemotherapychemotherapy
 SLNB is a standard established procedure for
node negative early stage breast cancer. SLNB
after NAC is gradually being accepted for
operable node positive breast cancer patients
who turn out to be cN0 after NAC
 NAC downstages axillary nodes in about 20-40% of
the patients
 There is potential for decreasing the extent of
axillary surgery with SNB vs. AND if the axillary
nodes are down-staged with NAC

20. RESULTS:
SLNB after NAC in biopsy proven node positive
patients results in reasonably acceptable FNR and
IR making it a valid alternative management
strategy to axillary dissection. More refined patient
selection and optimal techniques can improve the
FNR and INR in this patient population.

21. NCCN 2017

22. Evolution of ChemotherapyEvolution of Chemotherapy
 Improvements in disease-free survival (DFS) with single-
agent chemotherapy after radical mastectomy in the 1970s.
 Polychemotherapy was first evaluated by Bonadonna
– randomized women with node-positive breast cancer to 12
monthly cycles of cyclophosphamide, methotrexate, and 5-
fluorouracil (CMF) chemotherapy
– or no further therapy after radical mastectomy

23. Adjuvant ChemotherapyAdjuvant Chemotherapy
of Primary Breast Cancer:of Primary Breast Cancer:
 Chemotherapy Improves Disease-Free and Overall
Survival
 Polychemotherapy > Monochemotherapy
 Multiple Cycles > Single Exposure
 Anthracycline Combinations > CMF
 Taxanes > anthracycline alone in node +ve and high
risk node –ve
Adriamycin Doses < 40mg/m2
are Inferior to 60 mg/m2
(CALGB 8541)
Cyclophosphamide Doses > 600 mg/m2
are not Superior (NSABP B-22)
Chemotherapy Seems More Effective in ER- Than ER+ Disease (EBCTCG)

24. RFS(HR 0.71) and OS(0.79)
in node +ve pts
RFS(HR 0.65) and
OS(HR 0.65) in node –
ve ER-ve pts

25. ANTHRACYCLINES:AC vs CMFANTHRACYCLINES:AC vs CMF

26. AT 5 years
RFS 63% vs 53%
OS 70% vs 77%
AT 10 years
RFS 52% vs 45%
OS 62% vs 58%
FEC vs CMF

27. BCIRG 001 TAC vs FACBCIRG 001 TAC vs FAC
After a median follow-up of 124 months, disease-free survival was
62% for patients in the TAC group and 55% for patients in the FAC
group (HR]0·80 ,long rank p=0·0043).
10-year overall survival was 76% for patients in the TAC group and
69% for patients in the FAC group (HR 0·74; log-rank p=0·0020)
1,480 women with node-positive
breast cancer

28. ADDITION OF PACLITAXEL TO ACADDITION OF PACLITAXEL TO AC

NSABP-B28 (Mamounas et al.
2005):

3,060 LN+ patients
randomized to

AC × 4 ± Paclitaxel.

Addition of taxane improved 5-
year DFS (72→76%) and LRR,
despite delay of RT (9.7 vs.
3.7%).
 CALGB 9344 (Sartor et
al.2005;Henderson et al. 2003)
 Randomization : Standard dose AC
vs. dose escalation of doxorubicin ±
sequential addition of paclitaxel.
 At 5 years, the disease-free
survival rates were 65% for the
AC-treated cohort and 70% for
the AC-plus-paclitaxel treatment
group, and overall survival rates
were 77% and 80%, respectively.
 No DFS or OS improvement
with dose escalation of
doxorubicin.


29. AC vs TCAC vs TC

USOT (Jones et al. 2009):

1,016 Stage I–III patients randomized to AC × 4 vs. TCx4.

With a median of 7-year follow-up,

TC improved DFS (81 vs. 75%) and OS (87% TC v
82).

TC improved outcomes regardless of age, hormone
receptor, or HER2 expression status.

30. PACLI vs DOCE…WEEKLY vs 3PACLI vs DOCE…WEEKLY vs 3
WEEKLY..E1199WEEKLY..E1199

31. When compared with the
standard every-3-week
paclitaxel arm, after a median
follow-up of 12.1 years, DFS
significantly improved and
overall survival (OS)
marginally improved only for
the weekly paclitaxel and
every-3-week docetaxel arms .

32. DOSE-DENSE TREATMENT ANDDOSE-DENSE TREATMENT AND
COCURRENT vs SEQUENTIALCOCURRENT vs SEQUENTIAL
Four-year disease-free survival was 82% for the dose-dense regimens and 75%
for the others. There was no difference in disease-free or overall survival
between the concurrent (dose-dense) and sequential schedules.

33. SequentialSequential therapytherapy withwith
anthracyclines/alkylatorsanthracyclines/alkylatorsfollowe by taxanes provedfollowe by taxanes proved
superiorsuperior toto concurrentconcurrent taxane-taxane-
anthracycline- alkylatoranthracycline- alkylator treatments.treatments.
 BACKGROUND:
 Chemotherapy regimens that combine anthracyclines and taxanes result in improved disease-free and overall survival
among women with operable lymph-node-positive breast cancer. The effectiveness of concurrent versus sequential
regimens is not known.
 METHODS:
 We randomly assigned 5351 patients with operable, node-positive, early-stage breast cancer to receive four cycles of
doxorubicin and cyclophosphamide followed by four cycles of docetaxel (sequential ACT); four cycles of doxorubicin
and docetaxel (doxorubicin-docetaxel); or four cycles of doxorubicin, cyclophosphamide, and docetaxel (concurrent
ACT). The primary aims were to examine whether concurrent ACT was more effective than sequential ACT and
whether the doxorubicin-docetaxel regimen would be as effective as the concurrent-ACT regimen. The secondary
aims were to assess toxic effects and to correlate amenorrhea with outcomes in premenopausal women.
 RESULTS:
 At a median follow-up of 73 months, overall survival was improved in the sequential-ACT group (8-
year overall survival, 83%) as compared with the doxorubicin-docetaxel group (overall survival, 79%; hazard ratio for
death, 0.83; P=0.03) and the concurrent-ACT group (overall survival, 79%; hazard ratio, 0.86; P=0.09). Disease-free
survival was improved in the sequential-ACT group (8-year disease-free survival, 74%) as compared with the
doxorubicin-docetaxel group (disease-free survival, 69%; hazard ratio for recurrence, a second malignant condition, or
death, 0.80; P=0.001) and the concurrent-ACT group (disease-free survival, 69%; hazard ratio, 0.83; P=0.01). The
doxorubicin-docetaxel regimen showed noninferiority to the concurrent-ACT regimen for overall survival (hazard ratio,
0.96; 95% confidence interval, 0.82 to 1.14). Overall survival was improved in patients with amenorrhea for 6 months
or more across all treatment groups, independently of estrogen-receptor status.
 CONCLUSIONS:
 Sequential ACT improved disease-free survival as compared with doxorubicin-docetaxel or concurrent ACT, and it
improved overall survival as compared with doxorubicin-docetaxel. Amenorrhea was associated with improved survival
regardless of the treatment and estrogen-receptor status. (ClinicalTrials.gov number, NCT00003782.)

34. Typically, similar indications as adjuvant chemotherapy
Advantages of neoadjuvant chemotherapy:
–
assessment ofdisease response,
–
increased rate of BCT
–
Neoadjuvant chemotherapy converts 20–30% of patients
initially ineligible for BCT to eligible
–
Complete clinical (cCR) and pathological response rates
–
20–40% achieve cCR , 10–20% achieve pCR
–
Alow time for genetic testing

35. NCCN 2017

36. Clinical rationale for increasing useClinical rationale for increasing use
of neoadjuvant chemotherapyof neoadjuvant chemotherapy
 Studies in experimental tumour models
 Excellent clinical response rates in locally advanced breast cancer
(T3,T4 or TxN2)
 Pathological CRs of up to 15%
 Adjuvant chemotherapy has survival benefit in node positive and
negative breast cancer
 Breast-conservation possible

37. NSABP B-18
N=1450
clinical T1-3, N0-1
ACACACAC
Surgery
Surgery
No difference in outcome chemotherapy preop vs postop:
DFS DDFS OS
ACACACAC

38.  The outcomes of NACT was demonstrated in a 2007 meta-analysis
that included data from 5500 women participating in 1 of 14 trials
reported between 1991 and 2001. Compared to adjuvant
chemotherapy, NACT resulted in:
1. Equivalent overall survival (OS) (hazard ratio [HR] 0.98, 95% CI
0.87-1.09) and disease-free survival (DFS) (HR 0.97, 95% CI 0.89-
1.07)
2. Reduction in the risk of having a modified radical mastectomy
performed (HR 0.71, 95% CI 0.67-0.75)
3. An increased risk of locoregional recurrence (HR 1.21, 95% CI
1.02-1.43).
Meta-ANALYSISMeta-ANALYSIS

39.  Those patients with a documented pathologic
complete response at surgery had significant
improvements in both OS (HR 0.48, 95% CI 0.33-
0.69) and DFS (HR 0.48, 95% CI 0.37-0.63)
compared to patients with residual invasive disease.
Pathological CRPathological CR

40. Meta analysis of Neoadjuvant Chemo Trials‐Meta analysis of Neoadjuvant Chemo Trials‐
12 randomized controlled trials for which pCR defined12 randomized controlled trials for which pCR defined
and DFS/OS data available (N=12993)and DFS/OS data available (N=12993)

42. Can breast conservation be increasedCan breast conservation be increased
by PST ?by PST ?
Study Breast
Conservation
(%)
p
Scholl, 1994 82 vs 77 ns
Makris, 1998 89 vs 78 0.004
Fisher, 1998 67 vs 60 0.002
(RCTs of neoadjuvant vs adjuvant chemotherapy)

43. How should tumor location be documentedHow should tumor location be documented
 Collaboration of surgical, medical oncologist and radiologist
 Two major problems can occur:
– Either a very quick and complete response so that the primary
lesion cant be identified
– Or no response, in that case surgeon may have to intervene.
 Precise documentation of the tumor on sketch, inserting clips
or coils in the center of the lesion or placing a tattoo
 Stereo-tactic localization using mammography is another
option
 Complete pathological CR becoming more common, so it
could become a major issue .

44. Neoadjuvant TaxotereNeoadjuvant Taxotere
The Aberdeen TrialThe Aberdeen Trial
NSABP B27NSABP B27
GEPARDUOGEPARDUO

45. 4 cycles of Taxotere
4 cycles of CVAP
No Response
Response
Randomise
All Patients
4 cycles of
CVAP
First Phase
Smith et al, JCO 2002
Tax301 Study
Conducted by the Aberdeen Breast Group
Second phase
4 cycles of Taxotere
FinalAssessment/Surgery

46. 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%

47. 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
Bear et al, J Clin Oncol 2003; 21
( 2411 pts )

49. GEPARDUO trialGEPARDUO trial
von Minckwitz et al., J Clin Oncol 1999
von Minckwitz et al., J Clin Oncol 2001
Surgery
Surgery
GeparduoGeparduo
TT ≥≥ 2 cm2 cm
(stage I,II)(stage I,II)
(N=913)(N=913)
AT + Tam
AC-T
+TAMAdriamycinAdriamycin
TaxotereTaxotere
AdriamycinAdriamycin
CyclophosphamideCyclophosphamide
TaxotereTaxotere

51. Overview of Rand. Trial comparingOverview of Rand. Trial comparing
different Primary Systemic Therapydifferent Primary Systemic Therapy
Regimens in Breast CancerRegimens in Breast Cancer

52. SUMMARY:ADJUVANT CHEMOSUMMARY:ADJUVANT CHEMO
TRIALSTRIALS

53. CURRENTCURRENT
RECOMMENDATIONS:NCCN 2017RECOMMENDATIONS:NCCN 2017

54. ADJUVANT CHEMO:DEVITAADJUVANT CHEMO:DEVITA
 Women who warrant chemotherapy,
 Sequential anthracycline-and taxane-based treatment
remains the “gold standard.”
 While multiple possible variations
on this regimen exist, the experience to
datehas not demonstrated that any regimen
is better tolerated or more effective
than AC for four cycles followed by paclitaxel
chemotherapy, with paclitaxel given as
either four cycles every 2 weeks, or
as 12 weeks of weekly therapy.

55.  Meanwhile, neither additional
chemotherapy doses nor agents have
improved outcomes.
 Multiple studies have failed to demonstrate
that dose escalation of cyclophosphamide or
doxorubicin results in a lower risk of
recurrence.
 Theaddition of capecitabine or gemcitabine
to anthracycline-and taxane- based
chemotherapy regimens did not improve
efficacy.

56.  Hormone receptor status may be an important
predictor of benefit from chemotherapy.
 Tumors that are low or nonexpressors of ER
derive substantial benefit from the addition of
chemotherapy to tamoxifen;
 By contrast, tumors with high quantitative levels of
ER do not appear to gain substantially from
adding chemotherapy to endocrine therapy.
 HER2 overexpression is associated with a
relative benefit from anthracycline-based
chemotherapy,and HER2 tumors do not selectively
benefit from anthracyclines, as opposed to
CMF type chemotherapy treatments