This document summarizes key landmark clinical trials in breast cancer. It discusses trials related to prevention using tamoxifen and raloxifene, radiation therapy trials for DCIS and early stage breast cancer, breast-conserving therapy including accelerated whole-breast irradiation, neoadjuvant chemotherapy trials, and HER2 targeted neoadjuvant therapy trials. The trials demonstrated the effectiveness of tamoxifen and radiation therapy in breast cancer prevention and treatment, and showed that hypofractionated radiation regimens and partial breast irradiation are not inferior to standard radiation protocols. Neoadjuvant chemotherapy was found to increase breast-conserving surgery rates and pathologic complete response rates. Dual HER2 blockade neoadjuvant regim

1. LANDMARK
CLINICAL TRIALS
IN
BREAST CANCER
Dr. Aaditya Prakash,
Radiation oncology, BMCHRC

2. PREVENTION TRIALS

3. Randomized data on
chemoprevention
• Randomized study delivered placebo versus
tamoxifen
• 13,388 females for 5 years
• RR of invasive and non-invasive breast cancer
was reduced by 49 and 50%, respectively, with
the use of tamoxifen
• After 7 years of follow-up, tamoxifen led to a
32% reduction in osteoporotic fractures.
• Side-effects such as endometrial cancer, deep-
vein thrombosis, etc.
• The study concluded that tamoxifen use as a
breast cancer preventive agent is appropriate in
many women at increased risk for the disease.
NSABP
P1

4. Randomized data on
chemoprevention
• Prospective, double-blind, randomized trial
• Involved 19,747 postmenopausal females and
studied tamoxifen versus raloxifene in preventing
breast cancer
• The final analysis initiated after at least 327
incident invasive breast cancers were diagnosed:
163 and 168 cases of invasive breast cancer in
tamoxifen and raloxifene treated groups
• No differences were found for other invasive
cancer sites, ischemic heart disease events, or
stroke. Thromboembolic events occurred less
often in the raloxifene group, and the number
of osteoporotic fractures in the groups was
similar
• Generally, tamoxifen is more often recommended
in the premenopausal patients, and raloxifene for
the postmenopausal patients
• .
NSABP
P2

5. RADIATION THERAPY
TRIALS

6. NSABP B-02

7. DCIS

8. • With a median follow up of
8.9 years, RT approximately halved
the rate of ipsilateral breast events.
• RT was effective in all subgroups.
There were 291 “low-risk” cases of
DCIS that were low-grade, >20 mm
in size, and with negative surgical
margins identified.
• 10-year risk of an ipsilateral event in
those allocated to lumpectomy alone
was substantial at 30.1%, and even
with this relatively small number of
women, the effect of RT was highly
significant.
Meta-analysis
by the Early
Breast Cancer
Trialists’
Collaborative
Group
(EBCTCG),
Breast
Conservation
Trials
2011

9. DCIS
■ RTOG 9804 enrolled patients with smaller lesions, all
low- or intermediate-grade DCIS, and had a much
higher rate adjuvant tamoxifen use (62%).
■ Recurrence rates were 6.7% in the observation arm,
compared to 0.9% in the RT arm, after a median
follow-up of 7.2 years (HR = 0.11; 95% CI = 0.03 to
0.47; p = 0.0003).
■ This suggests that even in low-risk DCIS, RT can
lower the risk of in-breast recurrence.

10. DCIS

11. EARLY STAGE BREAST CANCER

12. NSABP-B06
(1976–1980)
25-Year follow-up of a randomized trial of 590, 632,
and 629 patients treated with mastectomy, lumpectomy
alone, or lumpectomy followed by adjuvant RT
Cumulative incidence of recurrence in the ipsilateral
breast was 14.3 versus 39.2% after lumpectomy with or
without RT, respectively (p < 0.001)
No significant differences were observed with
respect to DFS, DDFS, or OS
OS was ~ 60% for all 3 groups (at 12 years follow-
up)
Milan
(1973–1980)
20-Year follow-up of a randomized trial of 349
patients and 352 patients treated with mastectomy vs
quadrantectomy followed by adjuvant RT, respectively
Cumulative incidence of same-breast recurrence was
8.8 versus 2.3%, respectively
Overall survival 65 and 65% (p = NS)
Rates of death from all causes was 41.7 versus
41.2% (p = 1.0) and rates of death from breast cancer
were 26.1 versus 24.3% (p = 0.8) for the two groups
No significant difference between the two groups in
the rates of contralateral-breast carcinomas, distant
metastases, or second primary cancers

13. NCI (1980–
1986)
Randomized trial for stages I-II breast
cancer patients treated with mastectomy
(n=247) vs lumpectomy, followed by adjuvant
RT (n=237)
Node-positive patients on axillary dissection
received adjuvant
chemotherapy
Overall survival was 75% versus 77% at 10
years
No diffrence between OS (75 versus 77%) or
DFS observed
The probabilities of failure in the irradiated
breast were 12 and 20% by 5 and 8 years,
respectively
EORTC 10801 Randomized trial for stages II breast cancer
(<5cm) patients treated with mastectomy
(n=426) vs lumpectomy followed by adjuvant
RT (n=456)
At 10 years, OS (66 versus 65%) and DDFS
(66 versus 61%) were not different statistically
Locoregional recurrence after mastectomy
was 12 versus 20% after lumpectomy and RT (p
= 0.01)

14. BREAST-CONSERVING
THERAPY
Accelerated
Whole-Breast
Irradiation/Hypofractionated RT

15. • Randomized studied the efficacy of
hypofractionated versus standard radiation dose
regimen in whole breast irradiation for N- breast
cancer after lumpectomy (margin negative)
• Radiation regimens were 42.5 Gy in 16 fractions
versus 50 Gy in 25 fractions
• The risks of local recurrence at 10 years were 6.7
and 6.2 respectively, after standard or
hypofractionated regimens
• Good or excellent cosmetic outcome was seen in
71.3 and 69.8% of patients after standard or
hypofractionated regimens, respectively
• Thus, accelerated, hypofractionated whole-
breast irradiation was not inferior to standard
radiation treatment in women who had
undergone breast-conserving surgery at 10
years.
Whelan et
al
(Canada)

16. • Randomized trial studied standard versus
hypofractionated adjuvant RT in 2,236 women with
pT1–3a, pN0–1 breast cancer
• After surgery, patients were randomized to 50 Gy
in 25 fractions vs 41.6 Gy in 13 Fractions vs 39 Gy
in 13 fractions
• The rate of 5-year local-regional tumor relapse at 5
years was 3.6 versus 3.5% versus 5.2%, after 50,
41.6, and 39 Gy of radiation
• The Estimated Absolute differences in 5-year local-
regional relapse rates compared with 50 Gy were
0.2% (95% CI, 1.3–6%) after 41.6 Gy and 0.9%
(95% CI, 0.8–3.7%) after 39 Gy
• Lower rates of late adverse effects were reported
with 39 Gy and 50 Gy
• Thus, a lower total dose in a smaller number of
fractions offered similar rates of tumor control
and side effects as the standard dose regimen for
breast cancer
START
A, (UK)

17. • Similar study setting as in START A but
tested 50 Gy in 25 fractions versus 40 Gy in
15 fractions in 2,215 patients with pT1–
3apN0–1 breast cancer
• The rate of locoregional tumor relapse at 6
years was 2.2 versus 3.3% in the 40- and 50-
Gy groups, respectively.
• The estimated absolute differences in 6-year
locoregional relapse rates compared with 50
Gy was 0-7% after 40 Gy
• Lower rates of late adverse effects after 40
than with 50 Gy were reported.
START
B, (UK)

18. BREAST-CONSERVING
THERAPY
Accelerated
Partial Breast
Irradiation(APBI)

19. TARGIT-A TRIAL

20. TARGIT-A TRIAL

21. RandomizedTrials ofWhole-Breast
Vs PBI

22. RANDOMIZED STUDIES FOR STAGE I
BREAST CANCER COMPARING SURGERY
& HORMONE THERAPY
TO
SURGERY, RADIATION THERAPY, &
HORMONES

23. • 636 Stage T1N0 and ER+ breast
cancer patients over 70 years of
age were randomized to tamoxifen
(TAM) alone(n = 319) vs RT plus
TAM (n = 317)
• The 5-year LR rates were 1 and
7% (p <0.001), and favoured the
RT plus TAM group
• No significant differences in
mastectomy for LR, distant
metastasis, or 5-year OS (86 versus
87%) were observed
CALGB/
ECOG
trial

24. • 769 Early-stage breast cancer (tumor ≤
5 cm) patients were randomized to TAM
alone (n = 383) or RT plus TAM (n =
386)
• The 5-year LR rates were 7.7 versus
0.6% (p < 0.001), with a corresponding
5-year DFS rates of 84 versus 91% (p =
0.004), favoring the irradiation group
• The 5-year axillary recurrence rates (0.5
versus 2.5%) also favored combined RT
plus TAM (p = 0.049)
• Patients with stage T1 and ER positive
disease also benefitted from RT (5-year
LR rates of 0.4 versus 5.9%, p < 0.001)
• No significant differences in distant
metastasis or OS rates were observed
PMH

25. • Randomized 1,099 patients with N
negative invasive breast cancer (tumor ≤1
cm) to TAM alone (n = 336), RT plus
placebo (n = 336), or RT plus TAM (n =
337)
• Cumulative incidence of IBTR through 8
years was 16.5, 9.8, and 2.8% for TAM,
RT alone, and RT plus TAM, respectively
• RT reduced IBTR below the level
achieved with TAM alone, regardless of
estrogen receptor (ER) status
• TAM provided a significant reduction in
contralateral breast cancer (p = 0.039)
• OS rates were 93, 94, and 93% in the 3
groups (p = 0.93)
NSABP
B21

26. POST-MASTECTOMY
RADIATION THERAPY

27. • Randomized 318 premenopausal
breast cancer patients to PMRT
versus observation
• RT fields included chest wall,
supraclavicular, and internal
mammary lymph node regions
versus no PMRT
• The 20-year LR rates were 13
versus 39%, and favored adjuvant
RT (p = 0.0005)
• The 20-year OS rates were 47
versus 37%, and favoured PMRT
(p = 0.03)
British
Columbia
trial

28. • Randomized 1,708 premenopausal
patients with stage II and III breast
cancer to PMRT versus observation
• RT fields included chest wall,
supraclavicular, and internal
mammary lymph node regions
• All patients received adjuvant
chemotherapy
• The 10-year LR rates were 9 versus
32%, and favored adjuvant RT (p <
0.0001)
• The 10-year OS rates were 45
versus 54%, favored adjuvant RT
(p < 0.0001)
DBCG
82b trial

29. • Randomized 1,375 postmenopausal
patients with stage II and III breast
cancer to PMRT versus observation
• RT fields included chest wall,
supraclavicular, and internal
mammary lymph node regions
• All patients received hormonal
therapy with tamoxifen
• The 10-year LR rates were 8 versus
35%, and favored PMRT (p <
0.0001)
• The 10-year OS were 45 versus
36%, and favored adjuvant RT (p =
0.03)
DBCG 82c
trial

30. Re-analysis of the
Danish trials after 15-years of
follow-up
LOCOREGIONAL RECURRENCE AND OVERALL SURVIVAL AT 15
YEARS IN PATIENTS WITH 1–3 POSITIVE VERSUS >= 4 POSITIVE
LYMPH NODES

31. NEOADJUVANT
THERAPY TRIALS
CHEMO-THERAPY

32. Neoadjuvant Vs Adjuvant AC

34. ■ Neoadjuvant AC effectively downstaged both the primary
tumor (36% complete clinical response rate) and the
axillary lymph nodes (73% complete clinical nodal
response in patients with clinically positive lymph
nodes).
■ No differences in 5-year disease-free (67% both
groups, P = .99) and overall survival rates (80% both
groups, P = .83) were observed between treatment
groups.
■ Recently updated outcome results from the B-18 study
continue to demonstrate that the equivalence between
preoperative and postoperative chemotherapy, and
the significant correlation between pCR and outcome
has persisted through 9 years of follow up.

35. Neoadjuvant AC Plus Docetaxel

36. AC ACT P-VALUE
Clinical Response AC (n=1502) AC -> T (n=687) PValue
Complete response rate, % 40 65 < .001
Overall response rate, % 85 91 < .001
Pathologic Response AC (n=1492) AC -> T (n=718) PValue
Pathologic complete response
rate, %
13.7 25.6 < .001
Histologically positive nodes,
%
48.5 40.5 < .01
Surgical Procedure
Lumpectomy, % 61% 63% .70

37. NSABP B-27 Randomized 2411 operable
cancers to AC versus AC D
versus AC  S  D
Breast conservation rate was
same between arms.
The pCR rate favored AC 
D over AC (p < 0.001)
MDACC trial Randomized 258 patients with
stages I-IIIa
Weekly P  FAC versus
every 3 week P  FAC
Breast conservation 47 versus
38% favor weekly P-FAC
(p = 0.05)
The pCR rate favored weekly
P  FAC (p = 0.02)

38. ECTO trial Randomized 1,355 patients
with stages T2-T3, N0-N1
AP CMF S versus S
APCMF versus S A
CMF
Breast conservation 65 versus
34% in favor of AP CMF S (p
<0.001)
Gerpar–DUO trial Randomized 913 patients with
stages T2-T3, N0-N2
Dose dense AD  S versus AC
 D  S
Breast conservation 63 vs 58%
in favor of AC  D  S
(p = 0.05)
The pCR rate favored AC D
S ( p < 0.001)

39. NEOADJUVANT
THERAPY TRIALS
TARGET THERAPY

40. HER2 Targeted Therapy
The results were that 45.8% of
patients receiving dual HER2-
targeted therapy with docetaxel
achieved a pCR compared with
29.0% (95% CI, 20.6%-38.5%) of
patients receiving
trastuzumab and docetaxel alone.

41. HER2 Targeted Therapy
■ The majority of patients
achieved pCR in the breast
(61.6% in arm A, 57.3% in arm
B, and 66.2% in arm C), with
pCR including lymph nodes in
50.7% (arm A), 45.3% (arm B),
and 51.9% of patients (arm C).
■ 11 patients had declines in left
ventricular ejection fraction to
less than 50%, and diarrhea was
the most common adverse event.

42. HER2 Targeted Therapy
■ Gepar Quinto trial- EC(4) D + Trastuzumab pCR – 30.3%
D + Lapatinib pCR – 22.7%
■ Neo ALTTO trial- Lapatinib + Pacli pCR – 24%
Trastuzumab + Pacli pCR – 29%
T + L + Pacli pCR – 51.3%
■ NeoSphere trial – Pertuzumab + Trastuzumab + paclitaxel
pCR – 45.8%
■ Tryphaena trial – Pertuzumab + trastuzumab + Doce + Carbo
(in early & LABC) pCR – 66.2%

43. NEOADJUVANT
THERAPY TRIALS
ENDOCRINE HR+ THERAPY

46. ADJUVANT THERAPY
TRIALS

47. When to offer adjuvant therapy

48. COMPARISON OF PROSPECTIVE
TRIALS UTILIZING MULTIGENE TESTS
FOR PROGNOSTIC AND PREDICTIVE
FACTORS

49. ADJUVANT
CHEMOTHERAPY

50. ADJUVANT TREATMENT AND SURVIVAL
IMPROVEMENT OVER PAST 40 YEARS

51. q4
w
C: 100mg/m2/d, D1-14
M: 40mg/m2, D1,8
F: 600mg/m2, D1,8
386 pts
LN: positive
Menopausal: both
Hormone: N/A None
CMF x 12
RFS OS
20 yrs follow-up
New England Journal of Medicine 1976; 294: 405-410
New England Journal of Medicine 1995; 322: 901-966
Classic CMF
Istituto Nazionale Tumori, Milan, Italy
Gianni Bonadonna et al.
1973-1975
20yr
RR ↓Risk
Recur 65% 35%
OS 76% 24%

52. 2194 pts
Menopausal: both
LN: positive
*TAM non-responder
AC x 4
CMF x 6
A: 60mg/m2, D1
C: 600mg/m2,
D1
q3
w
C: 750mg/m2, D1
M: 40mg/m2, D1,8
F: 600mg/m2, D1,8
q4
w
NSABP B-15
1984-1988
Journal of Clinical Oncology 1990;8:1483-1496
AC x 4 6m period CMF x 3
C: 100mg/m2/d, D1-14
M: 40mg/m2, D1,8
F: 600mg/m2, D1,8
q4
w
Follow-up: 3 yrs

53. • Comprehensive meta‐analysis of randomized
controlled trials of chemotherapy showed that 6
months of anthracycline‐based chemotherapy
reduced mortality by 38% in women aged <50
years and by 20% in women aged 50–69 years,
irrespective of ER status, nodal status and other
tumour characteristics
• Similarly, 5 years of tamoxifen reduced mortality by
31% after ER‐positive breast cancer irrespective of
age, chemotherapy and tumour characteristics
• Oophorectomy or ovarian suppression, when given
as the only adjuvant systemic therapy, reduced
mortality by about 13%
• Impact of oophorectomy was attenuated when
chemotherapy was also given
EBCTCG
meta‐analys
is
for
chemother-
apy and
hormone
therapy
(2005)
Lancet

56. • Combined analyses of several
trials of anthracycline versus
anthracycline plus taxane
chemotherapy showed a signifi
cant survival advantage for
adding a taxane to the
treatment of HER2‐positive
and ER‐negative early‐stage
breast cancers
• A meta‐analysis of
taxane‐containing adjuvant
regimens showed a 15%
survival advantage for the
addition of taxanes, either
sequentially or concurrently, to
anthracyclines in the treatment
of node‐positive disease
Role of adjuvant
taxanes according
to biomarker
profile and nodal
status
Hayes et al .
(2007) N Engl J
Med
;De Laurentiis et
al.
(2008) J Clin
Oncol

57. DOSE DENSE THERAPY

58. ADJUVANT ENDOCRINE
HR+ THERAPY

59. NSABP B-14
• Tumors With ER  10 fmol/mg
• Histologically Neg. Axillary Nodes,N-
• TM or Lump. + Ax. Diss. +XRT
Stratification
• Age
• Clinical Tumor
Size
• Quantitative ER
• Type of
Operation
Placebo TAM

60. NSABP B-14:
NODE NEGATIVE PATIENTS
Tamoxifen Placebo p Value
DFS 56% 46% < 0.0001
OS 71% 65% = 0.0015
No advantage in continuing tamoxifen beyond 5 yrs
*Through 15 years in 2871 patients

61. NSABP B-21

62. NSABP B-21: OUTCOMES
■ Cumulative incidence of IBTR over an 8
year period was 16.5% with tamoxifen
alone, 9.3% with radiation and placebo,
and 2.8% with radiation and tamoxifen
■ Radiation reduced IBTR below the
level achieved with tamoxifen alone,
regardless of estrogen receptor status
■ Distant treatment failures were infrequent
and not significantly different among the
three groups (P=.28)
■ When tamoxifen-treated women were
compared with those who received
radiation and placebo, there was a
significant reduction in contralateral
breast cancer (hazard ratio, 0.45; P=.039).
■ Survival in the three groups was 93%,
94% and 93%, respectively
■ Tamoxifen was not as effective as breast
radiation in controlling the disease in
the breast
PATIENTS
(n)
TREATMENT
F/u
(years)
% IBTR
% RISK
REDUCTION
334 TAM 7 16.5 --
332 RT + Placebo -- 9.3 49
334 TAM + RT -- 2.8 81/63

63. • Comprehensive meta‐analysis of randomized
controlled trials of chemotherapy showed that 6
months of anthracycline‐based chemotherapy
reduced mortality by 38% in women aged <50
years and by 20% in women aged 50–69 years,
irrespective of ER status, nodal status and other
tumour characteristics
• Similarly, 5 years of tamoxifen reduced mortality
by 31% after ER‐positive breast cancer
irrespective of age, chemotherapy and tumour
characteristics
• Oophorectomy or ovarian suppression, when given
as the only adjuvant systemic therapy, reduced
mortality by about 13%
• Impact of oophorectomy was attenuated when
chemotherapy was also given
EBCTCG
meta‐analy
sis
for
chemother-
apy and
hormone
therapy
(2005)
Lancet

65. AROMATASE INHIBITORS

66. • A meta‐analysis of trials of
adjuvant hormone therapy in
menopausal women showed a
23% risk reduction in
recurrence by replacing 5 years of
tamoxifen with 5 years of an
aromatase inhibitor as adjuvant
therapy for ER‐positive breast
cancer, but no overall survival
benefit with a median follow‐up of
6 years
• Combining 2–3 years of tamoxifen
with 2–3 years of an aromatase
inhibitor reduced recurrence by
40% and mortality by 21%
• However, the absolute benefit
was just a 3% improvement in
recurrence‐free survival in either
strategy
Impact of
adjuvant AI
hormone
receptor
+ve breast
cancer
Dowsett et al.
(2009) J Clin
Oncol

67. OVARIAN
SUPPRESSION/ABLATION
TRIALS

68. NSABP B-03

69. SOFT/TEXT
■ SOFT: SUPPRESSION OF OVARIAN FUNCTION TRIAL
■ TEXT: TAMOXIFEN AND EXEMESTANE TRIAL (at NYU)
■ Both Phase III Trials; Exemestane Plus gonadotrophin-
releasing hormone (GnRH) Analogue as adjuvant therapy for
premenopausal women with hormone receptor positive breast
cancer
■ Goserelin (zoladex 3.6 sc monthly), leuprorelin (lupron 3.75 im
monthly), buserelin, triptorelin (3.75 im monthly)

70. TEXT & SOFT
TAMOXIFEN + OFS VS. EXEMESTANE + OFS
Tamoxifen 20 mg/day
+ OFS* (n = 1338)Premenopausal, HR+ BC
≤ 12 wks after surgery
N = 2672
Stratified by trial, use of chemotherapy, nodal status
*OFS
 TEXT: triptorelin 3.75 mg IM every 28 days for 6-8 weeks prior to initiation
of HT or concurrently with chemotherapy.
 SOFT: triptorelin, bilateral oophorectomy or Ovarian irradiation
TEXT
Exemestane 25 mg/day
+ OFS* (n = 1021)
Tamoxifen 20 mg/day
• Premenopausal HR+ BC
≤ 12 wks after surgery
(if no chemo) or
• ≤ 8 mos after chemo if
premen status confirmed
• N = 3066
SOFT
Tamoxifen + OFS*
Tamoxifen 20 mg/day
+ OFS* (n = 1024)
N = 2346
Exemestane 25 mg/day
+ OFS* (n = 1334)
Joint Analysis
 Median follow up: 68
months
 42% N+
 Neo/Adjuvant
chemotherapy: 58%
Pagani O, et al. NEJM July 2014.
N = 2344
Exemestane+ OFS*

71. SOFT/TEXT: Exemestane +
OFS better DFS
Median f/u 5.7 years

72. SOFT/TEXT: selected AEs
QOL not different
Early cessation of treatment 16 vs 11%

73. SOFT/TEXT
• Exemestane with ovarian function suppression is a new evidence
based treatment option for premenopausal women with HR+ early
breast cancer
• Some premenopausal women diagnosed with HR+ breast cancer have
an excellent prognosis with highly-effective endocrine therapy alone
(>97% BC free at 5 yrs)
• Need longer f/u, esp OS

74. Randomized trials of adjuvant
CT versus Ovarian
ablation/suppression with or
without Tamoxifen

76. HER2 Targeted Therapy
TARGET THERAPY TRIALS

78. • This pooled analysis of 5
randomized trials
reported a 48%
reduction in mortality
with the addition of
trastuzumab to
chemotherapy for
HER2‐positive
early‐stage breast cancer
• Cardiac toxicity was 2.5
times greater in patients
who received
trastuzumab, but overall
rates were low (4.5% in
the trastuzumab groups)
Impact of adding
trastuzumab to
adjuvant
chemotherapy
for HER2
positive breast
cancer
Viani et al.
(2007) BMC
Cancer

79. OTHER TARGETED
THERAPIES TRIALS

87. ■ Response rates and clinical benefit rates
(patients with complete response, partial
response, or stable disease for greater than
six months) were higher in the combination
arms (12.0% vs. 1.3% and 50.5% vs. 25.5%;
P<0.0001), respectively.
■ Patients with only bone metastases
benefited from the combination.

88. ■ These results are similar to the benefit seen
with chemotherapy (without their toxicity).
For instance, the median PFS with
capecitabine, taxanes or anthracyclines also
ranges between 6.2 months and 8.2 months.

89. ■ PALOMA-1 trial demonstrated a statistically significant
improvement in PFS when palbociclib was added to
letrozole in the treatment of postmenopausal women
with metastatic ER+/HER2-breast cancer who had not
previously received any systemic treatment for their
advanced disease.
■ With a median follow-up of approximately 30 months
for the palbociclib plus letrozole group and 28 months
for the letrozole alone group, the median PFS was 20.2
months (95% CI 13.8–27.5) and 10.2 months (95% CI 5.7–
12.6), respectively, (HR 0.488, 95% CI 0.319–0.748; one-
sided p = 0.0004).

91. SURGERY TRIALS

92. NSABP B-04
■ Between 1971-74, 1765 patients from 34 institutions
across USA and Canada participated
■ Objective - 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

93. Operable Breast Cancer
Clinic. Negative Node Clinic. Positive Node
Radical
Mast.
Total
Mast.
Total Mast.
+
XRT
Radical
Mast.
Total Mast.
+
XRT
NSABP B-04: LOCO-REGIONAL
Opened : July 1971
Closed : September 1974

94. Fisher, B. et al., NEJM 2002;347(8):567-575.
NSABP B-04: LOCO-REGIONAL
RFS (25 yrs)
Negative Node
P = .46
RFS (25
years)
Positive
Node
P = .40
Radical mastectomy 53% 36%
Total mastectomy +
XRT
52% 33%
Total mastectomy 50% --
• 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
• In node positive patients overall
survival 14% in each arm
• Hazard ratio for death among those
who were treated with total
mastectomy and radiation as compared
with those who underwent radical
mastectomy was 1.08 (95%
confidence interval, 0.91 to 1.28;
P=0.38)

95. NSABP- 06
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 & II with tumour size < 4 cm,N0/N1)

96. NSABP B-06: LOCO-REGIONAL
All patients with histologically positive axillary nodes receive L-
PAM + 5 FU
Total mastectomy performed in event of ipsilateral breast tumor
recurrence
Clinical Tumor Size  4.0 cm
Stratification
 Clinical Nodal Status
 Clinical Tumor Size
Total
Mastectomy
+ Ax. Diss.
Lumpectomy
+ Ax. Diss.
Lumpectomy
+ Ax. Diss.
+ XRT

97. NSABP B06 Results
Fisher, et al N Engl J Med,
Vol. 347, No. 16 · October
17, 2002

98. NSABP B06 Results
■ No difference in survival at 20
years
■ Lumpectomy without
postoperative irradiation higher
local recurrence 39.2% vs. 14.3%
■ Radiation therapy was
associated with a marginally
significant decrease in deaths
due to breast cancer
■ However, this decrease was
partially offset by an increase in
deaths from other causes
■ BCS New standard of care for
Stage I/IIFisher, et al N Engl J Med
Vol. 347, No. 16 · October
17, 2002

99. Local control and survival in
early breast cancer: Milan trial
■ Int J RadiatOncol Biol Phys. 1986 May;12(5):717-20.Veronesi U, Zucali R, LuiniA.
■ From 1973 to 1980, 701 patients with breast cancer measuring less than 2 cm
in pathological diameter and with no palpable axillary lymph nodes were
randomized to Halsted mastectomy (349) or to "quadrantectomy" with
axillary dissection and radiotherapy to the ipsilateral breast tissue (QUART)
(352)
■ The two groups were comparable in age distribution, size and site of primary
tumor; menopausal status; and frequency of axillary metastases
■ At 8 years, the disease-free survival was 77% for the Halsted patients and
80% for the "quadrantectomy" patients, while overall survival was 83% and
85%, respectively.
■ Breast cancer of small size (less than 2 cm) may be safely treated with
conservative treatment.
■ Mutilating operations are not justified.

100. AXILLARY DISSECTIONVS
SENTINEL NODE BIOPSYTRIALS

101. NSABP B-32
■ 5,611 women with operable,
clinically N0, invasive breast
cancer were randomized to SNR +
AD (Group 1) or to SNR alone
with AD only if SNs were positive
(Group 2).
■ 3,989 (71.1%) of 5,611 patients
were SN negative, and 3,986
(99.9%) of these SN negative
patients had follow-up information.
■ 1,975 women had SNR + AD
(Group 1) and 2,011 women had
AD alone (Group 2).
■ Median time on study was 9.4
years.
■ SN Identification rate 97%
■ 26% had positive node
■ 9.7% false negative rate ; less
common with >1SN,
■ OS, DFS, Regional Control
statistically equivalent
Enrollment 1999-2004

102. NSABP B-32
■ No significant difference in OS between patients who received
SNR + AD versus SNR alone (HR: 1.11, p = 0.27) at 10 years.
■ 10 year Kaplan-Meier (K-M) estimates for OS are 87.8% for
SNR alone and 88.9% for SNR + AD.
■ There continues to be no significant difference in DFS between
the two groups (HR: 1.01, p=0.92).
■ 10 year K-M estimates for DFS were 76.9% for both groups.
■ There was no significant difference in the rates of local-
regional recurrence between the two groups (HR: 1.09,
p=0.29).

103. ACOSOG Z0010
■ SN biopsy (SNB) with immunohistochemistry (IHC) of histologically
negative SN identifies metastases (mets) not seen by standard
histology.
■ 5,539 patients (pts) were entered into this prospective multicenter
observational study to determine the clinical significance of SN and
Bone Marrow (BM) micromets.
Methods
 Patients underwent lumpectomy and SNB with bilateral iliac crest BM
aspiration.
■ BM and histologically negative SN were evaluated with IHC in a
central laboratory
■ Overall survival (OS), disease-free survival, and locoregional
recurrence were determined.

104. ACOSOG Z0010
Results:
■ SN were successfully identified in 5,184 of 5,485 pts (94.5%)
■ Histologic SN mets were found in 1,239 pts (23.9%).
■ IHC detected an additional 350 pts (10.5%) with SN mets.
■ BM mets were identified by IHC in 105 of 3491 examined (3.0%).
■ BM IHC positivity significantly predicted decreased OS (p=0.015).
■ A multivariable analysis that included SN and BM status, ER, PR, grade, size, and
age showed that neither IHC detected mets in SN (p=0.66) or BM (p=0.08) were
independent predictors of OS
Conclusions:
■ The detection of BM mets by IHC in pts with clinical T1/2 N0M0 breast cancer
identifies those pts at significantly increased risk for death
■ In this study, SN IHC-detected mets appear to have no significant impact on
OS.
■ The routine examination of SN by IHC is not supported in this patient population by
this study.

105. Positive Sentinel
Node (891 patients)
Axillary
Dissection
(445)
No axillary
Dissection
(446)
Objective To determine the effects of complete axillary lymph node dissection (ALND)
on survival of patients with sentinel lymph node (SLN) metastasis of breast cancer
•All patients with +nodes received WBI and adjuvant systemic therapy
•Original goal = 1900
•End Points: Overall & Disease Free Survival and Local-Regional Failure
Positive Sentinel Node ACOSOG -Z0011
Trial Giuliano AE, et al
JAMA 2011;305:569-75

106. ACOSOG Z11 Results
■ 1999 to 2004. Patients were women with clinical T1-T2 invasive
breast cancer, no palpable adenopathy, and 1 to 2 SLNs containing
metastases identified by frozen section, touch preparation, or
hematoxylin-eosin staining on permanent section
■ Targeted enrollment was 1900 women with final analysis after 500
deaths, but the trial closed early because mortality rate was lower than
expected.
■ Closed early due to slow accrual and lower mortality than anticipated
■ No difference in OS or DFS
■ 70% vs. 25% (AXND vs. SNB) surgical morbidity: wound infections,
axillary seromas, paresthesias
■ Lymphedema 13% vs. 2%;
■ In patients with limited SN disease who receive BCS with WBI and
systemic therapy, SNB alone does not result in inferior survival

107. Randomized Multicenter Trial of Sentinel Node Biopsy Versus
Standard Axillary Treatment in Operable Breast Cancer: The
ALMANAC Trial
■ Multicenter randomized trial to compare quality-of-life outcomes
between patients with cN0 invasive breast cancer who received
SLNB V/S standard axillary treatment
■ The primary outcome measures were arm and shoulder
morbidity and quality of life
■ From November 1999 to October 2003, 1031 patients were
randomly assigned to undergo sentinel lymph node biopsy (n =
515) or standard axillary surgery (n = 516)
■ Patients with sentinel lymph node metastases proceeded to
delayed axillary clearance or received axillary radiotherapy
(depending on the protocol at the treating institution)
■ Intention-to-treat analyses of data at 1, 3, 6, and 12 months after
surgery are presented

108. ALMANAC
■ The relative risks of any lymphedema and sensory loss for the
sentinel lymph node biopsy group compared with the standard
axillary treatment group at 12 months were 0.37 (95%
confidence interval [CI] = 0.23 to 0.60;
■ absolute rates: 5% versus 13% respectively
■ Drain usage, length of hospital stay, and time to resumption of
normal day-to-day activities after surgery were statistically
significantly lower in the sentinel lymph node biopsy group
(all P<.001), and axillary operative time was reduced (P = .055).
■ Overall patient-recorded quality of life and arm functioning
scores were statistically significantly better in the sentinel
lymph node biopsy group throughout (all P≤.003).

109. NSABP 32 & ALMANAC
Conclusion: Sentinel lymph node biopsy is associated with
reduced arm morbidity and better quality of life than
standard axillary treatment and should be the treatment of
choice for patients who have early-stage breast cancer with
clinically negative nodes.

110. AMAROS trial
Methods
■ Patients with T1–2 primary breast cancer and no palpable lymphadenopathy were
enrolled
■ Randomly assigned (1:1) by a computer-generated allocation schedule to receive
either axillary lymph node dissection or axillary radiotherapy in case of a positive
sentinel node,
■ The primary endpoint was non-inferiority of 5-year axillary recurrence, considered
to be not more than 4% for the axillary radiotherapy group compared with an
expected 2% in the axillary lymph node dissection group.
Findings
■ Between Feb 19, 2001, and April 29, 2010, 4806 patients were enrolled at 34
centres from nine European countries,
■ 1425 patients with a positive sentinel node, 744 had been randomly assigned to
axillary lymph node dissection and 681 to axillary radiotherapy
■ Median follow-up was 6·1 years (IQR 4·1–8·0) for the patients with positive
sentinel lymph nodes

111. AMAROS trial
■ In the axillary lymph node dissection group, 220 (33%) of 672 patients who
underwent axillary lymph node dissection had additional positive nodes.
■ Axillary recurrence occurred in four of 744 patients in the axillary lymph
node dissection group and seven of 681 in the axillary radiotherapy group.
■ 5-year axillary recurrence was 0·43% (95% CI 0·00–0·92) after axillary
lymph node dissection versus 1·19% (0·31–2·08) after axillary radiotherapy.
■ The planned non-inferiority test was underpowered because of the low
number of events
■ Lymphoedema in the ipsilateral arm was noted significantly more often after
axillary lymph node dissection than after axillary radiotherapy at 1 year, 3
years, and 5 years.
Interpretation
■ Axillary lymph node dissection and axillary radiotherapy after a
positive sentinel node provide excellent and comparable axillary control
for patients with T1–2 primary breast cancer and no palpable
lymphadenopathy.
■ Axillary radiotherapy results in significantly less morbidity.

112. ONGOING PHASE 3 TRIALS

117. THANKS