LANDMARK TRIALS IN

BREAST CANCER
-Dr.A.Joseph Stalin Mch Postgraduate

PROF.DR.R.RAJARAMANS UNIT
CENTRE FOR ONCOLOGY
GOVT. ROYAPETTAH HOSPITAL
The farther backward you can look, the
farther forward you are likely to see.
Winston Churchill

Study the past if you would

define the future.
Confucius
A JOURNEY ON CARCINOMA BREAST

SURGICAL ASPECTS
CHEMOTHERAPHY
HORMONE THERAPHY
RADIOTHERAPHY
 SURGICAL ASPECTS
* RADICAL MASTECTOMY VS
MODIFIED RADICAL MASTECTOMY
* MODIFIED RADICAL MASTECTOMY VS
BREAST CONSRVATION SURGERY
* AXILLARY DISSECTION VS
SENTINEL NODE BIOPSY
 PRE INDUSTRIAL ERA
HIPPOCRATES- 2400 years back described
many forms of cancer and coined the term
CANCER.
1600 BC, the Edwin Smith Papyrus describes 8
cases of tumors or ulcers of the breast that
were treated by cauterization.
GALEN-200 AD classified tumours and
considered cancer as a systemic disease
related to excess of black bile.
 PRE INDUSTRIAL ERA
CONSIDERED AS
INCURABLE TILL 17TH
CENTURY
THEORY OF
HUMORALISM,
DIVINE CURSE
PREVAILED
 HALSTEDIAN ERA
VALSALVA(1704) ,LEDRAN(1757)&
MORGAGNI(1769) Local lesion capable of
cure by operation ,spreads through lymphatics
to regional nodes,tends to recur.
WILLIAM HALSTED(1894) popularised radical
mastectomy as the treatment of choice for
breast cancer ,considered breast cancer
strictly as a locoregional disease.
 HALSTEDIAN 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
 FISHER 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
 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*

Disagreement about local-regional management of primary breast cancer is related to differences in

perception of the biology of the disease. Other factors are secondary and obscure the reality that all
treatment must be related to biological considerations; otherwise, the basis for therapy is relegated to
speculation and to personal experience. As a result of extensive laboratory and clinical studies during
the past two decades, there has arisen an altered concept of cancer biology. The National Surgical
Adjuvant Project for Breast and Bowel Cancers (NSABP) has made a major contribution to the change
through findings from a series of prospective randomized clinical trials. That group of American and
Canadian investigators has implemented a series of trials aimed at answering biological as well 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.
This report will provide an overview of past and present NSABP contributions and will consider those
findings in relation to observations from other clinical trials of pertinence. It will emphasize that controversies
concerning breast cancer management are related to biological issues that cannot be resolved by
populism or appeals to emotion.
Cancer 46:1009-1025, 1980
 Prospective randomised clinical trial has been
recognised as a clinical problem solving tool
by the middle of 19th century
 NSABP 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.
SCHEMA
RESULTS
 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)
 MODIFIED RADICAL MASTECTOMY
VS BREAST CONSERVATIVE SURGERY
 NSABP 6
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)
 NSABP 6
2163 patients entered
the study from 1976-
1984.(354 patients from
St.Lukes hospital
excluded)
 NSABP 6
No significant difference
in overall survival ,
disease free survival
between three arm .
 NSABP 6
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)
 MILAN
Int J Radiat Oncol Biol Phys. 1986 May;12(5):717-20.
Local control and survival in early breast cancer: the Milan trial.
Veronesi U, Zucali R, Luini A.
Abstract
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. Disease-free and overall survival curves
show no difference between the two groups. Breast cancer of small size (less than
2 cm) may be safely treated with conservative treatment. Mutilating operations
are not justified.
PMID: 3519549 [PubMed - indexed for MEDLINE]
 NSABP 6&MILAN: CONCLUSIONS
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.
AXILLARY DISSECTION VS
SENTINEL NODE BIOPSY
 Background
Axillary lymph node status is an important prognostic factor in
women with early stage breast cancer.
Axillary dissection (AD) and histologic examination of lymph nodes
has traditionally been a routine component of surgery for patients
with early stage breast cancer.
Benefits of AD include improved local control. In addition, AD
provides information that guides prognosis as well as decisions
regarding adjuvant treatment.
However, these benefits must be weighed against significant risks of
lymphedema, nerve injury, and shoulder dysfunction associated
with AD.
Tumor cells generally metastasize from the primary tumor to one or
a few sentinel nodes (SN) before involving other lymph nodes.
Sentinel node resection (SNR) is a less invasive method of staging
the axilla with less morbidity compared to AD.
In patients with clinically node negative breast cancer, negative SNR
can identify patients without axillary nodal involvement, thus
obviating the need for a more extensive AD.
NSABP B-32 is a prospective randomized phase III trial designed to
determine whether a less invasive SNR provides the same survival
and regional control as a more aggressive AD in women with
clinically node negative breast cancer.
 NSABP B-32
Methods
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.
NSABP 32
 NSABP B-32
Results
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 is also no significant difference in distant DFS between the
two groups (HR: 1.09, p=0.29).
There was no significant difference in the rates of local-regional
recurrence between the two groups (HR: 1.09, p=0.29).
 Randomized Multicenter Trial of Sentinel Node Biopsy Versus
Standard Axillary Treatment in Operable Breast Cancer: The
ALMANAC Trial

Background: Sentinel lymph node biopsy in

women with operable breast cancer is routinely
used in some countries for staging the axilla
despite limited data from randomized trials on
morbidity and mortality outcomes. We
conducted a multicenter randomized trial to
compare quality-of-life outcomes between
patients with clinically node-negative invasive
breast cancer who received sentinel lymph node
biopsy and patients who received standard
axillary treatment.
 ALMANAC
Methods: 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. All statistical tests were two-sided.
 ALMANAC
Results: 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%) and 0.37
(95% CI = 0.27 to 0.50; absolute rates: 11% versus 31%),
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). These benefits were
seen with no increase in anxiety levels in the sentinel lymph node
biopsy group (P>.05).
 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.
 ACSOG Z011
Context Sentinel lymph node dissection
(SLND) accurately identifies nodal metastasis
of early breast cancer, but it is not clear
whether further nodal dissection affects
survival.
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.
From: Axillary Dissection vs No Axillary Dissection in Women With Invasive Breast Cancer and Sentinel Node
Metastasis: A Randomized Clinical Trial
JAMA. 2011;305(6):569-575. doi:10.1001/jama.2011.90

Figure Legend:
ALND indicates axillary lymph node dissection; SLND, sentinel lymph node dissection.

Copyright 2014 American Medical

Date of download: 1/15/2014
Association. All rights reserved.
 Design, Setting, and Patients The American College of
Surgeons Oncology Group Z0011 trial, a phase 3
noninferiority trial conducted at 115 sites and enrolling
patients from May 1999 to December 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.
 Interventions All patients underwent lumpectomy and
tangential whole-breast irradiation. Those with SLN
metastases identified by SLND were randomized to
undergo ALND or no further axillary treatment. Those
randomized to ALND underwent dissection of 10 or
more nodes. Systemic therapy was at the discretion of
the treating physician.
Main Outcome Measures Overall survival was the
primary end point, with a noninferiority margin of a 1-
sided hazard ratio of less than 1.3 indicating that SLND
alone is noninferior to ALND. Disease-free survival was
a secondary end point.
 Results Clinical and tumor characteristics were similar
between 445 patients randomized to ALND and 446
randomized to SLND alone. However, the median number
of nodes removed was 17 with ALND and 2 with SLND
alone. At a median follow-up of 6.3 years (last follow-up,
March 4, 2010), 5-year overall survival was 91.8% (95%
confidence interval [CI], 89.1%-94.5%) with ALND and
92.5% (95% CI, 90.0%-95.1%) with SLND alone; 5-year
disease-free survival was 82.2% (95% CI, 78.3%-86.3%) with
ALND and 83.9% (95% CI, 80.2%-87.9%) with SLND alone.
The hazard ratio for treatment-related overall survival was
0.79 (90% CI, 0.56-1.11) without adjustment and 0.87 (90%
CI, 0.62-1.23) after adjusting for age and adjuvant therapy.
 ACSOG Z011
Conclusion Among patients with limited SLN
metastatic breast cancer treated with breast
conservation and systemic therapy, the use of
SLND alone compared with ALND did not
result in inferior survival.
ACSOG Guidelines for Management of
Sentinel Lymph Node
BIOPST RESULTS GUIDELINES
Negative sentinel node No further axillary treatment,ALND may be omitted

Positive lymph node at ALND should be performed

presentation( proven by
fnac/core needle biopsy)

1 0r 2 positive Nodes ALND may be ommitted if

1.primary tumour < 5cm
2.clinically negative axilla
3.will receive whole breast radiation and
likely systemic theraphy
3 or more nodes ALND should be performed
 ACSOG GUIDELINE DONOT APPLY FOR THE
FOLLOWING

- Those undergoing mastectomy

- Those receiving neoadjuvant chemotheraphy
- Those receiving partial breast radiation or
radiation theraphy in prone position
CHEMOTHERAPHY
 WORLD WAR II Aftermath, Goodman & Gillman-
1946 demonstrated the anticancer effects of
nitrogen mustard
Sidney Fader -1948- used folic acid to treat
leukemia considered as father of modern
chemotheraphy
1951- Jane wright used MTX to treat breast
cancer.ThioTepa,Triethylene Thiophosphyrine
were also tried.
Polychemotheraphy developed -1950s ,based
on Goldie codman hypothesis.
CMF was the first used to treat breast cancer by
Bonadona
ADJUVANT CHEMOTHERAPHY

CMF REGIMEN
 N Engl J Med. 1976 Feb 19;294(8):405-10.
Combination chemotherapy as an adjuvant treatment in operable breast cancer.
Bonadonna G, Brusamolino E, Valagussa P, Rossi A, Brugnatelli L, Brambilla C, De
Lena M, Tancini G, Bajetta E, Musumeci R,Veronesi U.
Abstract
Prolonged cyclic combination chemotherapy with cyclophosphamide,
methotrexate and fluorouracil was evaluated as adjuvant treatment to radical
mastectomy in primary breast cancer with positive axillary lymph nodes. After 27
months of study, treatment occurred in 24 per cent of 179 control patients and in
5.3 per cent of 207 women given combination chemotherapy (P less than 10(-6)),
the advantage appearing statistically significant in all subgroups of patients.
Patients with four or more positive axillary nodes had a higher per cent of relapses
than those with fewer nodes. The initial new clinical manifestations occurred in
distant sites in 81.5 per cent of relapsed patients. Long-term chemotherapy
produced an acceptable toxicity, thus allowing the administration of a high
percentage of drug dosage. These results should be considered with caution, since,
at present, the effect of this therapy on survival and possible long-term side effects
remain unknown.
 MILAN TRIAL

N Engl J Med. 1976 Feb 19;294(8):405-10.

Combination chemotherapy as an adjuvant treatment in operable breast cancer.
Bonadonna G, Brusamolino E, Valagussa P, Rossi A, Brugnatelli L, Brambilla C, De
Lena M, Tancini G, Bajetta E, Musumeci R, Veronesi U.
Abstract
Prolonged cyclic combination chemotherapy with cyclophosphamide,
methotrexate and fluorouracil was evaluated as adjuvant treatment to radical
mastectomy in primary breast cancer with positive axillary lymph nodes. After 27
months of study, treatment occurred in 24 per cent of 179 control patients and in
5.3 per cent of 207 women given combination chemotherapy (P less than 10(-6)),
the advantage appearing statistically significant in all subgroups of patients.
Patients with four or more positive axillary nodes had a higher per cent of relapses
than those with fewer nodes. The initial new clinical manifestations occurred in
distant sites in 81.5 per cent of relapsed patients. Long-
term chemotherapy produced an acceptable toxicity, thus allowing the
administration of a high percentage of drug dosage. These results should be
considered with caution, since, at present, the effect of thistherapy on survival and
possible long-term side effects remain unknown.
 Current status of Milan adjuvant chemotherapy trials for node-positive and
node-negative breast cancer.
Bonadonna G, Valagussa P, Tancini G, Rossi A, Brambilla C, Zambetti M, Bignami
P, Di Fronzo G, Silvestrini R.
Abstract
This report summarizes the most important clinical results achieved at the Milan
Cancer Institute through various randomized trials with systemic
adjuvant chemotherapy. In the study testing surgery versus surgery plus 12 cycles
of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in node-positive
patients, the reduction in failure rate (34%) significantly favored CMF-treated
patients (P less than 0.001). Despite a reduction in the death rate of 23%, the
overall survival showed only a trend for CMF compared to surgery alone (P = 0.10).
In a second study, the 8-year results confirmed the lack of difference in relapse-
free survival and total survival rates between patients who received 12 and 6
cycles of CMF. The third study indicated that at 6 years, postmenopausal women
who had 1-3 positive lymph nodes and were treated with full-dose sequential non-
cross-resistant combinations had rates of relapse-free survival and total survival
that were superior to those previously achieved with CMF in the same menopausal
subset. In a limited series of patients with negative axillary nodes as well as
negative estrogen receptors, there was clear evidence of very poor prognosis in
women given only local-regional therapy, compared to women treated with
adjuvant CMF. Within the node-negative subset, the proliferative activity (labeling
index) of the primary tumor appears to be a more effective prognostic
discriminant than estrogen receptor status. The proportion of primary drug-
resistant tumor cells as well as the lack of relative dose intensity in
the drug programs tested so far probably represent the two most important
causes for the failure of adjuvant chemotherapy.
 NSABP 13

PROTOCOL B-13
A Protocol To Assess Sequential Methotrexate Fluorouracil In
Patients With Primary Breast Cancer And Negative Axillary Nodes
Whose Tumors Are Negative For Estrogen Receptors
Specific Aims
The primary objective of this study is to determine whether the
sequential combination MF is more effective than no treatment
with respect to disease-free survival and survival in patients whose
tumors are estrogen-receptor-negative.
In addition, this study, in conjunction with Protocol B-14, will permit
evaluation of treatment failure and survival in untreated patients
relative to their ER level.
NSABP 13
 NSABP 19
PROTOCOL B-19
A Clinical Trial to Compare Sequential Methotrexate, 5-
Fluorouracil (MF) with Conventional CMF in Primary
Breast Cancer Patients with Negative Nodes and Estrogen-
Receptor-Negative Tumors
Specific Aims
The objective of this study is to determine whether six
cycles of conventional cyclophosphamide, methotrexate
and 5-fluorouracil (CMF) are as effective with respect to
disease-free survival and survival as six cycles of sequential
methotrexate and 5-fluorouracil (MF) followed by
leucovorin for negative-node patients whose tumors are
estrogen-receptor-negative.
 Sequential Methotrexate 5-Fluorouracil (MF) for the Treatment of Node-Negative Breast Cancer Patients
with Estrogen-Receptor-Negative Tumors: Eight-Year Results from NSABP B-13 and First Report of Findings
from NSABP B-19 Comparing MF with Conventional CMF
Fisher B, Dignam J, Mamounas EP, Costantino J, Wickerham DL, Redmond C, Wolmark N, Dimitrov N, Bowman
D, Glass A, Atkins J, Abramson N, Sutherland C, Aron B, Margolese R, and other contributing NSABP
investigators
Journal of Clinical Oncology 14:7:1982-1992, 1996

Methods: A total of 760 patients were randomized to B-13; 1,095 patients with the same eligibility
requirements were randomized to B-19. Disease-free survival (DFS), distant disease-free survival
(DDFS), and survival were determined using life-table estimates.
Results: A significant benefit in overall DFS (74% v 59%; P < .001) was demonstrated at 8 years in all
B-13 patients who received MF (69% v 56% [P = .006] in those 50 years). A survival advantage
was evident in older patients (89% v 80%; P = .03). In B-19, through 5 years, an overall DFS
advantage (82% v 73%; P < .001) and a borderline survival advantage (88% v 85%; P = .06) were
evident with CMF. The DFS (84% v 72%; P < .001) and survival (89% v 84%; P = .04) benefits from
CMF were greater in women aged F or CMF after lumpectomy and breast irradiation resulted in a
low probability of ipsilateral breast tumor recurrence (IBTR). In B-13, the frequency of IBTR was
2.6% following MF versus 13.4% in women treated by lumpectomy; it was 0.6% following CMF in
B-19. Toxicity > or = grade 3 was more frequent among CMF patients in B-19. The age-related
difference in CMF benefit was not related to amount of drug received.
Conclusion: MF and CMF are effective for node-negative patients with ER-negative tumors. The
incidence of local-regional or distant metastases and IBTR decreased after either therapy. The
benefit from either therapy was evident in all patients, but the CMF advantage was greater in those
F may be used in patients with medical problems that would preclude CMF administration.
 30 years' follow up of randomised studies of adjuvant CMF in
operable breast cancer: cohort study
BMJ 2005; 330 (Published 27 Jan 2005)

Results After a median follow up of 28.5 years for the initial study,
adjuvant CMF was found to reduce the relative risk of relapse
significantly (hazard ratio 0.71, 95% confidence interval 0.56 to
0.91, P = 0.005) and death (0.79, 0.63 to 0.98, P = 0.04).
Administration of CMF for 12 cycles does not seem superior to a
shorter administration of six cycles. In the node negative and
oestrogen receptor negative trial, intravenous CMF significantly
reduced the relative risk of relapse of disease (0.65, 0.47 to 0.90, P
= 0.009) and death (0.65, 0.47 to 0.92, P = 0.01) at a median follow
up of 20 years.
Conclusions When delivered optimally, CMF benefits patients at
risk of relapse of distant disease without evidence of detrimental
effects in any of the examined subgroups.
ANTHRACYCLINES
 Br Med J. 1969 Aug 30;3(5669):503-6.
Clinical evaluation of adriamycin, a new antitumour
antibiotic.
Bonadonna G, Monfardini S, De Lena M, Fossati-Bellani F.
Abstract
Adriamycin, a new antitumour antibiotic of the
anthracycline group with a structural formula very similar
to daunorubicin, has proved to have potent tumour-
growth-inhibiting properties, and to be particularly
effective in childhood malignancies. Though adriamycin
produces a higher percentage of side-effects than
daunorubicin-namely, stomatitis and alopecia-a lower
dosage may be used for therapy.
 NSABP B 15
To determine, in patients with histologically positive axillary nodes
who are not classified as tamoxifen-responsive, whether short,
intensive adjuvant chemotherapy (AC, with or without interval
reinduction with CMF) is as effective as or more effective than
"conventional" CMF with respect to disease-free survival and survival.
 NSABP 15
J Clin Oncol. 1990 Sep;8(9):1483-96.
Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6
months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with
tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15.
Fisher B, Brown AM, Dimitrov NV, Poisson R, Redmond C, Margolese RG, Bowman D, Wolmark N, Wickerham
DL, Kardinal CG, et al.
Author information
Abstract
The National Surgical Adjuvant Breast and Bowel Project (NSABP) implemented protocol B-15 to compare 2
months of Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) and cyclophosphamide (AC) with 6 months
of conventional cyclophosphamide, methotrexate, and fluorouracil (CMF) in patients with breast cancer
nonresponsive to tamoxifen (TAM, T). A second aim was to determine whether AC followed in 6 months by
intravenous (IV) CMF was more effective than AC without reinduction therapy. Through 3 years of follow-up,
findings from 2,194 patients indicate no significant difference in disease-free survival (DFS, P = .5), distant disease-
free survival (DDFS, P = .5) or survival (S, P = .8) among the three groups. Since the outcome from AC and CMF was
almost identical, the issue arises concerning which regimen is more appropriate for the treatment of breast cancer
patients. AC seems preferable since, following total mastectomy, AC was completed on day 63 versus day 154 for
conventional CMF; patients visited health professionals three times as often for conventional CMF as for AC;
women on AC received therapy on each of 4 days versus on each of 84 days for conventional CMF; and nausea-
control medication was given for about 84 days to conventional CMF patients versus for about 12 days to patients
on AC. The difference in the amount of alopecia between the two treatment groups was less than anticipated.
While alopecia was almost universally observed following AC therapy, 71% of the CMF patients also had hair loss
and, in 41%, the loss was greater than 50%. This study and NSABP B-16, which evaluates the worth of AC therapy
in TAM-responsive patients, indicate the merit of 2 months of AC therapy for all positive-node breast cancer
patients.
 J Natl Cancer Inst. 2000 Dec 20;92(24):1991-8.
HER2 and choice of adjuvant chemotherapy for invasive breast cancer: National Surgical Adjuvant Breast and
Bowel Project Protocol B-15.
Paik S, Bryant J, Tan-Chiu E, Yothers G, Park C, Wickerham DL, Wolmark N.
Author information
Abstract
BACKGROUND:
Recent retrospective analyses have suggested that breast cancer patients whose tumors overexpress HER2 derive
preferential benefit from treatment with anthracyclines such as doxorubicin. This has led some clinicians to
propose that HER2 should be used as a predictive marker in choosing between anthracycline-based regimens and
combination chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). We evaluated this
recommendation in a retrospective study of National Surgical Adjuvant Breast and Bowel Project Protocol B-15, in
which patients received a combination of doxorubicin and cyclophosphamide (AC), CMF, or AC followed by CMF.
We hypothesized that AC would be superior to CMF only in the HER2-positive patients.
METHODS:
Immunohistochemical detection of HER2 was performed on tumor sections from 2034 of 2295 eligible patients.
We used statistical analysis to evaluate the interaction between the efficacy of the assigned treatments and HER2
overexpression. All statistical tests were two-sided.
RESULTS:
Tumor sections from 599 patients (29%) stained positive for HER2. AC was superior to CMF in HER2-positive
patients only, although differences in outcomes did not reach statistical significance. In the HER2-positive cohort,
relative risks of failure (i.e., after AC treatment as compared with CMF treatment) were 0.84 for disease-free
survival (DFS) (95% confidence interval [CI] = 0.65--1.07; P =.15), 0.82 for survival (95% CI = 0.63--1.06; P =.14), and
0.80 for recurrence-free survival (RFS) (95% CI = 0.62--1.04; P =.10). Tests for interaction between treatment and
HER2 status were suggestive but not statistically significant (P =.19 for DFS, P =.11 for survival, and P =.08 for RFS).
CONCLUSIONS:
These results, together with overview results indicating minor overall superiority for anthracycline-based regimens
relative to CMF, indicate a preference for the AC regimen in patients with HER2-positive tumors. Both AC and CMF
regimens may be considered for patients with HER2-negative tumors.
CMF VS CAF REGIMEN
 2005 by American Society of Clinical Oncology
Randomized, Controlled Trial of Cyclophosphamide, Methotrexate,
and Fluorouracil Versus Cyclophosphamide, Doxorubicin, and
Fluorouracil With and Without Tamoxifen for High-Risk, Node-
Negative Breast Cancer: Treatment Results of Intergroup Protocol
INT-0102
 SWOG INT0102
Abstract
Purpose We evaluated the efficacy of cyclophosphamide, methotrexate, and fluorouracil (CMF)
versus cyclophosphamide, doxorubicin, and fluorouracil (CAF) in node-negative breast cancer
patients with and without tamoxifen (TAM), overall and by hormone receptor (HR) status.
Patients and Methods Node-negative patients identified by tumor size (> 2 cm), negative HR, or
high S-phase fraction (n = 2,690) were randomly assigned to CMF, CAF, CMF + TAM (CMFT), or CAF +
TAM (CAFT). Cox regression evaluated overall survival (OS) and disease-free survival (DFS) for CAF
versus CMF and TAM versus no TAM separately. Two-sided CIs and one-sided P values for planned
comparisons were calculated.
Results Ten-year estimates indicated that CAF was not significantly better than CMF (P = .13) for the
primary outcome of DFS (77% v 75%; HR = 1.09; 95% CI, 0.94 to 1.27). CAF had slightly better OS
than CMF (85% v 82%, HR = 1.19 for CMF v CAF; 95% CI, 0.99 to 1.43); values were statistically
significant in the planned one-sided test (P = .03). Toxicity was greater with CAF and did not
increase with TAM. Overall, TAM had no benefit (DFS, P = .16; OS, P = .37), but the TAM effect
differed by HR groups. For HR-positive patients, TAM was beneficial (DFS, HR = 1.32 for no
TAM v TAM; 95% CI, 1.09 to 1.61; P = .003; OS, HR = 1.26; 95% CI, 0.99 to 1.61; P = .03), but not for
HR-negative patients (DFS, HR = 0.81 for no TAMv TAM; 95% CI, 0.64 to 1.03; OS, HR = 0.79; 95% CI,
0.60 to 1.05).
Conclusion CAF did not improve DFS compared with CMF; there was a slight effect on OS. Given
greater toxicity, we cannot conclude CAF to be superior to CMF. TAM is effective in HR-positive
disease, but not in HR-negative disease.
EBCTCG 2010 OVERVIEW

POLYCHEMOTHERAPHY VS NONE
10 YR RESULTS IN
23500 PATIENTS
CMF VS NO ADJUVANT
ANTHRACYCLINES VS NO ADJUVANT
ANTHRACYCLINES(AC) VS CMF
ADJUVANT CHEMOTHERAPHY HAS
DEFNITIVE BENEFIT IN ALL
SUBGROUPS
 Overall, we can conclude that CMF adjuvant chemotherapy is better than no treatment for early-
stage breast cancer. For low-risk patients, the above studies conclude that six cycles of oral CMF or
four cycles of AC every 3 weeks are equivalent in efficacy. Clinical trials that have incorporated
doxorubicin and epirubicin into polychemotherapy regimens (CAF and CEF for six cycles) show a
modest but clear benefit for anthracycline-based therapy compared to six cycles of CMF in adjuvant
breast cancer. Based on these results, anthracycline therapy with six cycles of CAF or CEF is
recommended for higher-risk patients (ie, node-positive patients), and may be used as a
benchmark for newer regimens incorporating taxanes and other novel agents. It is important to
note that six cycles of CAF/CEF chemotherapy regimens have not been directly compared to four or
six cycles of AC in the adjuvant setting. Also, there is no current evidence of excessive cardiac
toxicity in women with normal heart function who receive anthracyclines at the cumulative doses
utilized in standard adjuvant programs. The trade-off for a small survival benefit with anthracyclines
is a different treatment-related toxicity profile including higher incidences of alopecia, vomiting,
and cytopenias compared to CMF. With the availability of effective antiemetics (5-HT3 receptor
antagonists and NK1 inhibitors) and the use of growth factor support, most of these acute toxicities
can be fairly manageable. Data regarding the long-term toxicities of anthracyclines demonstrate a
low risk of cardiomyopathy and treatmentrelated leukemia. Overall, we seldom recommend CMF as
adjuvant therapy in our practice, and most often recommend anthracycline-based therapy,
although we remain very interested in the development of nonanthracycline combinations other
than CMF. - See more at: http://www.cancernetwork.com/review-article/anthracycline-vs-
nonanthracycline-adjuvant-therapy-breast-cancer#sthash.J7msq62m.dpuf
TAXANES
 CALGB 9344
3128 patients with positive LNs were randomized
to 3 groups
A(60mg/m2)C x 4 course +/- Taxol (175mg/m2) x 4 courses
A(75mg/m2)C x 4 course +/- Taxol (175mg/m2) x 4 courses
A(90mg/m2)C x 4 course +/- Taxol (175mg/m2) x 4 courses
At 5 years, disease free survival was 69%, 66%
and 67 % for patients with different adrimycin
dosage
The hazard reduction from adding paclitaxel to AC
were 17% for recurrence (p=0.0011) and 18% for
death (p=0.0098)
JCO 2003;21:976-983
 CALGB 9344 Adjuvant Study
R
N=3,170
A A60 C 4 P4
Node+ N
D
O A75 C 4
Statification:
Premenopausal & M
Postmenopausal I A90 C 4 No P
Z
E

A = Doxorubicin (doses shown)

C = Cyclophosphamide (600 mg/m2)
P = Paclitaxel (175 mg/m2 3 hour infusion)
ER+ or PR+ patients received Tamoxifen 5 y
 2005 by American Society of Clinical Oncology
Paclitaxel After Doxorubicin Plus Cyclophosphamide As Adjuvant
Chemotherapy for Node-Positive Breast Cancer:
Results From NSABP B-28
Abstract
Purpose The primary aim of National Surgical Adjuvant Breast and Bowel Project (NSABP) B-28 was
to determine whether four cycles of adjuvant paclitaxel (PTX) after four cycles of adjuvant
doxorubicin/cyclophosphamide (AC) will prolong disease-free survival (DFS) and overall survival
(OS) compared with four cycles of AC alone in patients with resected operable breast cancer and
histologically positive axillary nodes.
Patients and Methods Between August 1995 and May 1998, 3,060 patients were randomly
assigned (AC, 1,529; AC followed by PTX [AC PTX], 1,531). Patients 50 years and those younger
than 50 years with estrogen receptor (ER) or progesterone receptor (PR) -positive tumors also
received tamoxifen for 5 years, starting with the first dose of AC. Postlumpectomy radiotherapy was
mandated. Postmastectomy or regional radiotherapy was prohibited. Median follow-up is 64.6
months.
Results The addition of PTX to AC significantly reduced the hazard for DFS event by 17% (relative
risk [RR], 0.83; 95% CI, 0.72 to 0.95; P = .006). Five-year DFS was 76% 2% for patients randomly
assigned to AC PTX compared with 72% 2% for those randomly assigned to AC. Improvement in
OS was small and not statistically significant (RR, 0.93; 95% CI, 0.78 to 1.12; P = .46). Five-year OS
was 85% 2% for both groups. Subset analysis of the effect of paclitaxel according to hormone
receptors or tamoxifen administration did not reveal statistically significant interaction (for DFS, P =
.30 and P = .44, respectively). Toxicity with the AC PTX regimen was acceptable for the adjuvant
setting.
Conclusion The addition of PTX to AC resulted in significant improvement in DFS but no significant
improvement in OS with acceptable toxicity. No significant interaction between treatment effect
and receptor status or tamoxifen administration was observed.
 BCIRG 001

Lancet Oncol. 2013 Jan;14(1):72-80. doi: 10.1016/S1470-2045(12)70525-9. Epub 2012 Dec 12.
Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive breast cancer: 10-year follow-up of the phase 3 randomised BCIRG 001
trial.
Mackey JR, Martin M, Pienkowski T, Rolski J, Guastalla JP, Sami A, Glaspy J, Juhos E, Wardley A, Fornander T, Hainsworth J, Coleman R, Modiano
MR,Vinholes J, Pinter T, Rodrguez-Lescure A, Colwell B, Whitlock P, Provencher L, Laing K, Walde D, Price C, Hugh JC, Childs BH, Bassi K, Lindsay
MA, Wilson V,Rupin M, Hou V, Vogel C; TRIO/BCIRG 001 investigators.
Collaborators (72)
Author information
Abstract
BACKGROUND:
We compared standard adjuvant anthracycline chemotherapy with anthracycline-taxane combination chemotherapy in women with operable node-
positive breast cancer. Here we report the final, 10-year follow-up analysis of disease-free survival, overall survival, and long-term safety.
METHODS:
BCIRG 001 was an open label, phase 3, multicentre trial in which 1491 patients aged 18-70 years with node-positive, early breast cancer and a
Karnofsky score of 80% or more were randomly assigned to adjuvant treatment with docetaxel, doxorubicin, and cyclophosphamide (TAC) or
fluorouracil, doxorubicin, and cyclophosphamide (FAC) every 3 weeks for six cycles. Randomisation was stratified according to institution and number
of involved axillary lymph nodes per patient (one to three vs four or more). Disease-free survival was the primary endpoint and was defined as the
interval between randomisation and breast cancer relapse, second primary cancer, or death, whichever occurred first. Efficacy analyses were based
on the intention-to-treat principle. BCIRG 001 is registered with ClinicalTrials.gov, number NCT00688740.
FINDINGS:
Enrolement took place between June 11, 1997 and June 3, 1999; 745 patients were assigned to receive TAC and 746 patients were assigned to
receive FAC. After a median follow-up of 124 months (IQR 90-126), disease-free survival was 62% (95% CI 58-65) for patients in the TAC group and
55% (51-59) for patients in the FAC group (hazard ratio [HR] 080, 95% CI 068-093; log-rank p=00043). 10-year overall survival was 76% (95% CI 72-
79) for patients in the TAC group and 69% (65-72) for patients in the FAC group (HR 074, 061-090; log-rank p=00020). TAC improved disease-free
survival relative to FAC irrespective of nodal, hormone receptor, and HER2 status, although not all differences were significant in these subgroup
analyses. Grade 3-4 heart failure occurred in 26 (3%) patients in the TAC group and 17 (2%) patients in the FAC group, and caused death in two
patients in the TAC group and four patients in the FAC group. A substantial decrease in left ventricular ejection fraction (defined as a relative
decrease from baseline of 20% or more) was seen in 58 (17%) patients who received TAC and 41 (15%) patients who received FAC. Six patients who
received TAC developed leukaemia or myelodysplasia, as did three patients who received FAC.
INTERPRETATION:
Our results provide evidence that the initial therapeutic outcomes seen at the 5-year follow-up with a docetaxel-containing adjuvant regimen are
maintained at 10 years. However, a substantial percentage of patients had a decrease in left ventricular ejection fraction, probably caused by
anthracycline therapy, which warrants further investigation.
 2006 by American Society of Clinical Oncology
Sequential Adjuvant Epirubicin-Based and Docetaxel Chemotherapy
for Node-Positive Breast Cancer Patients: The FNCLCC PACS 01 Trial
Abstract
Purpose The PACS 01 trial compared six cycles of fluorouracil, epirubicin, and cyclophosphamide
(FEC) with a sequential regimen of three cycles of FEC followed by three cycles of docetaxel (FEC-D)
as adjuvant treatment for women with node-positive early breast cancer.
Patients and Methods Between June 1997 and March 2000, 1,999 patients with operable node-
positive breast cancer were randomly assigned to either FEC every 21 days for six cycles, or three
cycles of FEC followed by three cycles of docetaxel, both given every 21 days. Hormone-receptor
positive patients received tamoxifen for 5 years after chemotherapy. The primary end point was 5-
year disease-free survival (DFS).
Results Median follow-up was 60 months. Five-year DFS rates were 73.2% with FEC and 78.4% with
FEC-D (unadjusted P = .011; adjusted P = .012). Multivariate analysis adjusted for prognostic factors
showed an 18% reduction in the relative risk of relapse with FEC-D. Five-year overall survival rates
were 86.7% with FEC and 90.7% with FEC-D, demonstrating a 27% reduction in the relative risk of
death (unadjusted P = .014; adjusted P = .017). The incidence of grade 3 to 4 neutropenia, the need
for hematopoietic growth factor, and incidence of nausea/vomiting were higher with FEC.
Docetaxel was associated with more febrile neutropenia in the fourth cycle, stomatitis, edema, and
nail disorders. Though rare overall, there were fewer cardiac events after FEC-D (P = .03),
attributable mainly to the lower anthracycline cumulative dose.
Conclusion Sequential adjuvant chemotherapy with FEC followed by docetaxel significantly
improves disease-free and overall survival in node-positive breast cancer patients and has a
favorable safety profile.
 J Clin Oncol. 2003 Apr 15;21(8):1431-9. Epub 2003 Feb 13.
Randomized trial of dose-dense versus conventionally scheduled and
sequential versus concurrent combination chemotherapy as
postoperative adjuvant treatment of node-positive primary breast
cancer: first report of Intergroup Trial C9741/Cancer and Leukemia
Abstract Group B Trial 9741.
PURPOSE:
Using a 2 x 2 factorial design, we studied the adjuvant chemotherapy of women with axillary node-positive breast
cancer to compare sequential doxorubicin (A), paclitaxel (T), and cyclophosphamide (C) with concurrent
doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) for disease-free (DFS) and overall survival (OS);
to determine whether the dose density of the agents improves DFS and OS; and to compare toxicities.
PATIENTS AND METHODS:
A total of 2,005 female patients were randomly assigned to receive one of the following regimens: (I) sequential A
x 4 (doses) --> T x 4 --> C x 4 with doses every 3 weeks, (II) sequential A x 4 --> T x 4 --> C x 4 every 2 weeks with
filgrastim, (III) concurrent AC x 4 --> T x 4 every 3 weeks, or (IV) concurrent AC x 4 --> T x 4 every 2 weeks with
filgrastim.
RESULTS:
A protocol-specified analysis was performed at a median follow-up of 36 months: 315 patients had experienced
relapse or died, compared with 515 expected treatment failures. Dose-dense treatment improved the primary end
point, DFS (risk ratio [RR] = 0.74; P =.010), and OS (RR = 0.69; P =.013). Four-year DFS was 82% for the dose-dense
regimens and 75% for the others. There was no difference in either DFS or OS between the concurrent and
sequential schedules. There was no interaction between density and sequence. Severe neutropenia was less
frequent in patients who received the dose-dense regimens.
CONCLUSION:
Dose density improves clinical outcomes significantly, despite the lower than expected number of events at this
time. Sequential chemotherapy is as effective as concurrent chemotherapy.
 Fluorouracil, Epirubicin, and Cyclophosphamide With Either
Docetaxel or Vinorelbine, With or Without Trastuzumab, As Adjuvant
Treatments of Breast Cancer: Final Results of the FinHer Trial 2009 by
American Society of Clinical Oncology

Abstract
Purpose Docetaxel has not been compared with vinorelbine as adjuvant treatment of early breast
cancer. Efficacy and long-term safety of a short course of adjuvant trastuzumab administered
concomitantly with chemotherapy for human epidermal growth factor receptor 2 (HER2) positive
cancer are unknown.
Patients and Methods One thousand ten women with axillary nodepositive or high-risk node-
negative breast cancer were randomly assigned to receive three cycles of docetaxel or vinorelbine,
followed in both groups by three cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC).
Women with HER2-positive cancer (n = 232) were further assigned to either receive or not receive
trastuzumab for 9 weeks with docetaxel or vinorelbine. The median follow-up time was 62 months
after random assignment.
Results Women assigned to docetaxel had better distant diseasefree survival (DDFS) than those
assigned to vinorelbine (hazard ratio [HR] = 0.66; 95% CI, 0.49 to 0.91; P = .010). In the subgroup
of HER2-positive disease, patients treated with trastuzumab tended to have better DDFS than those
treated with chemotherapy only (HR = 0.65; 95% CI, 0.38 to 1.12; P = .12; with adjustment for
presence of axillary nodal metastases, HR = 0.57; P = .047). In exploratory analyses, docetaxel,
trastuzumab, and FEC improved DDFS compared with docetaxel plus FEC (HR = 0.32; P = .029) and
vinorelbine, trastuzumab, and FEC (HR = 0.31; P = .020). The median left ventricular ejection
fraction of trastuzumab-treated patients remained unaltered during the 5-year follow-up; only one
woman treated with trastuzumab was diagnosed with a heart failure.
Conclusion Adjuvant treatment with docetaxel improves DDFS compared with vinorelbine. A brief
course of trastuzumab administered concomitantly with docetaxel is safe and effective and
warrants further evaluation.
 2 years versus 1 year of adjuvant trastuzumab for HER2-positive
breast cancer (HERA): an open-label, randomised controlled trial.
Lancet. 2013 Sep 21;382(9897):1021-8. doi: 10.1016/S0140-6736(13)61094-6. Epub
2013 Jul 18.
Abstract
BACKGROUND:
Trastuzumab has established efficacy against breast cancer with overexpression or amplification of the HER2 oncogene. The
standard of care is 1 year of adjuvant trastuzumab, but the optimum duration of treatment is unknown. We compared 2
years of treatment with trastuzumab with 1 year of treatment, and updated the comparison of 1 year of trastuzumab versus
observation at a median follow-up of 8 years, for patients enrolled in the HERceptin Adjuvant (HERA) trial.
METHODS:
The HERA trial is an international, multicentre, randomised, open-label, phase 3 trial comparing treatment with trastuzumab
for 1 and 2 years with observation after standard neoadjuvant chemotherapy, adjuvant chemotherapy, or both in 5102
patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival. The comparison of 2 years
versus 1 year of trastuzumab treatment involved a landmark analysis of 3105 patients who were disease-free 12 months
after randomisation to one of the trastuzumab groups, and was planned after observing at least 725 disease-free survival
events. The updated intention-to-treat comparison of 1 year trastuzumab treatment versus observation alone in 3399
patients at a median follow-up of 8 years (range 0-10) is also reported. This study is registered with ClinicalTrials.gov, number
NCT00045032.
FINDINGS:
We recorded 367 events of disease-free survival in 1552 patients in the 1 year group and 367 events in 1553 patients in the
2 year group (hazard ratio [HR] 099, 95% CI 085-114, p=086). Grade 3-4 adverse events and decreases in left ventricular
ejection fraction during treatment were reported more frequently in the 2 year treatment group than in the 1 year group
(342 [204%] vs 275 [163%] grade 3-4 adverse events, and 120 [72%] vs 69 [41%] decreases in left ventricular ejection
fraction, respectively). HRs for a comparison of 1 year of trastuzumab treatment versus observation were 076 (95% CI 067-
086, p<00001) for disease-free survival and 076 (065-088, p=00005) for overall survival, despite crossover of 884 (52%)
patients from the observation group to trastuzumab therapy.
INTERPRETATION:
2 years of adjuvant trastuzumab is not more effective than is 1 year of treatment for patients with HER2-positive early breast
cancer. 1 year of treatment provides a significant disease-free and overall survival benefit compared with observation and
remains the standard of care.
 NEOADJUVANT
CHEMOTHERAPHY
 J Clin Oncol. 1997 Jul;15(7):2483-93.
Effect of preoperative chemotherapy on local-regional disease
in women with operable breast cancer: findings from National
Surgical Adjuvant Breast and Bowel Project B-18.
 NSABP 18
Abstract
PURPOSE:
To determine whether preoperative doxorubicin and cyclophosphamide (AC) permits more lumpectomies to be
performed and decreases the incidence of positive nodes in women with primary breast cancer.
PATIENTS AND METHODS:
Women (n = 1,523) were randomized to National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18; 759
eligible patients received postoperative AC and 747, preoperative AC. The clinical size of breast and axillary tumors
was determined before each of four cycles of AC and before surgery. Tumor response to preoperative therapy was
clinically complete (cCR), partial (cPR), stable (cSD), or progressive disease (cPD). Tissue from patients with a cCR
was evaluated for a pathologic complete response (pCR).
RESULTS:
Breast tumor size was reduced in 80% of patients after preoperative therapy; 36% had a cCR. Tumor size and
clinical nodal status were independent predictors of cCR. Twenty-six percent of women with a cCR had a pCR.
Clinical nodal response occurred in 89% of node-positive patients: 73% had a cCR and 44% of those had a pCR.
There was a 37% increase in the incidence of pathologically negative nodes. Before randomization, lumpectomy
was proposed for 86% of women with tumors < or = 2 cm, 70% with tumors 2.1 to 5.0 cm, and 3% with tumors >
or = 5.1 cm. Clinical tumor size and nodal status influenced the physician's decision. Overall, 12% more
lumpectomies were performed in the preoperative group; in women with tumors > or = 5.1 cm, there was a 175%
increase.
CONCLUSION:
Preoperative therapy reduced the size of most breast tumors and decreased the incidence of positive nodes. The
greatest increase in lumpectomy after preoperative therapy occurred in women with tumors > or = 5 cm, since
women with tumors less than 5 cm were already lumpectomy candidates. Preoperative therapy should be
considered for the initial management of breast tumors judged too large for lumpectomy.
 NSABP Protocol B-27. Preoperative doxorubicin plus
cyclophosphamide followed by preoperative or postoperative
docetaxel.
 Preoperative Chemotherapy: Updates of National Surgical
Adjuvant Breast and Bowel Project Protocols B-18 and B-27.

Abstract
Purpose: National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-18 was designed to determine
whether four cycles of doxorubicin and cyclophosphamide (AC) administered preoperatively improved breast
cancer disease-free survival (DFS) and overall survival (OS) compared with AC administered postoperatively.
Protocol B-27 was designed to determine the effect of adding docetaxel (T) to preoperative AC on tumor response
rates, DFS, and OS.
Patients and Methods: Analyses were limited to eligible patients. In B-18, 751 patients were assigned to receive
preoperative AC, and 742 patients were assigned to receive postoperative AC. In B-27, 784 patients were assigned
to receive preoperative AC followed by surgery, 783 patients were assigned to AC followed by T and surgery, and
777 patients were assigned to AC followed by surgery and then T.
Results: Results from B-18 show no statistically significant differences in DFS and OS between the two groups.
However, there were trends in favor of preoperative chemotherapy for DFS and OS in women less than 50 years
old (hazard ratio [HR] = 0.85, P = .09 for DFS; HR = 0.81, P = .06 for OS). DFS conditional on being event free for 5
years also demonstrated a strong trend in favor of the preoperative group (HR = 0.81, P = .053). Protocol B-27
results demonstrated that the addition of T to AC did not significantly impact DFS or OS. Preoperative T added to
AC significantly increased the proportion of patients having pathologic complete responses (pCRs) compared with
preoperative AC alone (26% v 13%, respectively; P < .0001). In both studies, patients who achieved a pCR continue
to have significantly superior DFS and OS outcomes compared with patients who did not.
Conclusion: B-18 and B-27 demonstrate that preoperative therapy is equivalent to adjuvant therapy. B-27 also
showed that the addition of preoperative taxanes to AC improves response.
J Clin Oncol. 2008 Feb 10;26(5):778-85.
 Clin Breast Cancer. 2002 Oct;3 Suppl 2:S69-74.
Neoadjuvant docetaxel in breast cancer: 3-year survival results from
the Aberdeen trial.

Abstract
Over the past 30 years there has been an increased use of neoadjuvant (or
primary) chemotherapy for treating patients with breast cancer. However, while it
is clear that chemotherapy given in the adjuvant setting after surgery does prolong
patients' overall and disease-free survival, the evidence that chemotherapy in the
neoadjuvant setting also increases survival remains unproven. In the Aberdeen
study, 162 patients with large and locally advanced breast cancer underwent 4
cycles of CVAP (cyclophosphamide/vincristine/doxorubicin/prednisone) primary
chemotherapy. Patients with a complete or partial response were then
randomized to either 4 further cycles of CVAP or 4 cycles of docetaxel (100
mg/m2). It was shown that the addition of sequential docetaxel (100 mg/m2) to
CVAP neoadjuvant chemotherapy resulted in a significantly enhanced clinical
response rate (94% vs. 64%) and a substantially increased complete
histopathological response rate (34% vs. 16%) when compared to patients
receiving CVAP alone. Furthermore, patients receiving docetaxel had an increased
breast conservation rate (67% vs. 48%) and an increased survival at a median
follow-up of 3 years. It is important to note that this was a small study, and the
survival results should be interpreted with caution. The results are encouraging,
however, and further studies are urgently required.
 GEPAR duo TRIAL
Neoadjuvant docetaxel followed by adjuvant doxorubicin and
cyclophosphamide in patients with stage III breast cancer

Background: To evaluate clinical and pathologic response to neoadjuvant

docetaxel therapy in patients with stage III breast cancer.
Patients and methods: Forty-five patients were planned to receive four cycles of
docetaxel 100mg/m2 every 3 weeks, followed by surgery, four cycles of
doxorubicin 60mg/m2 and cyclophosphamide 600mg/m2 (AC) every 3 weeks,
radiation therapy (RT), and tamoxifen when indicated.
Results: After four cycles of neoadjuvant docetaxel, the clinical response rate
within the breast was 59% (95% CI 42% to 73%) and overall (breast and axilla) was
49% (95% CI 38% to 72%) in the intention-to-treat (ITT) population. At the time of
surgery, 10% (n=4) of patients had a pathologic complete response (pCR) in the
breast, 27% (n=11) had a pCR within the axillary lymph nodes, and 7% (n=3) had a
pCR in the breast and axilla (95% CI 2% to 21%). An additional 5% (n=2) had
minimal residual invasive tumor (<5mm). The 5-year overall survival rate was 80%.
The percentage of patients with grade 3/4 neutropenia was similar during
docetaxel (93%) and AC (86%), while a greater percentage of patients had febrile
neutropenia during docetaxel treatment (27%) compared with AC treatment (7%).
Conclusions: Neoadjuvant docetaxel followed by surgery, adjuvant AC, hormonal
therapy where indicated, and RT is an active regimen for patients with stage III
breast cancer.
 Breast Cancer Res Treat. 2003;79 Suppl 1:S19-24.
Neoadjuvant docetaxel in locally advanced breast cancer.

Neoadjuvant chemotherapy produces substantial increases in clinical response rates and rates of breast
conserving therapy. Pathologic response rate, though generally low, is an important outcome as it is presumably
associated with eradication of micrometastatic disease and may likely result in improved outcomes. Anthracyclines
have long been considered the most efficacious chemotherapy agents for neoadjuvant therapy of early breast
cancer. Unfortunately, not all patients respond to neoadjuvant anthracycline-based chemotherapy. In an effort to
improve primary tumor response, docetaxel, an active agent in breast cancer, has been evaluated in the
neoadjuvant setting. Several randomized trials, including the NSABP B-27, GEPAR-duo, and the Aberdeen trial,
evaluating docetaxel in sequence with a doxorubicin-based neoadjuvant regimen have been reported, with
encouraging findings. We designed the Aberdeen trial with two primary aims: (1) to evaluate primary docetaxel in
patients that initially fail a neoadjuvant anthracycline-based polychemotherapy regimen, and (2) to compare a
docetaxel-based neoadjuvant regimen with a standard anthracycline-based regimen in patients who do respond to
the first four cycles of the anthracycline-based regimen. Eligible patients (n = 162) had previously untreated large
(> or = 3 cm) or locally advanced (T3, T4, T x N2) breast cancer. All received four cycles of CVAP, after which clinical
response was assessed. Responding patients were then randomized to four additional cycles of CVAP or to
docetaxel 100 mg/m2 every 3 weeks for four cycles. Patients failing to respond to CVAP received the docetaxel
regimen. After the first four cycles of CVAP, the overall response rate (ORR) was 67%. Ultimately, responses were
higher in the group randomized to docetaxel compared with those continuing CVAP (cCR: 94% vs. 66%; p = 0.001;
pCR 34% vs. 16%; p = 0.04). The addition of docetaxel improved overall survival and disease-free survival for
patients responding to four cycles of CVAP as compared with those receiving eight cycles of CVAP. Relative dose
intensity was higher and the incidence of severe leukopenia was lower in the group randomized to docetaxel.
These data and data from the NSABP B-27 and GEPAR-duo trials strongly support a combined
anthracycline/docetaxel regimen in the neoadjuvant setting.
PMID: 12868802 [PubMed - indexed for MEDLINE]
HORMONE THERAPHY
 Tamoxifen for Prevention of Breast Cancer: Report of the National
Surgical Adjuvant Breast and Bowel Project P-1 Study

Abstract
Background: The finding of a decrease in contralateral breast cancer incidence following tamoxifen administration for
adjuvant therapy led to the concept that the drug might play a role in breast cancer prevention. To test this hypothesis,
the National Surgical Adjuvant Breast and Bowel Project initiated the Breast Cancer Prevention Trial (P-1) in 1992.
Methods: Women (N = 13 388) at increased risk for breast cancer because they 1) were 60 years of age or older, 2) were
3559 years of age with a 5-year predicted risk for breast cancer of at least 1.66%, or 3) had a history of lobular carcinoma
in situ were randomly assigned to receive placebo (n = 6707) or 20 mg/day tamoxifen (n = 6681) for 5 years. Gail's
algorithm, based on a multivariate logistic regression model using combinations of risk factors, was used to estimate the
probability (risk) of occurrence of breast cancer over time. Results: Tamoxifen reduced the risk of invasive breast cancer
by 49% (two-sided P<.00001), with cumulative incidence through 69 months of follow-up of 43.4 versus 22.0 per 1000
women in the placebo and tamoxifen groups, respectively. The decreased risk occurred in women aged 49 years or
younger (44%), 5059 years (51%), and 60 years or older (55%); risk was also reduced in women with a history of lobular
carcinoma in situ (56%) or atypical hyperplasia (86%) and in those with any category of predicted 5-year risk. Tamoxifen
reduced the risk of noninvasive breast cancer by 50% (two-sided P<.002). Tamoxifen reduced the occurrence of estrogen
receptor-positive tumors by 69%, but no difference in the occurrence of estrogen receptor-negative tumors was seen.
Tamoxifen administration did not alter the average annual rate of ischemic heart disease; however, a reduction in hip,
radius (Colles'), and spine fractures was observed. The rate of endometrial cancer was increased in the tamoxifen group
(risk ratio = 2.53; 95% confidence interval = 1.354.97); this increased risk occurred predominantly in women aged 50
years or older. All endometrial cancers in the tamoxifen group were stage I (localized disease); no endometrial cancer
deaths have occurred in this group. No liver cancers or increase in colon, rectal, ovarian, or other tumors was observed in
the tamoxifen group. The rates of stroke, pulmonary embolism, and deep-vein thrombosis were elevated in the
tamoxifen group; these events occurred more frequently in women aged 50 years or older.
Conclusions: Tamoxifen decreases the incidence of invasive and noninvasive breast cancer. Despite side effects resulting
from administration of tamoxifen, its use as a breast cancer preventive agent is appropriate in many women at increased
risk for the disease. [J Natl Cancer Inst 1998;90:137188]
1998 Oxford University Press
 PROTOCOL B-14
A Clinical Trial to Assess Tamoxifen in Patients With Primary Breast
Cancer and Negative Axillary Nodes Whose Tumors are Positive for
Estrogen Receptors
 NSABP 14
Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National
Surgical Adjuvant Breast and Bowel Project B-14 randomized trial.
Fisher B, Dignam J, Bryant J, Wolmark N.
Author information
Abstract
BACKGROUND:
Previously reported information from B-14, a National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized,
placebo-controlled clinical trial, demonstrated that patients with estrogen receptor (ER)-positive breast cancer and negative
axillary lymph nodes experienced a prolonged benefit from 5 years of tamoxifen therapy. When these women were
rerandomized to receive either placebo or more prolonged tamoxifen therapy, they obtained no additional advantage from
tamoxifen through 4 years of follow-up. Because the optimal duration of tamoxifen administration continues to be
controversial and because there have been 3 more years of follow-up and a substantial increase in the number of events
since our last report, an update of the B-14 study is appropriate.
METHODS:
Patients (n = 1172) who had completed 5 years of tamoxifen therapy and who were disease free were rerandomized to
receive placebo (n = 579) or tamoxifen (n = 593). Survival, disease-free survival (DFS), and relapse-free survival (RFS) were
estimated by the Kaplan-Meier method; the differences between the treatment groups were assessed by the log-rank test.
Relative risks of failure (with 95% confidence intervals) were determined by the Cox proportional hazards model. P values
were two-sided.
RESULTS:
Through 7 years after reassignment of tamoxifen-treated patients to either placebo or continued tamoxifen therapy, a slight
advantage was observed in patients who discontinued tamoxifen relative to those who continued to receive it: DFS = 82%
versus 78% (P =.03), RFS = 94% versus 92% (P =.13), and survival = 94% versus 91% (P =.07), respectively. The lack of benefit
from additional tamoxifen therapy was independent of age or other characteristics.
CONCLUSION:
Through 7 years of follow-up after rerandomization, there continues to be no additional benefit from tamoxifen
administered beyond 5 years in women with ER-positive breast cancer and negative axillary lymph nodes.
 Lancet Oncol. 2010 Dec;11(12):1135-41. doi: 10.1016/S1470-
2045(10)70257-6. Epub 2010 Nov 17.
Effect of anastrozole and tamoxifen as adjuvant treatment for early-
stage breast cancer: 10-year analysis of the ATAC trial.
 ATAC
Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5
years' adjuvant treatment for breast cancer.
Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker
GY, Tobias JS; ATAC Trialists' Group.
Author information
Abstract
The standard adjuvant endocrine treatment for postmenopausal women with hormone-receptor-
positive localised breast cancer is 5 years of tamoxifen, but recurrences and side-effects restrict its
usefulness. The aromatase inhibitor anastrozole was compared with tamoxifen for 5 years in 9366
postmenopausal women with localised breast cancer. After a median follow-up of 68 months,
anastrozole significantly prolonged disease-free survival (575 events with anastrozole vs 651 with
tamoxifen, hazard ratio 0.87, 95% CI 0.78-0.97, p=0.01) and time-to-recurrence (402 vs 498, 0.79,
0.70-0.90, p=0.0005), and significantly reduced distant metastases (324 vs 375, 0.86, 0.74-0.99,
p=0.04) and contralateral breast cancers (35 vs 59, 42% reduction, 12-62, p=0.01). Almost all
patients have completed their scheduled treatment, and fewer withdrawals occurred with
anastrozole than with tamoxifen. Anastrozole was also associated with fewer side-effects than
tamoxifen, especially gynaecological problems and vascular events, but arthralgia and fractures
were increased. Anastrozole should be the preferred initial treatment for postmenopausal women
with localised hormone-receptor-positive breast cancer.
 ATAC
Abstract
BACKGROUND:
The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial was designed to compare the efficacy and safety of
anastrozole (1 mg) with tamoxifen (20 mg), both given orally every day for 5 years, as adjuvant treatment for
postmenopausal women with early-stage breast cancer. In this analysis, we assess the long-term outcomes after a median
follow-up of 120 months.
METHODS:
We used a proportional hazards model to assess the primary endpoint of disease-free survival, and the secondary endpoints
of time to recurrence, time to distant recurrence, incidence of new contralateral breast cancer, overall survival, and death
with or without recurrence in all randomised patients (anastrozole n=3125, tamoxifen n=3116) and hormone-receptor-
positive patients (anastrozole n=2618, tamoxifen n=2598). After treatment completion, we continued to collect data on
fractures and serious adverse events in a masked fashion (safety population: anastrozole n=3092, tamoxifen n=3094). This
study is registered as an International Standard Randomised Controlled Trial, number ISRCTN18233230.
FINDINGS:
Patients were followed up for a median of 120 months (range 0-145); there were 24,522 woman-years of follow-up in the
anastrozole group and 23,950 woman-years in the tamoxifen group. In the full study population, there were significant
improvements in the anastrozole group compared with the tamoxifen group for disease-free survival (hazard ratio [HR] 091,
95% CI 083-099; p=004), time to recurrence (084, 075-093; p=0001), and time to distant recurrence (087, 077-099;
p=003). For hormone-receptor-positive patients, the results were also significantly in favour of the anastrozole group for
disease-free survival (HR 086, 95% CI 078-095; p=0003), time to recurrence (079, 070-089; p=00002), and time to
distant recurrence (085, 073-098; p=002). In hormone-receptor-positive patients, absolute differences in time to
recurrence between anastrozole and tamoxifen increased over time (27% at 5 years and 43% at 10 years) and recurrence
rates remained significantly lower on anastrozole than tamoxifen after treatment completion (HR 081, 95% CI 067-098;
p=003), although the carryover benefit was smaller after 8 years. There was weak evidence of fewer deaths after recurrence
with anastrozole compared with tamoxifen treatment in the hormone-receptor-positive subgroup (HR 087, 95% CI 074-
102; p=009), but there was little difference in overall mortality (095, 95% CI 084-106; p=04). Fractures were more
frequent during active treatment in patients receiving anastrozole than those receiving tamoxifen (451 vs 351; OR 133, 95%
CI 115-155; p<00001), but were similar in the post-treatment follow-up period (110 vs 112; OR 098, 95% CI 074-130;
p=09). Treatment-related serious adverse events were less common in the anastrozole group than the tamoxifen group (223
anastrozole vs 369 tamoxifen; OR 057, 95% CI 048-069; p<00001), but were similar after treatment completion (66 vs 78;
OR 084, 95% CI 060-119; p=03). No differences in non-breast cancer causes of death were apparent and the incidence of
other cancers was similar between groups (425 vs 431) and continue to be higher with anastrozole for colorectal (66 vs 44)
and lung cancer (51 vs 34), and lower for endometrial cancer (six vs 24), melanoma (eight vs 19), and ovarian cancer (17 vs
28). No new safety concerns were reported.
 Neoadjuvant chemotherapy with trastuzumab followed by
Neo adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in
patients with HER2-positive locally
Neoadjuvant chemotherapy with advanced breast cancer (the NOAH trial): a
randomised controlled superiority trial with a parallel HER2-negative cohort
Background
The monoclonal antibody trastuzumab has survival benefit when given with chemotherapy to patients
with early, operable, and metastatic breast cancer that has HER2 (also known as ERBB2) overexpression or
amplification. We aimed to assess event-free survival in patients with HER2-positive locally advanced or
inflammatory breast cancer receiving neoadjuvant chemotherapy with or without 1 year of trastuzumab.
Methods
We compared 1 year of treatment with trastuzumab (given as neoadjuvant and adjuvant treatment;
n=117) with no trastuzumab (118), in women with HER2-positive locally advanced or inflammatory breast
cancer treated with a neoadjuvant chemotherapy regimen consisting of doxorubicin, paclitaxel,
cyclophosphamide, methotrexate, and fluorouracil. Randomisation was done with a computer program
and minimisation technique, taking account of geographical area, disease stage, and hormone receptor
status. Investigators were informed of treatment allocation. A parallel cohort of 99 patients with HER2-
negative disease was included and treated with the same chemotherapy regimen. Primary endpoint was
event-free survival. Analysis was by intention to treat. This study is registered, number ISRCTN86043495.
Findings
Trastuzumab significantly improved event-free survival in patients with HER2-positive breast cancer (3-
year event-free survival, 71% [95% CI 6178; n=36 events] with trastuzumab, vs 56% [4665; n=51
events] without; hazard ratio 059 [95% CI 038090]; p=0013). Trastuzumab was well tolerated and,
despite concurrent administration with doxorubicin, only two patients (2%) developed symptomatic
cardiac failure. Both responded to cardiac drugs.
Interpretation
The addition of neoadjuvant and adjuvant trastuzumab to neoadjuvant chemotherapy should be
considered for women with HER2-positive locally advanced or inflammatory breast cancer to improve
event-free survival, survival, and clinical and pathological tumour responses.
 Program for the Assessment of Clinical Cancer Tests
(PACCT-1): Trial Assigning Individualized Options for
Treatment: The TAILORx Trial

Women with estrogen receptor and/or progesterone

receptor positive, lymph node negative (cancer that has not
spread to the lymph nodes), HER2/neu negative breast
cancer are eligible to enroll in TAILORx. The tumor size must
be 1.1 to 5.0 cm (or 0.5 mm to 1.0 cm, with unfavorable
histologic features). Participants must meet standard
clinical criteria and be medically suitable candidates for
adjuvant chemotherapy.
 Hormone Therapy With or Without Combination Chemotherapy in
Treating Women Who Have Undergone Surgery for Node-Negative
Breast Cancer (The TAILORx Trial)
GROUP 1 (SECONDARY STUDY GROUP 1; ONCOTYPE DX RECURRENCE
SCORE [ODRS] < 11): Patients receive standard hormonal therapy (e.g.,
tamoxifen alone orally (PO), aromatase inhibitor [e.g., anastrozole,
letrozole, or exemestane] alone PO, or tamoxifen PO followed by
aromatase inhibitor PO) at the discretion of the treating physician for 5 or
10 years.
GROUP 2 (PRIMARY STUDY GROUP; ODRS 11-25): Patients are stratified
according to tumor size (=< 2.0 cm vs >= 2.1 cm), menopausal status
(postmenopausal vs premenopausal vs perimenopausal), planned
chemotherapy (taxane-containing [i.e., paclitaxel, docetaxel] vs non
taxane-containing), planned radiotherapy (whole breast with no boost
planned vs whole breast with boost planned vs partial breast irradiation
planned vs no planned radiation therapy [for patients who have had a
mastectomy]) and Oncotype DX Recurrence Score (11-15 vs 16-20 vs 21-
25). Patients are then randomized to receive either hormonal therapy
alone or combination chemotherapy and hormonal therapy.
 To determine whether adjuvant hormonal
therapy with chemotherapy is better than
adjuvant hormonal therapy alone in women
whose tumors fall in a range where the
benefit from chemotherapy is uncertain as
indicated by a molecular test. The primary
studyendpoint is disease-free survival.
Another primary endpoint is overall survival.
RADIOTHERAPHY
 Lancet. 2011 Nov 12;378(9804):1707-16. doi: 10.1016/S0140-
6736(11)61629-2. Epub 2011 Oct 19.
Effect of radiotherapy after breast-conserving surgery on 10-year
recurrence and 15-year breast cancer death: meta-analysis of
individual patient data for 10,801 women in 17 randomised trials.
Abstract
BACKGROUND:
After breast-conserving surgery, radiotherapy reduces recurrence and breast cancer death, but it may do so more for some
groups of women than for others. We describe the absolute magnitude of these reductions according to various prognostic
and other patient characteristics, and relate the absolute reduction in 15-year risk of breast cancer death to the absolute
reduction in 10-year recurrence risk.
METHODS:
We undertook a meta-analysis of individual patient data for 10,801 women in 17 randomised trials of radiotherapy versus no
radiotherapy after breast-conserving surgery, 8337 of whom had pathologically confirmed node-negative (pN0) or node-
positive (pN+) disease.
FINDINGS:
Overall, radiotherapy reduced the 10-year risk of any (ie, locoregional or distant) first recurrence from 350% to 193%
(absolute reduction 157%, 95% CI 137-177, 2p<000001) and reduced the 15-year risk of breast cancer death from 252%
to 214% (absolute reduction 38%, 16-60, 2p=000005). In women with pN0 disease (n=7287), radiotherapy reduced these
risks from 310% to 156% (absolute recurrence reduction 154%, 132-176, 2p<000001) and from 205% to 172%
(absolute mortality reduction 33%, 08-58, 2p=0005), respectively. In these women with pN0 disease, the absolute
recurrence reduction varied according to age, grade, oestrogen-receptor status, tamoxifen use, and extent of surgery, and
these characteristics were used to predict large (20%), intermediate (10-19%), or lower (<10%) absolute reductions in the
10-year recurrence risk. Absolute reductions in 15-year risk of breast cancer death in these three prediction categories were
78% (95% CI 31-125), 11% (-20 to 42), and 01% (-75 to 77) respectively (trend in absolute mortality reduction 2p=003).
In the few women with pN+ disease (n=1050), radiotherapy reduced the 10-year recurrence risk from 637% to 425%
(absolute reduction 212%, 95% CI 145-279, 2p<000001) and the 15-year risk of breast cancer death from 513% to 428%
(absolute reduction 85%, 18-152, 2p=001). Overall, about one breast cancer death was avoided by year 15 for every four
recurrences avoided by year 10, and the mortality reduction did not differ significantly from this overall relationship in any of
the three prediction categories for pN0 disease or for pN+ disease.
INTERPRETATION:
After breast-conserving surgery, radiotherapy to the conserved breast halves the rate at which the disease recurs and
reduces the breast cancer death rate by about a sixth. These proportional benefits vary little between different groups of
women. By contrast, the absolute benefits from radiotherapy vary substantially according to the characteristics of the
patient and they can be predicted at the time when treatment decisions need to be made.
 BREAST CONSERVATION

Local relapse: BC surgery +/- RT

Studies Median Op LR LR
Follow-up w/o RT with RT
NSABP B-06 125 months Lump- 35% 9%
ectomy
Scottish 68 months Lump- 24% 6%
Cancer Trial ectomy
Uppsala-rebro 106 months Segment- 22% 7%
Study Group ectomy

Ontario 91 months Lump- 35% 11%

Cancer Inst. ectomy
Milano III 109 months Quadrant- 22% 5%
ectomy
 J Natl Cancer Inst. 2012 Jul 18;104(14):1080-93. doi: 10.1093/jnci/djs272. Epub 2012 Jul 17.
Mammography screening and breast cancer mortality in Sweden.
Autier P, Koechlin A, Smans M, Vatten L, Boniol M.
Author information
Abstract
BACKGROUND:
Swedish women aged 40-69 years were gradually offered regular mammography screening since 1974,
and nationwide coverage was achieved in 1997. We hypothesized that this gradual implementation of
breast cancer screening would be reflected in county-specific mortality patterns during the last 20 years.
METHODS:
Using data from the Swedish Board of Health and Welfare from 1960 to 2009, we used joinpoint
regression to analyze breast cancer mortality trends in women aged 40 years and older (1,286,000 women
in 1995-1996). Poisson regression models were used to compare observed mortality trends with expected
trends if screening had resulted in breast cancer mortality reductions of 10%, 20%, or 30% among women
screened during 18 years of follow-up after the introduction of screening. All statistical tests were two-
sided.
RESULTS:
From 1972 to 2009, breast cancer mortality rates in Swedish women aged 40 years and older declined by
0.98% annually, from 68.4 to 42.8 per 100,000, and it continuously declined in 14 of the 21 Swedish
counties. In three counties, breast cancer mortality declined sharply during or soon after the
implementation of screening; in two counties, a steep decline started at least 5 years after screening was
introduced; and in two counties, breast cancer mortality increased after screening started. In counties in
which screening started in 1974-1978, mortality trends during the next 18 years were similar to those
before screening started, and in counties in which screening started in 1986-1987, mortality increased by
approximately 12% (P = .007) after the introduction of screening compared with previous trends. In
counties in which screening started in 1987-1988 and in 1989-1990, mortality declined by approximately
5% (P = .001) and 8% (P < .001), respectively, after the introduction of screening. Conclusion County-
specific mortality statistics in Sweden are consistent with studies that have reported limited or no impact
of screening on mortality from breast cancer.
 As have other gadgets in medical tool box-
steth,Echo,MRI the clinical trial has been
adapted and refined to new users ,has
acquired its own place in medical culture. As
with other tools,however the real function of
RCT ha been and remains to assist and not to
replace CLINICAL JUDGEMENT
- Clinics of North America(2000)
THANK U