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Systemic treatment of early breast cancera biological perspective
Journal of Surgical Oncology 2011;103:619–626
Systemic Treatment of Early Breast Cancer—A Biological Perspective
MBBS,1 ALISON STOPECK, MD,2 AND HOPE S. RUGO, MD *
1University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, California
2University of Arizona, Arizona Cancer Center, Tucson, Arizona
Breast cancer is the most common non-skin cancer affecting women worldwide. In the United States, over 90% of tumors are diagnosed as either insitu or localized to the breast or regional lymph nodes. Surgical treatment and adjuvant radiotherapy play an important role in loco-regionaltreatment of early stage breast cancer. Systemic adjuvant therapy is targeted towards isolated circulating and/or disseminated tumor cells to preventsystemic recurrence. This review will describe the diverse tumor biology of human breast cancer and how it influences decisions with regard to theuse of adjuvant therapies.
J. Surg. Oncol. 2011;103:619–626. ß 2011 Wiley-Liss, Inc.
growth factor receptor 2 (HER-2) and more recently, gene expressionprofiles. The age of patient at diagnosis, menopausal status, co-morbid-
Breast cancer is the most common non-cutaneous cancer affecting
ities, and patient choice are also essential considerations.
women worldwide. In the United States over 90% of tumors are diag-
This review will briefly describe our current understanding of the
nosed as either in situ or localized to the breast or regional lymph nodes
diversity of tumor biology and how it influences decisions with regard to
[1]. Appropriate loco-regional management of early stage breast cancer
the use of adjuvant therapy. We will discuss a number of ongoing trials in
(ESBC) is of utmost importance. Complete surgical resection has been a
women with ESBC designed to further delineate predicted response to
critical part of management since the late 1800s [2]. Radiotherapy is an
adjuvant treatment. With greater understanding of tumor biology, it is
important adjunct to breast-conserving surgery that can reduce the
hoped that individually targeted adjuvant treatment will allow greater
incidence of local recurrence and may improve overall survival in
benefit to patients while minimizing unnecessary toxicity.
Breast tumors that are clinically and by imaging limited to the breast
and loco-regional lymph nodes and thereby considered surgically
resectable are referred to as ESBC. Although these tumors are clinically
restricted to loco-regional tissue, there is often early dissemination of
Neo-adjuvant therapy refers to treatment administered prior to sur-
potentially viable tumor cells [4,5]. The role of systemic adjuvant
gical resection of a tumor; conversely, adjuvant treatment is adminis-
therapy is to destroy these isolated circulating and/or disseminated cells
tered post-operatively. Chemotherapy in the neo-adjuvant setting
before they become viable distant recurrences. Once overt metastases
significantly increases the number of patients who are able to have
have occurred outside loco-regional lymph nodes, treatment can control
breast-conserving surgery compared to mastectomy [10,11]. In
but not eradicate disease and prognosis is generally poor.
addition, the delay in surgery required for administration of neo-adju-
Systemic adjuvant therapy refers to hormonal, chemotherapy, and
vant chemotherapy results in comparable recurrence and survival out-
targeted biological agents given following resection of a primary tumor.
comes compared to post-operatively administered adjuvant therapies
Randomized trials of adjuvant chemotherapy for ESBC have been
[12]. Pathologic complete remission (pCR) in breast and axillary nodes
conducted for over 50 years [6,7] with resulting substantial improve-
following neo-adjuvant therapy strongly predicts long-term disease-free
ments in morbidity and overall survival. In the United States, a 24%
and overall survival, particularly in HR-negative disease, and thus acts
reduction in death from breast cancer was seen between the year 1990
as an early biomarker for anti-tumor effects of therapy [12–15].
and 2000 due to both the implementation of widespread screening andadvances in adjuvant therapy [8]. By the year 2000, it was estimated thatapproximately 80% of women with node positive or locally advanced
Biological Determinants Currently Utilized in
disease received adjuvant hormonal and/or chemotherapy, directly
reducing death from breast cancer by an estimated 12–22% [8]. Ameta-analysis of 194 randomized trials by The Early Breast Cancer
Proliferation of breast tumors is most commonly determined in
Trialist Group published in 2005 demonstrated a reduction in death by
clinical practice by histologic grade and by expression of a nuclear
up to 38% with addition of adjuvant hormonal and chemotherapy for
protein, Ki-67. Proliferative or high-grade tumors are associated with
significantly inferior survival compared with tumors with low
Even in 1961, it was recognized that adjuvant chemotherapy
appeared to be of greater benefit to some individuals, including younger
*Correspondence to: Dr. Hope S. Rugo, University of California San
women with node-positive disease [7]. Our understanding of the
Francisco Helen Diller Family Comprehensive Cancer Center, San
advantage of adjuvant systemic treatment remains dependent on numer-
Francisco, CA. Fax: 415-353-9592. E-mail: [email protected]
ous tumor and patient related variables which affect the prognosis,
Received 8 November 2010; Accepted 24 November 2010
efficacy, and toxicity of treatment. Important variables include the stage
and intrinsic biological features of the tumor including proliferation
rate, hormone receptor (HR) status, expression of human epidermal
histological grade [16]. In addition, high-grade tumors are more respon-
with ESBC based on data from published, large phase III trials, the
sive to chemotherapy which targets actively proliferating cells [17,18].
Overview Analysis, and the surveillance epidemiology and end-results
These findings suggest a greater role of adjuvant chemotherapy in
(SEER) database, as well as predicted benefits from systemic therapy
patients with more highly proliferative tumors [19].
[44]. Problems with this tool include lack of HER-2 data, reporting of
The proliferation of a tumor may be routinely classified more accu-
overall recurrence rather than only distant recurrence, and the inability
rately by an assay for cellular and/or nuclear proteins. A high versus low
to vary predicted benefits of systemic therapy based on an improved
Ki-67, has been demonstrated to separate grade II tumors into low- and
understanding of the impact of tumor biology on response. In addition,
high-risk groups, thereby predicting breast cancer specific recurrence
the information initially obtained from the SEER database was
and survival [20]. The difference in outcome with this classification was
restricted to women aged 36–69 years. A population-based validation
independent of other recognized prognostic variables.
study involving over 4,000 women found that the program did not
HR positivity refers to tumors that express the estrogen receptor (ER)
predict outcome accurately for women outside of this age-range, and
and/or progesterone receptor (PR), as determined by immunohisto-
for women younger than 36, the observed outcomes were approximately
chemical staining (IHC). Although less common in premenopausal
10% worse than those predicted [45]. Thus, although Adjuvant!
women, approximately 80% of tumors in post-menopausal women
Online represents a helpful clinical tool, it has specific functional
are HR positive [9]. Most but not all HR-positive tumors are of low
histological grade [21]. These tumors can progress years and even
Several newer tests may provide stronger prognostic and predictive
decades post-primary surgery, and approximately 50% of recurrences
information [46]. Molecular profiling is now being used to better define
occur more than 5 years following initial diagnosis [9]. The benefit of
prognosis and predict therapy response in breast tumors, in addition to
adjuvant hormonal therapy is restricted to women with HR-positive
standard clinicopathologic factors. Expression of certain genes has been
tumors [22]. A number of clinical trials have demonstrated improved
shown to correlate with biological behavior, outcome, and response to
disease-free survival with adjuvant or neo-adjuvant aromatase inhibitors
specific therapies. The 21 gene recurrence score assay, Oncotype DX
compared to tamoxifen for post-menopausal women with HR-positive
(Genomic Health, Redwood City, CA), is a commercially available test
tumors [23–26]. However, improved survival has only been observed in
that evaluates expression of 21 genes; 16 cancer related (including HRs,
trials that compare sequential tamoxifen followed by an aromatase
HER-2, and proliferation-associated genes as well as others), and 5
inhibitor for a total of 5 years to tamoxifen therapy alone or with
reference. The resulting composite score, known as a recurrence score
extended adjuvant hormonal therapy (i.e., 5 years of tamoxifen com-
(RS) is associated with prognosis and response to hormone and chemo-
pared to 5 years of tamoxifen followed by 5 years of aromatase inhi-
bition) [27,28]. Interestingly, trials comparing 5 years of tamoxifen to
Validation of this assay was undertaken utilizing a subset of patients
5 years of aromatase inhibition have not yet demonstrated survival
enrolled in NSABP B14 and NSABP B21 for whom archived tumor
benefit, likely due to a combination of the long natural history of
tissue was available. In B21, patients with node-negative, HR-positive
HR-positive disease in post-menopausal women, and competing mor-
breast cancer were randomized to receive 5 years of tamoxifen with or
bidities in this aging population [29,30]. Regardless of stage, HR-
without adjuvant chemotherapy (predominantly cyclophosphamide,
positive breast tumors are less likely to benefit from neo-adjuvant
methotrexate, and fluorouracil). Tumor samples from 651 patients
and adjuvant chemotherapy compared with HR-negative or HER-2-
who had participated in the trial were available [47]. Depending on
the gene expression score, patients were categorized as having low (54%
In addition to HR status, HER-2 is an important determinant of
of patients enrolled), intermediate (20.6%), or high (25.5%), risk of
prognosis and treatment. HER-2 is a tyrosine kinase receptor involved in
recurrence. The benefit of combining chemotherapy with hormone
cell growth and proliferation that is over-expressed in 20–25% of breast
therapy was only significant for patients with tumors assigned a high
cancers due to amplification of the HER-2 gene [33–36]. HER-2-
RS, in whom the 10-year Kaplan–Meier estimate for freedom from
positive tumors are associated with higher grade, larger size, and have
distant recurrence was improved from 60% to 88% (HR 0.26, CI 0.13–
earlier lymph node involvement than HER-2-negative disease [36,37],
0.53). There was no significant benefit to receiving chemotherapy over
and in the absence of HER-2-targeted treatment are associated with
tamoxifen therapy alone in patients whose tumors had low RS.
earlier distant relapse and a reduction in overall survival [33,34].
Unfortunately, the study was underpowered to document potential small
Interestingly, these tumors are also highly chemosensitive, in particular
benefits from chemotherapy for patients whose tumors scored in the
to anthracyclines and taxanes. The addition of 1 year of trastuzumab, a
intermediate-risk category and thus a large cooperative group trial
monoclonal antibody directed against the extracellular domain of the
(TailoRx) is evaluating the ability of this test to predict chemotherapy
HER-2 receptor, to adjuvant chemotherapy in women with HER-2-
benefit in a modified intermediate-risk group. Recent data also suggest
positive ESBC, results in a 33% reduction in the risk of death at 3 years
that this test may be of value in predicting response to chemotherapy in
patients with HR-positive, node-positive disease [48] as well as pCR in
Triple-negative breast cancer refers to tumors lacking expression of
HR and over-expression of HER-2. These tumors account for between
The prognostic value of the 21 gene RS first demonstrated in B14 has
11% and 26% of breast cancer diagnoses [39–41], and occur more
been validated in a large retrospective case control study involving
frequently in young women, in particular African American women,
almost 5,000 women with node-negative ER-positive breast cancer [50].
and are the most common form of breast cancer found in women
The 10-year breast cancer death rates in patients who received tamox-
carrying mutations in the BRCA1 gene. They are often of higher grade,
ifen were 2.8% for those with low RS, 10.7% for those with intermediate
and are associated with inferior overall survival [39–42]. Recurrence
RS, and 15.5% with high RS. The RS also predicted prognosis for
rates in these tumors are highest in the first 4 years [41], and although
untreated patients as well as in post-menopausal patients treated with
many are highly chemotherapy responsive, development of rapid resist-
ance, early visceral metastases, and short survival characterize recurrent
The 70-gene expression assay, MammoPrint (Agendia, Irvine, CA),
is also commercially available to predict risk of distant recurrence in
A free web-based computer tool, Adjuvant! Online is available for
women with early stage breast cancer. This test, which was developed to
health professionals to assist decisions about adjuvant treatment.
predict a short interval from diagnosis to distant recurrence in patients
Using variables including age, co-morbidities, ER status, tumor size
with breast cancer, requires fresh frozen tissue for microarray analysis,
and grade, and node status, this program graphically displays predicted
so tissue must be processed appropriately at the time of surgery or at
risks of both recurrence and death at 10 years of follow-up for patients
initial biopsy. The 70 genes analyzed include many involved in the
Systemic Treatment of Early Breast Cancer
regulation of cell cycle, invasion, metastasis, and angiogenesis [52].
who can then be treated with surgery or neo-adjuvant hormone therapy
Tumors are categorized as having either a good or poor prognostic
as indicated [61]. Patients with high-risk disease are randomized to a
signature with a poor signature associated with a significantly higher
menu of novel-targeted agents in combination with paclitaxel. Biopsies
risk of distant metastases (HR 5.1; CI 2.9–9, P-value <0.001) [53]. On
and MRI scans are performed during treatment to document tumor
multi-variant analysis, the 70-gene prognostic signature was superior to
response; and the trial utilizes an adaptive study design which allows
standard prognostic factors such as tumor size, grade, HR status, and
early indicators of response or resistance to therapy to drive subsequent
lymph node involvement in predicting recurrence. The MINDACT trial
is a large, international phase III trial which compares the genomic
In general, current clinical trial designs are attempting to focus on
prognostic test to traditional clinical-pathological methods for assessing
tumor biology, both in patient selection as well as choice of targeted
the risk of breast cancer recurring in women with lymph node negative
agents and appropriate chemo- or hormone therapy partners. There are
or 1–3 node-positive disease. It is hypothesised that using the genomic
numerous other interventional neo-adjuvant and adjuvant clinical trials
test in addition to traditional methods will result in more accurate risk
currently recruiting patients with ESBC. A selection of these, focusing
assessment and ultimately help physicians and patients make better
particularly on those designed to focus on specific biologic subsets, are
decisions about who can safely avoid chemotherapy and its potential
side effects. A better understanding of the value that these tests add to
standard IHC results including ER, PR, HER-2, and Ki67 is important
with trastuzumab in combination with chemotherapy for the treatment
for justifying the increased costs associated with molecular testing as
of early stage, HER-2-positive cancers is now well established, with
clear benefits seen in both disease-free and overall survival. Controversy
The intrinsic subtype model represents another genomic assessment
remains about the use of trastuzumab in very small HER-2-positive
of tumor biology. This model, initially described by Perou et al. [54],
tumors, the most effective and least toxic chemotherapy parter(s), and
describes four classes of breast tumors on the basis of genomic profiles:
the appropriate duration of trastuzumab therapy. Despite the success of
luminal, basal, HER-2 over-expressing, and normal-like. Subsequently,
this treatment, patients still experience distant recurrence and thus
the luminal subtype has been further classified into at least two sub-
current trials are exploring novel, rationally designed therapies for this
groups: luminal A and luminal B [55]. These subtypes are associated
disease. Lapatinib is an orally active tyrosine kinase inhibitor of both the
with outcome [55–57] and response to neo-adjuvant chemotherapy
HER-2 and epidermal growth factor (EGFR) receptors. Trials in patients
[31,43,58]. The use of intrinsic genetic subtypes to predict prognosis
with HER-2-positive metastatic breast cancer have demonstrated effi-
and response to chemotherapy is not currently utilized in clinical
cacy as a single agent and when combined with chemotherapy [62,63].
practice outside of clinical trials.
Despite dual inhibition of EGFR and HER-2, clinical activity appears to
Concordance between various gene expression profiles, including
be restricted to tumors with HER-2 over-expression [64]. Trials cur-
MammoPrint, the 21 gene RS, and the intrinsic subtype model was
rently underway in HER-2-positive ESBC include the randomized,
demonstrated by Fan et al. [59]. All three molecular profiling methods
multi-center, phase III trial ALTTO trial (adjuvant lapatinib and or
predict prognosis and, at least to some degree, response to adjuvant
trastuzumab treatment optimization). In this trial, patients with resected
therapy. However, further delineation and characterization of particular
HER-2-positive breast cancer receive anthracycline-based neo-adju-
genomic characteristics which correlate with response to specific che-
vant/adjuvant therapy and are randomized to paclitaxel with either
motherapeutic and targeted agents is necessary for optimizing and
lapatinib, trastuzumab, or trastuzumab in combination with lapatinib.
individualizing care and is the goal of the next generation of clinical
Multiple neo-adjuvant trials with slightly different designs are studying
lapatinib, trastuzumab, and the combination with standard chemother-
The 2007 American Society of Clinical Oncology recommendations
apy, including NeoALTTO, CALGB 40601, and NSABP B41; initial
on use of tumor markers suggests that specific gene expression tests can
data from NeoALTTO is expected at the end of 2010. Many of these
be used to stratify women with ER positive, node negative, breast cancer
trials will be examining gene expression profiles and correlative end-
both in terms of prognosis and benefit of adjuvant chemotherapy, in
points in an effort to predict improved outcomes or pCR [61].
addition to 5 years of tamoxifen [60]. Clearly this is just the beginning of
In addition to predicting a benefit from HER-2-targeted therapy,
being able to apply a better understanding of tumor biology to making
over-expression of HER-2 may be associated with increased benefit
appropriate treatment recommendations for the treatment of early stage
from certain chemotherapeutic agents, especially anthracyclines. A
randomized trial compared the outcomes for 710 women receivinganthracycline-based adjuvant chemotherapy to those who received anon-anthracycline regime [65]. HER-2 amplification was associated
with inferior outcomes regardless of treatment administered, although
Tailoring Treatment to Biological Aspects of Tumors
this finding has not been demonstrated in all studies [66]. Interestingly,women with HER-2-positive tumors who received anthracycline-based
In addition to increasing rates of breast-conserving therapy, neo-
regimens had significantly improved outcomes, including relapse-free
adjuvant systemic therapy potentially allows earlier systemic treatment
and overall survival. In 2008, Gennari et al. [67] published a pooled
of subclinical circulating and disseminated tumor cells. However, the
analysis of eight randomized trials including over 5,000 patients, and
most important benefit in terms of understanding tumor biology and
compared chemotherapy regimens with or without anthracyclines.
development of novel therapeutics is the ability to assess response to
Anthracycline-based regimens significantly improved disease-free
treatment in vivo, and obtain serial tumor samples during treatment.
and overall survival in patients with HER-2-positive tumors but not
This has become an increasingly popular trial design, with a relatively
in those who had HER-2-negative disease. Because of the close prox-
rapid read-out of efficacy based on in breast and axillary response to
imity of the Her-2 and topoisomerase II genes on chromosome 17, co-
specific therapy. Although historically, pathologic response to neo-
amplification of both genes has been demonstrated in up to one-third of
adjuvant chemotherapy has correlated with long-term outcome, this
HER-2-positive breast cancers. As topoisomerase II is a specific target
is not the case for relatively indolent tumors, as hormone therapy may
of anthracycline therapy, this may be, at least in part, the mechanism
result in excellent outcome despite a relatively poor response to chemo-
behind the improved efficacy of anthracyclines desmontrated above in
therapy in the neo-adjuvant setting. The multi-center and novel I-SPY2
trial initially obtains risk information using the 70-gene expression
Because of the increased cardiac toxicity observed from both anthra-
assay (MammoPrint) and excludes patients with low-risk disease,
cyclines and trastuzumab therapy, there is interest in designing active,
TABLE I. Examples of Currently Active Adjuvant Trials in Breast Cancer (Source clinicaltrials.gov Accessed 10/5/2010–10/11/2010)
Compare four different schedules chemotherapy
Randomized phase III: ACy(IV) 2nd weekly  6
-P 2nd weekly  6 or ACy(oral) weekly  15 -P
2nd weekly  6 or ACy(IV) 2nd weekly  6-P weekly  12 or ACy(oral) weekly  15-P weekly  12 H given to all HER-2 positive
Compare different schedules of chemotherapy
Compare various chemotherapy regimens and
8 chemotherapy regimens followed by oralCy and M for 12 months H given to allHER-2 positive
Investigate the role of adding B to chemotherapy
Randomized phase III: TCy or TACy or TCyB
Investigate role of ovarian suppression in addition
Randomized phase III trial: Ta or TaOS or ExOS
Investigate the benefit of chemotherapy in patients
Randomized phase III trial: RS: <11 Ta or
Ai Æ chemotherapy, RS: 11–25 randomized to
Ta or Ai plus chemotherapy or Ta or Ai alone,RS: >25 T or Ai þ chemotherapy
Randomized phase III: ACy-P or ACyB-PB or
Investigate the role of D in reducing bone metastases Randomized phase III: DVdc or Vdc
HER-2 positive: Investigate the role of adding B to
Randomized phase III: TCH-H or TCHB-HB or
Investigate difference between 6 and 12 months of H
Randomized phase III: FEC-TH-H (12 months) or
Randomized phase III: T or L or T-L or TL
Triple negative: investigate the role of B
Hormone therapy: Ta—Tamoxifen: selective estrogen receptor modulator; Os—ovarian suppression either chemically, surgically, or via radiotherapy; Ex—Exemestane: aromatase inhibitor; Le—Letrozole: aromatase inhibitor; An—Anastrozole: aromatase inhibitor; Ai—aromatase inhibitor (physician choice). Chemotherapy: T—Docetaxel: taxane chemotherapy, microtubule inhibitor; P—Paclitaxel: taxane chemotherapy, microtubule inhibitor; I—Ixabepilone: microtubulestabilizer; C—Carboplatin: platinum chemotherapy; A—doxorubicin: anthracycline chemotherapy; E—Epirubicin: anthracycline chemotherapy; Cy—Cyclophosphamide: alkalating chemotherapy; F—Fluorouracil: anti-metabolite chemotherapy; M—Methotrexate: anti-metabolite chemotherapy; G—Gemcitabine: anti-metabolite chemotherapy. Biological therapy: B—Bevacizumab: antibody to vascular endothelial growth factor; H—Trastuzumab: antibody to HER-2; L—Lapatinib: inhibits tyrosine kinase ofHER-2 and EGFR; N—Neratinib: inhibits tyrosine kinase of HER-2 and EGFR; F—Figitumab: monoclonal antibody to insulin-like growth factor; Abt—ABT-888:PARP (polyADP-ribose polymerase) inhibitor; In—Iniparib: PARP inhibitor; Amg—AMG-386: angiopoietin 1/2 neutralizing peptibody; Co—Conatumumab:monoclonal antibody to TRAIL (tumor necrosis factor-related apoptosis inducing ligand) receptor 2. Other: ZA—Zoledronic acid: Bisphosphonate; D—Denosunab: Monoclonal antibody to RANK ligand; Vdc—Vitamin D and Calcium; RS—recurrence score:Calculated from 21 gene recurrence score assay (OncotypeDx); IV—intravenous.
non-anthracycline containing regimens for patients with HER-2-
An association between resistance to tamoxifen in tumors that are
positive cancer. TCH (docetaxel, carboplatin, and trastuzumab) is
HR positive and over-express HER-2 has been reported in some [36,71]
one combination which has been investigated in the adjuvant and
but not all studies [72,73]. It has been suggested that aromatase inhibi-
metastatic settings based on marked synergy in preclinical studies
tors may be superior to tamoxifen in HER-2-positive tumors but this has
[68]. In the adjuvant setting, treatment with TCH resulted in superior
not been proven in large adjuvant trials comparing tamoxifen to aroma-
DFS and OS compared to doxorubicin and cyclophosphamide followed
tase inhibitors [71]. Consequently, there is currently insufficient evi-
by docetaxel (AC/D), as did the addition of trastuzumab to the AC/D
dence to change current recommendations regarding adjuvant hormone
regimen. TCH resulted in less cardiac toxicity, although toxicity from
therapy options for women with HR positive, HER-2 over-expressing
AC/D with trastuzumab was rare. This trial was not designed to directly
compare TCH to the anthracycline plus trastuzumab regimen, so
possible differences in efficacy between these regimens remains a
of particular benefit to patients with triple-negative tumors. A small neo-
question. In addition, the prospective, phase III BETH trial is investi-
adjuvant trial which investigated the combination of paclitaxel and
gating trastuzumab in combination with chemotherapy regimens with
carboplatin chemotherapy, plus the addition of trastuzumab in patients
or without an anthracycline and also with or without bevacizumab,
with HER-2 disease demonstrated improved response in patients with
an antibody to the vascular endothelial growth factor (VEGF) [61].
triple-negative tumors [74]. pCR in these patients was 67%, which was
over-expression of VEGF has been associated with poorer outcome in
significantly higher than the 45% seen in study participants overall.
HER-2-positive disease [69], and preliminary data in the metastatic
Cisplatin appears to be particularly effective in patients with triple-
setting suggests efficacy from combined blockade of these two path-
negative breast cancer associated with mutations in the BRCA1 gene but
the effectiveness in sporadic disease is less impressive [75,76]. Trials
Systemic Treatment of Early Breast Cancer
TABLE II. Examples of Currently Active Neo-Adjuvant Trials in Breast Cancer (Source clinicaltrials.gov Accessed 10/5/2010–10/11/2010)
HER-2 positive: investigate the difference
Investigate the role of combining P to T, L,
Triple negative: investigate the role of the
Investigate the role of different schedules of In
Randomized phase II trial: P or PIn (weekly)
Hormone therapy: Ta—Tamoxifen: selective estrogen receptor modulator; Os—ovarian suppression either chemically, surgically, or via radiotherapy; Ex—Exemestane: aromatase inhibitor; Le—Letrozole: aromatase inhibitor; An—Anastrozole: aromatase inhibitor; Ai—aromatase inhibitor (physician choice). Chemotherapy: T—Docetaxel: taxane chemotherapy, microtubule inhibitor; P—Paclitaxel: taxane chemotherapy, microtubule inhibitor; I—Ixabepilone: microtubulestabilizer; C—Carboplatin: platinum chemotherapy; A—doxorubicin: anthracycline chemotherapy; E—Epirubicin: anthracycline chemotherapy; Cy—Cyclophosphamide: alkalating chemotherapy; F—Fluorouracil: anti-metabolite chemotherapy; M—Methotrexate: anti-metabolite chemotherapy; G—Gemcitabine: anti-metabolite chemotherapy. Biological therapy: B—Bevacizumab: antibody to vascular endothelial growth factor; H—Trastuzumab: antibody to HER-2; L—Lapatinib: inhibits tyrosine kinase ofHER-2 and EGFR; N—Neratinib: inhibits tyrosine kinase of HER-2 and EGFR; F—Figitumab: monoclonal antibody to insulin-like growth factor; Abt—ABT-888:PARP (polyADP-ribose polymerase) inhibitor; In—Iniparib: PARP inhibitor; Amg—AMG-386: angiopoietin 1/2 neutralizing peptibody; Co—Conatumumab:monoclonal antibody to TRAIL (tumor necrosis factor-related apoptosis inducing ligand) receptor 2. Other: ZA—Zoledronic acid: Bisphosphonate; D—Denosunab: Monoclonal antibody to RANK ligand; Vdc—Vitamin D and Calcium; RS—recurrence score:Calculated from 21 gene recurrence score assay (OncotypeDx); IV—intravenous.
exploring the effect of platinum-based chemotherapy on pathological
metastatic setting have been promising [83,84], and a pivotal phase III
response in triple-negative tumors are currently underway [61].
trial has completed accrual with results expected in early 2011. The role
The development of new blood vessels from existing tissue—or
of PARP inhibition in early stage triple-negative and BRCA-associated
angiogenesis—is an important factor in tumor growth [77]. This process
breast cancer is also under investigation in the neo-adjuvant trial setting,
may be particularly important in triple-negative breast cancer, in which
including several trials testing various PARP inhibitors with different
higher levels of VEGF have been demonstrated [78]. Small numbers of
chemotherapy regimens and dosing schedules [61].
patients involved in subset analysis from first line metastatic trials havedemonstrated a non-significant improvement in progression-free sur-
vival for patients with triple-negative tumors [79]. Interim analysis froma small neo-adjuvant phase II trial evaluating the combination of
Systemic adjuvant therapy for breast cancer improves survival for
bevacizumab to platinum-based chemotherapy in women with triple-
many patients with ESBC. The balance of the risks of these therapies
negative disease, included demonstration of a pCR or near pCR in 37%
against the potential benefits is paramount to any treatment recommen-
of patients [80]. A large phase III trial, BEATRICE, is currently eval-
dation. Understanding the importance of individual biological features
uating the benefit of the addition of 12 months of bevacizumab to
of tumors and their impact on prognosis and treatment responses is now
adjuvant chemotherapy in this patient population. CALGB 40603 is
required for providing patients with optimal and individualized care.
a randomized, phase II trial in the neo-adjuvant setting which is inves-
Improved methods for tumor profiling has become a priority for the next
tigating the effect of bevacizumab, carboplatin, or the combination
generation of clinical trials that select patients and treatments based on
along with standard taxane and anthracycline-based chemotherapy in
tumor biology, rather than anatomy. Although beyond the scope of this
patients with triple-negative breast cancer, with a primary endpoint of
review, variations in host metabolism, manifested by polymorphisms in
key enzymes, also appears to have a significant role in determining
Poly(ADP-ribose) poymerase (PARP) inhibitors are one of the most
toxicity and potential efficacy of specific anti-tumor therapies [85].
exciting targeted therapies for triple-negative breast cancer. A major
Work in this fascinating area is ongoing.
mechanism used to repair single strand breaks in DNA is base excision
Maximizing the benefit of adjuvant therapy while minimizing
repair, via the PARP enzyme. When PARP is inhibited, single strand
toxicity remains the ultimate goal of therapy. Although there has been
DNA breaks are not repaired and can lead to double stranded breaks.
significant progress in this area, future research will provide insights
Many triple-negative tumor share various biological features with
into the diversity of breast tumors, further our understanding of the
tumors occurring in BRCA carriers and BRCA is important in repairing
complex relationships between the host and its response to cancer,
double stranded DNA. Apoptosis results if DNA is not repaired satis-
and will help predict response to anti-tumor therapies and their
factorily in a tumor cell [81,82]. Phase II trials of PARP inhibitors in the
Immunohistochemistry of estrogen and progesterone receptors
1. Surveillance, Epidemiology and End Results (SEER). http://seer.-
reconsidered: Experience with 5,993 breast cancers. Am J Clin
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Department Of Oncology Faculty of Medicine, Dentistry and Clinical Oncology Research Publications 2012 Clinical trials Bliss JM, Kilburn LS, Coleman RE , Forbes JF, Coates AS, Jones SE, Jassem J, Delozier T, Andersen J, Paridaens R, Van de Velde CJH, Lonning PE, Morden J, Reise J, Cisar L, Menschik T, Coombes RC. Disease-related outcomes with long-term follow-up: an updated analysis of
European Journal of Obstetrics & Gynecology and Reproductive Biology, 47 (1992) 121-127 992, Accepted for publication 13 August 1992. The reliability, acceptability and applications of basal body temperature (BBT) records in the diagnosis and treatment of infertility. Antonio R. Martinez, Marcel H.A van Hooff, Erik Schoute, Maartje van der Meer, Frank J.M. Broekmans and Peter G.A. Ho