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U p d a t e o f t h e O x f o r d O v e r v i e w : N e wI n s i g h t a n d P e r s p e c t i v e s i n t h e E r a o f P e r s o n a l i z e d M e d i c i n e

By Kathleen I. Pritchard, MD, Jonas Bergh, MD, PhD, and Harold J. Burstein MD, PhD

Overview: There is great appreciation for the heterogeneity

of breast cancers, particularly of hormone-receptor positive

b reast can cers. A g o al o f mo d ern o n co lo gy man ag in g su ch

h etero g eneity is to d etermin e h o w to in d ivid ualize th erap y

based on the specific pathological and biological features of a

given tumor. Two distinctive clinical literatures exist to guide

treatmen t o f h o rmo n e-recepto r-p o sitive b reast can cer. T h e

Oxford Overview, a seminal meta-analysis effort, has recently

b e en u pd a te d , a n d s u gg e st s t h at n e ar l y a l l p a ti e nt s w i th

ER-positive tumors benefit from adjuvant endocrine therapy.

I n a d di t io n, t h e o v er v ie w fi nd s t h at n e ar l y a l l s u bs e ts o f

p atien ts with ER-p o sitive tu mo rs also b en efit fro m mo d ern

adjuvant chemotherapy regimens. Meanwhile, retrospective

subset analyses of specific trials or populations suggests that

t h e b e ne fi ts o f c h em ot h er a py a r e n ot s o u ni f or m , a n d i n

particular that molecular diagnostics assays can identify pa-

t i en t s w h o d o n ot w a rr a nt c h em ot h er a py . T hi s a r ti c le w i ll

highlight recent data and controversies in personalizing adju-

vant breast cancer therapy.

THE OXFORD Overview of the Early Breast Cancer

Trialists Collaborative Group (EBCTCG) dates back to

1984 when investigators responsible for trials of systemic

adjuvant systemic therapy from all around the globe met

initially, not in Oxford, but at Heathrow Airport to examine

the first meta-analysis of adjuvant systemic therapy trials.

The Overview has always involved collaboration between

the Oxford Secretariat led by Sir Richard Peto and a

consortium of investigators. A series of distinguished past

chairs have included I. Craig Henderson, MD, a prominent

breast cancer medical oncologist initially from Harvard

University and later the University of California San Fran-

cisco Helen Diller Family Comprehensive Center, and

William C. Wood, MD, then Chief of Surgery at Emory

University. The EBCTCG is currently chaired by Kathy

Pritchard, MD, of Toronto and Martine Piccart, MD, PhD,

of Brussels. The Steering Committee and Executive of the

EBCTCGboth of which include members of the Oxford

Secretariat and clinical investigators (the Trialists)exten-

sively meet, teleconference, and e-mail to bring analyses

and publications to fruition. Between 2005 and 2011,

data collection and analyses have resulted in five major

publications.1-5

The Overview concept dating back to 1984 has not

changed. Collaboration between physicians and biostatisti-

cians based in Oxford and around the world was sought,

built, and sustained. Data were initially collected from all

randomized trials of systemic adjuvant and, later, local-

regional therapy. The Overview methodology involves the

collection of individual patient data, which includes a widevariety of items such as dates of randomization and treat-

ment allocation. Patients can be stratified by age, node

status, and other criteria and the log-rank statistics from

each trial are combined to give an overall estimate of the

effect of different treatments either in the whole patient

population or in various stratified subsets.

Outcomes include recurrence, which can be adjusted to

include or exclude contralateral breast cancers and deaths.

Deaths from unknown causes are usually included with

deaths from breast cancer unless specifically stated other-

wise. Recurrences can be divided into local and/or distant

with and without contralateral breast cancers. The

EBCTCG has also been interested in collecting informationon deaths from cardiac events, stroke, and other cancers.

In 1984, the Oxford Overview showed unequivocally for

the first time that tamoxifen improved survival and that

cyclophosphamide, methotrexate, and 5-fluorouracil (CMF)

chemotherapy improved survival. It was also shown that

ovarian ablation, which had been mainly tested in small

underpowered trials with nonsignificant results, did, in and

of itself, improve overall survival, particularly in women

whose tumors had positive estrogen receptors (ER). By 1990,

it became clear that 5 years of tamoxifen was better than 1

or 2 years and that tamoxifen effects were greater in women

with ER-positive cancers. It was first shown in 1990 that

tamoxifen reduced the rate of contralateral breast cancer

and that chemotherapy was effective in both older and

younger women.

By 1995, the huge effect of 5 years of tamoxifen was

clearly demonstrated, and it was obvious from both direct

and indirect comparisons within the Overview that 5 years

of tamoxifen was superior to shorter durations of treatment.It was seen for the first time that tamoxifen prevented

contralateral breast cancers only in women whose initial

tumors were ER positive. That year, the Overview also

demonstrated that anthracycline-containing regimens, at

least when given in higher dosages, were better than CMF-

type chemotherapy.

By 2000, the Overview was able to report on long-term

results, such as 15-year outcomes with chemotherapy, dem-

onstrating sustained benefit in older and in younger women.

There was great controversy at this time suggesting that,

particularly in the CMF trials, the effects of chemotherapy

might be greater in women with ER-negative tumors than in

those with ER-positive tumors, a controversy which contin-ues to this day. In 2000, it was also clearly seen that the

15-year effects of 5 years of tamoxifen were sustained and

of great magnitude. The ATLAS, ATtOM, and a few other

small trials were combined and opened the door to the

suggestion that 5 years of tamoxifen might not be optimal

and that longer tamoxifen might further reduce disease-free

From the Odette Cancer Center, McMaster University, Hamilton, ON, Karolinska

Institutet, Stockholm, Sweden, and the Dana-Farber Cancer Institute, Boston, MA.

Authors disclosures of potential conflicts of interest are found at the end of this article.

Address reprint requests to Harold J. Burstein, Dana-Farber Cancer Institute, 450

Brookline Avenue, Boston, MA 02215; email: [email protected].

2012 by American Society of Clinical Oncology.1092-9118/10/1-10

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recurrence. This remains an important and unresolved

question. It was also clear that ovarian ablation and/or

suppression was effective but not significantly so whenadded to chemotherapy, perhaps because of chemotherapy-

induced amenorrhea.

In 2005, structural changes were required in the Overview

process. The Trialists formed a new steering committee and

organized subcommittees, many of which continue today to

work very effectively. Many new trials were added and there

were many additional years of follow-up for all major ques-

tions. However, data from many major trials, particularly

those of taxanes, were missing in 2005.

In 2006, the Trialists and their subcommittees met and

a series of priorities were set. These included investigations

of the type of anthracycline-based regimen; all taxane trials;

aromatase inhibitors; trastuzumab; and chemoendocrine

therapy, particularly in relation to the ER-positive com-

pared with ER-negative issue in pre- and postmenopausal

women. These meetings led five important publications on

tamoxifen, chemotherapy, and loco-regional therapy.1-5

Nearly 30 years since its inception, the Overview remains

highly relevant and informative. In comparison to individual

trials even huge trials tallying thousands of patients as

has become common in early-stage breast cancerthe Over-

view has several methodologic virtues that make it a unique

data resource. In particular, the Overview is important for

(1) having all the worldwide data; (2) avoiding publication

bias; (3) giving average effect sizes; and (4) clarifying the

timeframes of effects through large sample size and long-

term follow-up.

R e ce n t No t ab l e F i n di n g s f ro m t h e O v erv i ew

Endocrine Therapy

In the main tamoxifen Overview, more than 54,500

women were studied in trials of tamoxifen compared with

no tamoxifen and more than 45,000 in trials of longer

compared with shorter tamoxifen. The effects of 5 years of

tamoxifen on breast cancer recurrence and mortality are

shown in Fig. 1.

Fundamentally, tamoxifen has long and strong sustained

effects on local recurrence, contralateral breast cancer, and

distant and multiple recurrences. Tamoxifen benefits as

measured by proportional risk reduction are similar regard-less of age, stage, grade, or tumor size and with and without

background chemotherapy.

Figure 2 examines the effect of ER and progesterone

receptor (PgR) expression on the benefits with tamoxifen.

Tamoxifen is similarly effective in patients with ER-positive

disease regardless of PgR expression. Patients with ER-

negative but PgR-positive tumors do not get benefit from

tamoxifen, nor do patients with ER- and PgR-negative

tumors.

Figure 3 explores the relationship of quantitative levels of

ER with the benefits of tamoxifen. It demonstrates that

higher ER levels are associated with stronger effects of

tamoxifen.Figure 4 shows the effects of tamoxifen over time. They

are large in years 0 to 1, 2 to 4 and 5 to 10 in terms of

recurrence, but by year 10 and beyond, the effects no longer

increase although the previous gains are not lost. In mortal-

ity however, the benefits come out a little later in years 2 to

4 and then years 5 to 9 and they persist into the 10 to

15year follow-up. Thus, there is a carryover effect on

recurrence of 5 years of tamoxifen that goes on to at least 10

years and in mortality that goes on to at least 15 years.

The Overview has been pivotal in demonstrating the

benefits of endocrine therapy for ER-positive breast cancer.

Five years of tamoxifen in ER-positive disease reduces

recurrences by a relative risk of 38%, breast cancer deathsby approximately 30%, and all deaths by approximately

KEY POINTS

The Oxford Overview suggests benefits for adjuvant

endocrine therapy for all patients with ER positive

breast cancer.

The Oxford Overview suggests benefits for anthra-

cycline- and taxane-based adjuvant chemotherapy

regardless of nodal, ER, or PR status.

Molecular diagnostic assays may identify ER-positive

tumors that may not warrant chemotherapy.

Reconciling the historic overview and newer per-

sonalized approaches to early breast cancer is a

compelling clinical challenge.

Fig. 1. Effects of approximately 5 yearsof tamoxifen on the 15-year probabilitiesof recurrence and of breast cancer mortal-ity for ER-positive disease.

Abbreviations; ER, estrogen receptor;RR, recurrence rate; SE, standard error;(O-E)/V, (observed-expected)/variance.

Reprinted from The Lancet, 378, EarlyBreast Cancer Trialists CollaborativeGroup, Davies C, Godwin J, et al. Relevanceof breast cancer hormone receptors andother factors to the efficacy of adjuvanttamoxifen: Patient-level meta-analysis ofrandomised trials, 771784, 2011, withpermission from Elsevier.

PRITCHARD, BERGH, AND BURSTEIN

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22%. Contralateral breast cancer is reduced by approxi-

mately 40%. Tamoxifen for 5 years benefits all women with

ER-positive disease and benefits those with very high levels

of ER even more. To date, ER expression is the sole deter-

minant of likely benefit from tamoxifen. Endometrial cancer,

however, is increased by 2.3-fold following 5 years of tamox-

ifen. The rate of endometrial cancer increases as much as

4-fold with 10 years of tamoxifen.

Fig. 2. Relevance of measured ER andPR status to the effects of tamoxifen on the10-year probably of recurrence.

Abbreviations: ER, estrogen receptor; PR,progesterone receptor; RR, recurrence rate;SE, standard error; (O-E)/V, (observed-expected)/variance.

Reprinted from The Lancet, 378, EarlyBreast Cancer Trialists CollaborativeGroup, Davies C, Godwin J, et al. Relevanceof breast cancer hormone receptors andother factors to the efficacy of adjuvant

tamoxifen: Patient-level meta-analysis ofrandomised trials, 771784, 2011, withpermission from Elsevier.

Fig. 3. Relationship of quantitative

levels of ER with benefits of tamoxifen.Abbreviations: O-E, observed-expect-

ed; ER, estrogen receptor; SE, standarderror.

Reprinted from The Lancet, 378, EarlyBreast Cancer Trialists CollaborativeGroup, Davies C, Godwin J, et al. Rele-

vance of breast cancer hormone recep-tors and other factors to the efficacy ofadjuvant tamoxifen: Patient-level meta-analysis of randomised trials, 771784,2011, with permission from Elsevier.

UPDATE OF THE OXFORD OVERVIEW

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Radiation Therapy

The Overview has also enabled powerful analyses of the

effects of radiotherapy for early-stage breast cancer. The

proportional effects of radiotherapy after breast-conserving

surgery are substantial for both node-negative and node-

positive disease as shown in Fig. 5. There are substantial

reductions in any recurrence and improvements in breast

cancer survival with postsurgical radiotherapy after breast-

conserving surgery.An important question regarding radiotherapy for breast

cancer has been whether all-cause mortality would be en-

hanced by radiation treatments or whether late (rare) side

effects of radiation might negate treatment benefits in

breast cancerspecific mortality. The Overview, with its

large number of trials and patients, is uniquely positioned to

address this question. Recent data (Fig. 6) indicate that

radiotherapy after breast-conserving surgery reduces breast

cancer recurrence and all-cause mortality among both node-

positive and node-negative disease. A one in four rule

applies for patients with pN0 and pN1 disease in that one

death is prevented for every four recurrences that are

prevented. These benefits are not substantially reduced byside effects and are durable through 15 years of follow-up.

Chemotherapy

The recent overview analysis was published in The Lancet

in December 2011 and was based on the analysis of 100,000

randomly selected patients treated in different randomized

studies.5

In short, the overview contained the quinquennial update

of the following:

Nontaxane chemotherapy compared with taxanes in44,000 patients

Different anthracycline based regimens in 6,000 pa-

tients

Anthracyclines in the comparisons compared with CMF

in 18,000 patients

Randomized studies in 32,000 patients comparing no

chemotherapy with polychemotherapy

For this EBCTCG round, the chemotherapy regimens

were, for the first time, grouped based on scheduling and

dose intensity, with particular focus on the CMF- and

anthracycline-based regimens. All outcome analyses were

done based on individual patient tumor data with as long of

follow-up as possible for each study. Individual patient datawere also included from some unpublished randomized stud-

Fig. 4. Abbreviations: ER, estrogen receptor; y, year; SE, standard error; (O-E)/V, (observed-expected)/variance.Reprinted from The Lancet, 378, Early Breast Cancer Trialists Collaborative Group, Davies C, Godwin J, et al. Relevance of breast cancer

hormone receptors and other factors to the efficacy of adjuvant tamoxifen: Patient-level meta-analysis of randomised trials, 771784, 2011,with permission from Elsevier.


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ies, thereby reducing the potential risks of publication bias

of studies with a positive outcome, the latter being pub-

lished earlier. Data were analyzed for recurrence, breast

cancerspecific survival, and overall mortality.

A summary of major findings includes the following re-

sults:

The use of taxanes added a statistically significant

reduced risk of breast cancer death by 14% (2.7% absolute

Fig. 5. Effect of radiotherapy afterbreast-conserving surgery on 10-year riskof any (loco-regional or distant) first recur-rence on 15-year risk of breast cancerdeath in women with pathologically veri-fied node status.

Abbreviations: SE, standard error; RR, re-currence rate; BCS, breast-conserving sur-gery; RT, radiotherapy.

Reprinted from The Lancet, 378, EarlyBreast Cancer Trialists CollaborativeGroup, Darby S, McGale P, et al. Effect ofradiotherapy after breast-conserving sur-gery on 10-year recurrence and 15-year

breast cancer death: Meta-analysis of indi-vidual patient data for 10,801 women in17 randomized trials, 17071716, 2011,

with permission from Elsevier.

Fig. 6. Effect of radiotherapy after breast-conserving surgery on 10-year risk of any (loco-regional or distant) first recurrence on 15-yearrisks of breast cancer death and death from any cause in 10,801 women (67% with pathologically node-negative disease) in 17 trials.3

Abbreviations: SE, standard error; RR, recurrence rate; BCS, breast-conserving surgery; RT, radiotherapy.Reprinted from The Lancet, 378, Early Breast Cancer Trialists Collaborative Group, Darby S, McGale P, et al. 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 womenin 17 randomized trials, 17071716, 2011, with permission from Elsevier.


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gain, p 0.0005, 2.2% absolute overall survival gain)

compared with anthracycline-based regimens at 8-years

follow-up. This effect was not statistically significant withonly a 6% relative effect if the anthracycline control arm was

given with a high cumulative anthracycline dose (Fig. 6).

There was no difference in schedule or taxane drug

(paclitaxel or docetaxel).

There was no difference whether endocrine therapy was

given concurrently or in sequence with chemotherapy.

There were no age-related effects by the delivered

chemotherapies, taxane, or anthracycline-based regimens.

Indeed, there was a trend suggesting greater chemotherapy

effect in the age 55 to 69 group than in younger women.

The anthracycline and taxane regimens had similar

antitumoral effects irrespective of patient age, tumor ER

status, whether tamoxifen was given, the combination of ERby HER2, or the interaction of ER and grade. (Fig. 7).

Four cycles of doxorubicin and cyclophosphamide pro-

duced a similar result as six courses of standard CMF at 10

years follow-up. Anthracycline regimens with higher doses,however, reduced the breast cancer mortality by about 4%

at 10 years (a relative improvement of 22%, p 0.004)

compared with CMF. The overall mortality was improved by

the same extent.

In comparison with no chemotherapy, CMF-like regi-

mens and anthracycline-based regimens reduced overall

mortality by 6% at 10 years. No subgroup could be readily

identified that did not benefit from chemotherapy. The

CMF-based studies revealed a less distinct message; the

effect seemed less obvious for the elderly (irrespective of

ER status). This could be because of a combination of factors:

lower compliance in those studies run decades ago; no access

to modern antiemetic regimens; a lack of supportive caremeasurement; and less patient motivation to accept toxicity

Fig. 7. Studies comparing the add-on ef-fect by taxanes, most AC x 4. Demonstrationof the outcome (breast cancer survival andoverall survival) when the comparator armcontained higher doses of the nontaxanedrugs, mostly anthracyclines.

Abbreviations: AC, doxorubicin/cyclo-phosphamide; RR, recurrence rate; SE, stan-

dard error; (O-E)/V, (observed-expected)/variance.

Reprinted from The Lancet, 379, EarlyBreast Cancer Trialists Collaborative Group,Peto R, Davies C, et al. Comparisons be-tween different polychemotherapy regi-mens for early breast cancer: Meta-analysesof long-term outcome among 100,000

women in 123 randomized trials, 432444,2012, with permission from Elsevier.


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Fig. 8. Breast cancer mortality for anthracyclines compared with no adjuvant chemotherapy. Outcomes for different cumulative anthracy-clines doses,age groups, node status, ER status. and thecombination of ER statusand histopathologic grade. All forestplots reveal a very similarpattern of the same relative magnitude of chemotherapy.

Abbreviations: ER, estrogen receptor; CAF, cyclophosphamide/doxorubicin/fluorouracil; SE, standard error; 4AC/EC, four cycles of doxoru-bicin/cyclophosphamide or epirubicin/cyclophosphamide; NS, nodal status.

Reprinted from The Lancet, 379, Early Breast Cancer Trialists Collaborative Group, Peto R, Davies C, et al. Comparisons between different

polychemotherapy regimens for early breast cancer: Meta-analyses of long-term outcome among 100,000 women in 123 randomized trials,432444, 2012, with permission from Elsevier.


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since an eventual benefit by adjuvant therapies was not

known at the time these studies were done.

T h e E ra o f P e rs o na l i ze d B re as t Ca nc e r T re at m en t

During the last decade, there have been major attempts

to tailor adjuvant chemotherapy and, to a lesser degree,

the choices for adjuvant endocrine therapy, based on consid-

eration of the unique biologic features of breast cancers. This

effort has grown from recognition of major breast cancersubsets defined by widely used histopathologic markers

(ER, PgR, and human epidermal growth factor receptor 2

[HER2]) as well as traditional pathology (grade, proliferation)

and molecular diagnostics (intrinsic subsets/OncotypeDX

characteristics).6 These schemes of prognostication and

therapy prediction separate breast cancer into distinct sub-

groups, with different management, based principally on

tumor histopathology, abetted by detailed insights from

gene expression profiling of tumors.

A number of retrospective analyses from prospective,

randomized trials have suggested that the proportional

benefits of chemotherapy are not, in fact, the same for all

kinds of breast cancer.6-9 In addition, previous studies have

also revealed that chemotherapyin particular CMF-based

therapiesmay have no or little value to patients with high

ERs levels and that the major antitumoral effect for the

premenopausal patients may be because of induction of

amenorrhea.10 These subset analyses have suggested that

the clinical benefit of chemotherapy is most dramatic in

tumors with low or no ER expression (including triple-

negative cancers), overexpression of HER2, higher grade,

and higher proliferative scores. Conversely, endocrine ther-

apies are most effective in tumors with higher levels of ER

expression, lower levels of HER2, lower grade, and lower

proliferative scores. Retrospective subset analyses of specific

phase III studies have frequently found that the benefit of

adding taxane-based therapy is least pronounced amongcancers that are ER positive and HER2 negative (the ma-

jority of most breast cancers), although these data must now

be seen in the global context of the Overview findings to the

contrary. However, consistent with the findings in single

adjuvant trials, neoadjuvant studies have suggested that

complete pathologic response to chemotherapy is far less

common in tumors that are ER positive. Molecular assays

have emerged that appear to predict the likelihood of che-

motherapy benefit, particularly in addition to adjuvant

endocrine therapy. Tumors classified as having a luminal A

intrinsic subtype or a low recurrence score on the On-

cotypeDX assay, tend to derive minimal benefit from the

addition of chemotherapy to endocrine therapy. It is unclearwhether this is because the relative gain by chemotherapy is

the same, but with an absolute gain that is too small to affect

outcomes among patients with low-risk disease, or whether

there truly is no benefit with chemotherapy. These assays

correlate well if imperfectly with other tumor features such

as grade, proliferation, and quantitative levels of ER and

HER2, fitting with subset hypotheses about the importance

of those pathologic features.

Finally, the advent of anti-HER2 therapy in the adjuvant

setting with trastuzumab has radically altered the natural

history of HER2-positive breast cancers. These tumors,

which traditionally had a less favorable prognosis, now

appear to have as good a prognosis as HER2-negativetumors. The use of trastuzumab for HER2-positive cancers

and the additional use of adjuvant endocrine therapy for

ER-positive cancers has meant that issues of endocrine

therapy or not or chemotherapy or not are less compelling

now than decades ago. The persistent question has become:

are there sufficient data to tailor treatments based on

specific biomarker subsets, or do all patients need the same

treatments?

Ca n W e R e co n ci l e t h e O v e rv ie w a n d t h e In d iv i du a l

Treatment Paradigms?

We now confront the paradox of the Overview. In large

measure, the Overview argues for adjuvant chemotherapy

for all women, regardless of tumor biology or stage. This

blanket observation seems at odds with the growing litera-

ture that suggests that individual tumorsand thus indi-

vidual patientsrespond differently to chemotherapy and

endocrine therapy. Can these observations be reconciled?

The reason why the EBCTCG analysis demonstrates rel-

atively similar antitumoral effects in all the different sub-

groups is so far not understood. There are two particular

strengths of the Overview that should not be forgotten.

First, the Overview is an enormous data repository that

dwarfs in the number of events and the duration of follow-up

of the available data from any given study. This gives the

Overview power to see effects that might be missed in

smaller, retrospective efforts. Of note, the previously pub-

lished reports on selectivity of the chemotherapy effects are

the result of subgroup analysis on materials with much less

statistical power and in some studies lacking inclusion of all

randomly selected patients and overlapping 95% confidence

intervals for some of the interesting findings.

Secondly, by including data from almost all adjuvant

trials, the Overview minimizes the temptation to focus on

positive, published studies, a bias particularly notable in the

literature on biomarker subsets where negative studies

are all but unpublishable. These are important consider-ations that should give clinicians pause before dismissing

the Overview findings.

At the same time, there are features of the Overview

design that may overstate the benefits of chemotherapy. The

Overview reports on proportional risk reduction and related

absolute differences in outcome. However, for most patients,

the absolute gains are the driving force for decisions on

chemotherapy. Differences in absolute benefit from chemo-

therapy clearly vary based on tumor stage and on the

residual degree of risk that remains despite adjuvant endo-

crine therapy. In addition, the Overview has not been able to

capture adequate information on chemotherapy-induced

amenorrhea so as to tease out the effects of chemotherapy onovarian function in women with ER-positive tumors, though

chemotherapy benefit is notably similar regardless of age

and ER status.5

More critically, perhaps, is that differences in treatment

effect may hinge on consideration of multiple variables that

the Overview has not as yet grappled with in detail. It could

simply be because the EBCTCG data just describes mean

effects for all the different subgroups without enabling the

identification of distinct subgroups with claimed different

biology and outcome. The characterization of subsets of

ER-positive cancers, in particular, by molecular assays sug-

gests that simultaneous consideration of ER levels, HER2

expression, and grade/proliferation is important for classi-fying cancers and determining treatment benefit. As yet, the


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Overview analyses looking at quantitative hormone receptor

levels or considering 2 2 analyses of ER by HER2 or ER

by grade may not be sufficiently multiplexed to figure out

which patients can avoid chemotherapy. A major limitation

with the present Overview is the lack of data on prolifera-

tion, gene expression, modern immunohistochemical mea-

surements of receptors, quality controlled pathology

classification, and central marker review. Information on

these variables would, of course, have added value to theEBCTCG processes and analyses, and some investigators

may claim that these shortcomings may explain some of the

results. Despite these shortcomings, the example of ER

values in the overall EBCTCG suggest very robust results in

relation to adjuvant tamoxifen, further supporting the va-

lidity of the EBCTCG findings.4

Additional methodologic details may be relevant. Several

studies that have identified selective benefit for chemother-

apy have centrally reanalyzed ER or HER2 data on some

patients, a detailed pathologic step not preformed in the

EBCTCG database.8,10 Similarly, the Overview used a sur-

rogate strategy for high proliferation/higher OncotypeDx

scores by using grade as reported by local laboratories (in

particular, poorly differentiated cancers) that have not been

confirmed. Furthermore, the EBCTCG demonstration of

similar effects of chemotherapies, independent of studied

subgroups, could merely be a reflection of an inherent

common biology of breast cancer with a similar type of

sensitivity to the commonly used cytostatics. However, this

seems counterintuitive based on present extensive knowl-

edge of breast cancer biology in relation to outcome and

therapy strategies, but it has happened before in the era of

science that conclusions made with the best intentions have

required modification.

A possible explanation to the general findings of a similar

relative magnitude in antibreast cancer effects in the

adjuvant setting by taxanes and anthracyclines could bethat all epithelial breast cancers seem to share so far

unidentified gene cassettes associated with a similar sensi-

tivity to chemotherapy. This could, to some extent, be

potentially substantiated by ongoing studies on human

breast cancer stem cells from primary cultures, which indi-

cate a common phenotype for most breast cancer stem cells

in relation to a specific receptor status, despite the fact that

cancers per se have different tumor and receptor character-

istics (Johan Hartman, Irma Fredriksson, Jonas Bergh,

verbal communications, March 1, 2012).

At its heart, the task of reconciling the invaluable data

from the ongoing Oxford Overview with the emerging data

from subset studies using novel markers remains the fun-

damental challenge for adjuvant therapy for breast cancer.

Ongoing collaboration and research will be critical for help-

ing clinicians and patients understand these different but

important clinical datasets and solving the riddle of the

Overview paradox.

Authors Disclosures of Potential Conflicts of Interest

Author

Employment orLeadershipPositions

Consultant orAdvisory Role

StockOwnership Honoraria

ResearchFunding

ExpertTestimony

OtherRemuneration

Kathleen I. Pritchard GlaxoSmithKline;Novartis; OrthoBiotech; Pfizer;

Roche; Sanofi;YM BioSciences

AstraZeneca;GlaxoSmithKline;Novartis; Pfizer;

Roche; Sanofi

AstraZeneca;Novartis; Pfizer;

Sanofi

Jonas Bergh Affibody; Amgen;AstraZeneca;

Bayer;GlaxoSmithKline;i3innovus; Onyx;

Pfizer; Sanofi;Tapestry

Pharmaceuticals

AstraZeneca;Pfizer; Roche;

Sanofi

Merck; Pfizer;Roche

AstraZeneca;Roche

Harold J. Burstein*

*No relevant relationships to disclose.

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