LAND MARK TRIALS - KIRAN.pptx

1. LANDMARK TRIALS IN
BREAST CANCER

2. OUTLINE
• PREVENTION TRIALS
• SURGERY TRIALS
• RADIATION THERAPY TRIALS
• CHEMO-THERAPY TRIALS
• ENDOCRINE THERAPY TRIALS
• TARGETTED THERAPY TRIALS

3. CHEMO-PREVENTION TRIALS

4. 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.
• 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

5. Randomized data on
chemoprevention
• 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
• 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

6. SURGERY TRIALS

7. • WILLIAMHALSTED(1894)
Popularisedradical mastectomy asthe treatment of
choice for breast cancer,considered breast cancer
strictly asalocoregional disease.

10. • The Contribution of Recent NSABP Clinical Trials of Primary
Breast Cancer Therapy to an Understanding of Tumor Biology
-An Overview of Findings BERNARD FISHER, MD, CAROL
REDMOND, SCD, EDWIN R. FISHER, MD AND
PARTICIPATING NSABP INVESTIGATORS*(Cancer-
46:1009-1025, 1980 )
Group of American and Canadian investigators has implemented a
series of trials aimed at answering biological aswell as clinical
questions.
Those studies have not only been concerned with defining proper
local-regional treatment but have also pointed out the need for, and
value of, systemic therapy when used in conjunction with operation.

11. 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 clinically node negative patients and other
for clinically node positive patients.
• Radical Mastectomy served as control arm for both

12. 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

13. 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)

14. NSABP B-04:
CONCLUSION: MRM =RM(OS,DFS)

15. • MODIFIEDRADICALMASTECTOMY VS
BREASTCONSER
V
A
TIVESURGER
Y

16. 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)

17. NSABP B-06: LOCO-REGIONAL
All patients with histologically positive axillary nodes receive
CHEMOTHERAPY
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

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

19. 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/II
Fisher, et al N Engl J Med
Vol. 347, No. 16 · October
17, 2002

20. Local control and survival in early
breast cancer: Milan trial
• Int J Radiat Oncol Biol Phys. 1986 May;12(5):717-20. Veronesi U, Zucali R, Luini A.
• 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.

21. NSABP B06 &MILAN Results
BCS with RT New standard of care for
Operable breast cancer

22. AXILLARY DISSECTION VS
SENTINEL NODE BIOPSY
TRIALS

23. • Background
• Axillary lymph node status isanimportant prognostic factorin
women with early stagebreastcancer.
• Axillary dissection (AD) and histologic examination of lymph nodes has
traditionally been a routine component of surgery for patients with
early stagebreastcancer.
• Benefits of ADinclude improved local control. In addition,AD
provides information that guidesprognosis aswell asdecisions
regarding adjuvanttreatment.
• However,these benefits must be weighed againstsignificant risksof
lymphedema, nerve injury, and shoulder dysfunction associated withAD.
• Tumorcells generally metastasizefrom the primary tumor to oneor afew
sentinel nodes(SN)before involving other lymphnodes.
• Sentinel node resection (SNR)isalessinvasivemethod of staging the
axilla with lessmorbidity compared toAD.
• In patients with clinically node negativebreast cancer,negativeSNRcan
identify patients without axillary nodal involvement, thus obviating the
need for amore extensiveAD.

24. 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).
• 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

25. 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).

26. 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.

27. 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.

28. 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

29. 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

30. 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

31. 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).

32. 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.

33. 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

34. 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.
• 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.

35. RADIATION THERAPY
TRIALS

36. NSABP B-02

37. DCIS

38. • 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

39. 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.

40. DCIS

41. EARLY STAGE BREAST CANCER

42. 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

43. 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)

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

45. • Randomized studied the efficacy of hypo-
fractionated 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)

46. • 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)

47. • 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)

48. THERAPY
Accelerated
Partial Breast Irradiation(APBI)

49. TARGIT-A TRIAL

50. TARGIT-A TRIAL

51. Randomized Trials of Whole-Breast
Vs PBI

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

53. • 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

54. • 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

55. • 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

56. POST-MASTECTOMY
RADIATION THERAPY

57. • 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

58. • 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

59. • 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

60. 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

61. NEOADJUVANT THERAPY
TRIALS
CHEMO-THERAPY

62. Neoadjuvant Vs Adjuvant AC

64. • 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.

65. Neoadjuvant AC Plus Docetaxel

66. 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

67. 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)

68. 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)

69. NEOADJUVANT THERAPY
TRIALS
TARGET THERAPY

70. 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.

71. 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.

72. 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%

73. NEOADJUVANT THERAPY
TRIALS
ENDOCRINE HR+ THERAPY

76. ADJUVANT THERAPY TRIALS

77. When to offer adjuvant therapy

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

79. ADJUVANT CHEMOTHERAPY

80. ADJUVANT TREATMENT AND SURVIVAL
IMPROVEMENT OVER PAST 40 YEARS

81. 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%

82. 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

83. • 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

86. • 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

87. DOSE DENSE THERAPY

88. ADJUVANT ENDOCRINE HR+
THERAPY

89. 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

90. 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

91. NSABP B-21

92. 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

93. • 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

95. AROMATASE INHIBITORS

96. • 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

97. OVARIAN
SUPPRESSION/ABLATION
TRIALS

98. NSABP B-03

99. 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)

100. 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*

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

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

103. 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

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

106. HER2 Targeted Therapy
TARGET THERAPY TRIALS

108. • 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

109. OTHER TARGETED THERAPIES
TRIALS

117. • 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.

118. • 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.

119. • 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).

121. ONGOING PHASE 3 TRIALS

126. THANKS