Post San Antonio Breast Cancer Symposium Briefing
（北區）
時間：2013年1月20日（日）地點：三軍總醫院 B1第一演講廳
時間
09:10
|
09:20
09:20
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10:00
10:00
|
10:40
議程
講師
座長
俞志誠 理事長
臺灣乳房醫學會
Opening
陳訓徹 主任
長庚醫院
Overview of SABCS 2012
俞志誠
Local Regional Treatment for Breast Cancer
10:40
|
11:00
黃俊升 教授
台大醫院
Break
11:00
|
11:40
Basic Science and Translational Research
11:40
|
12:20
Advances in Basic Breast Cancer Research
戴明燊 醫師
三軍總醫院
12:20
|
13:30
Lunch Symposium
The difference between eBC and mBC treatment
study design – taking Avastin study as an example
盧彥伸 醫師
台大醫院
Screening and Molecular Image of Breast Cancer
郭玟伶 醫師
長庚醫院
13:30
|
14:10
14:10
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14:50
14:50
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15:00
15:00
|
15:40
15:40
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16:20
16:20
|
16:40
盧彥伸 醫師
台大醫院
劉自嘉
侯明鋒
林璟宏 醫師
台大醫院
Chemotherapy: Update
Break
Hormonal Therapy: Update
杜世興 主任
國泰醫院
Targeted Therapy: Update
曾令民 醫師
臺北榮總
楊圳隆
Discussion & Closing
張金堅 院長
澄清醫院 中港院區
摘要及 CV
講師 CV
陳訓徹主任
學歷 台北醫學大學畢業
經歷 長庚醫院外科部主治醫師
臺北長庚醫院外科部主任
長庚醫院乳房外科部主任
長庚大學醫學系副教授
黃俊升教授
學歷
經歷
美國哈佛大學公共衛生學院碩士
台灣大學臨床醫學研究所博士
台灣大學醫學院外科副教授
台大醫院外科部主治醫師
台大醫院乳房醫學中心主任
盧彥伸醫師
學歷
臺灣大學臨床醫學研究所肄業
中國醫藥學院醫學系畢業
經歷
臺大醫院腫瘤醫學部主治醫師
財團法人恩主公醫院腫瘤科主治醫師
臺大醫院腫瘤醫學部兼任主治醫師
臺大醫院腫瘤醫學部住院醫師
臺大醫院內科住院醫師
戴明燊醫師
學歷
英國倫敦大學皇后瑪麗學院癌症研究中心 博士班畢業
經歷
三軍總醫院血液腫瘤科總醫師
三軍總醫院內科部總醫師
國防醫學院醫學系 內科學科助理教授
郭玟伶醫師
學歷
臺北醫學大學醫學系
經歷
台北長庚醫院一般外科主治醫師
台北長庚醫院乳房外科專責主治醫師
台灣乳房醫學會副祕書長
林璟宏醫師
學歷
台灣大學臨床醫學研究所碩士班畢業
經歷
台大醫院內科住院醫師
台大醫院血液科總住院醫師
台大醫院腫瘤醫學部總住院醫師
台大醫院腫瘤醫學部主治醫師
曾令民醫師
學歷
國防醫學院醫學系
經歷
台北榮民總醫院一般外科主治醫師
國立陽明大學醫學院 外科助理教授
美國德州休士頓 MD Anderson 癌病中心研究員
台灣乳房醫學會秘書長
台灣癌症臨床研究合作組織乳癌研究委員
杜世興主任
學歷
中國醫藥大學醫學士
經歷
台北國泰醫院一般外科主治醫師
臺北國泰醫院乳癌中心主任
臺北醫學大學兼任臨床講師
康泰醫療教育基金會顧問
台灣內分泌外科醫學會常務理事
台灣乳房醫學會理事
課程摘要
Overview of SABCS 2012
MBC Management and Clinical Trials:
Chemotherapy + Targeted therapy
when endocrine-therapy is not a choice
Outline: Chemotherapy  targeted agents, An Update from SABCS
Chemotherapy in EBC and MBC
Docetaxel adjuvant in EBC (poster)
– Cooling gel pad for skin and nail toxicity (poster)
Docetaxel + capecitabine vs docetaxel + epirubicin in MBC (poster)
CA 163-132: Ixabepillone (poster)
HER2 + MBC:
to be continued……
HER2 - MBC
AVADO: Bevasizumab for first-line
ATHENA: Bevasizumab + taxanes (poster)
Bevasizumab + paclitaxel (poster)
Bevasizumab + Weekly TG (poster)
RIBBON-2: Bevasizumab for second-line
NU 07B1: Sorafenib + Paclitaxel
SOLTI-0701: Sorafenib+ Capecitabine
CIRG/TORI 010: Motesanib + Paclitaxel
AVADO : Conclusions
Updated results confirm the initial analyses
Bevacizumab 15mg/kg q3w significantly improves PFS and ORR
Limited impact on the known safety profile of docetaxel
No difference in OS between study arms
Impact of subsequent therapies
Bevacizumab use with later lines of therapy may influence OS estimates
Local Regional Treatment Control for Breast Cancer
Sentinel Lymph Nodes
Indication for SLNB
Pre-operative evaluation and detection
Intra-operative assessment
Predictive value of sentinel lymph nodes
Prediction of the status of Non-SLN
Sentinel lymph nodes biopsy after neoadjuvant chemotherapy
Evaluation of prognosis by sentinel lymph nodes status
Others
Pre-SLNB Evaluation and Detection
Ultrasound +/- Fine needle aspiration cytology (FNA)
CT based lymphatic mapping and localization
PET with SPET-CT lymphoscintigraphy
Intra-operative assessment and technique
SLN number for processing
Programmed training
Reagents
Indocyanine green (ICG) fluoresecence
Lymphazurin Blue
Touch imprint cytology
GeneSearch BLN Assay
Meta-analysis
UK NEW START training program
>80% UK surgeons registered
Models of training
Mentorship model: for SLNB naïve breast units and surgeons, first 5 cases supervised by an expert
trainer in the trainees hospital, SLNB and then ALND for 30 cases
Apprenticeship model: for SLNB naïve surgeons in breast units where SLNB was standard of care. 30
cases performed under direct supervision of a NEW ATART accredited trainer, SLNB only
99% localization rate
FNR<10%
Index quadrant injection technique is easy to learn and is associated with low failed localization and
false-negative rates even in inexperienced hands
No learning curve was identified for successful sentinel node identification and false-negative rate
Identifying multiple SLNs when they exist reduces the false-negative rate. These data suggest that the upper
threshold for the number of SLNs that should be removed is 5
Basic Science and Translational Research
Estrogen forms a complex with estrogen receptor (ER), which binds to estrogen response elements (EREs) in the
promoter region of estrogen-responsive genes, regulates their transcription and, consequently, mediates
physiological or tumorigenic effects. Thus, sequence variants in EREs have the potential to affect
estrogen-ER-ERE interaction, and this case-control study examined the hypothesis that polymorphisms of EREs
are associated with breast cancer development and progression.
A total of 12,737 ER-binding sites in the whole genome predicted by a genome-wide computational algorithm
were blasted with single-nucleotide polymorphisms (SNPs) sequences. Twenty-one SNPs located adjacent to or
within introns 1 or 2 of known genes and with more than 5% of minor allele frequency were identified and
genotyped.
SNPs in ERE related to three genes, GOLGA2, NRCAM or PCDH17, showed a significant association with breast
cancer susceptibility. Particular attention was on rs12539530, the SNP being within intron 2 of NRCAM, a
neuron-related cell adhesion molecule known to also express in breast cancer cell, because a significant combined
effect of this SNP and SNPs of ER to increase breast cancer risk was found. Interestingly, this combined effect
became more significant in women having experienced a prolonged period of life-time estrogen exposure,
supporting a hormonal etiology of NRCAM regulated by ER in breast tumorigenesis. More importantly, the same
interaction between SNPs of ER and NRCAM-ERE showed significant correlations with both breast cancer
recurrence and the five-year survival rate of patients, but had opposite effects in early-stage and late-stage
patients.
These findings provide support for diverse roles of ERE-ER polymorphism in determining susceptibility in
different stages of breast cancer development.
Advances in Basic Breast Cancer Research
While work continues on optimizing treatment regimens for hormonal and chemotherapy-based
adjuvant therapy, there continue to be patients who either do not respond or who develop resistance to
these therapies.
Targeted biologic agents hold the promise of fine-tuning therapy based on specific attributes of the
individualtumor. The first such therapy to come into wide use was trastuzumab (Herceptin®), which
targets the HER2 receptor and has shown clinical activity against breast cancers with a mutation of the
HER2 gene or an amplification of its gene product. Although trastuzumab administered as a single
therapy did not turn out to be the magic bullet that was originally hoped for, it has proven to be very
effective when used in combination with other drugs, especially in neoadjuvant therapy.
Two papers from the 2008 SABCS presented results from studies where trastuzumab was used in
combination with anthracycline-taxane therapy for neoadjuvant treatment of breast cancer patients.
TRASTUZUMAB
The NOAH (NeOAdjuvant Herceptin) trial is the largest neoadjuvant study to evaluate the addition of
trastuzumab to anthracycline- and taxane-based chemotherapy for patients with HER2-positive locally
advanced breast cancer
(LABC). Primary efficacy analysis of this trial was reported by Luca Gianni, MD, from the Instituto
Nazionale Tumori in Milan, Italy.11
Patients were treated with chemotherapy (ATx3, Tx4, CMFx3; n=113) or with chemotherapy and
trastuzumab (n=115). A control group of HER2-negative patients with LABC received chemotherapy
only (n=99). The primary endpoint was EFS, with a median follow-up time of 3 years. EFS was
significantly improved in HER2-positive patients who received chemotherapy and trastuzumab,
compared with HER2-positive patients who received chemotherapy only (70.1% vs 53.3%, respectively;
HR=0.56, P=.006.)
Subgroup analysis showed a treatment advantage for trastuzumab, not only for the entire patient series,
but for all subgroups of patients (non-inflammatory vs inflammatory, ER/PgR positive vs ER/PgR
negative, clinically node-negative vs clinically node-positive, pCR vs nonpCR OS, a secondary endpoint,
was also improved in patients receiving trastuzumab, but the
difference was not significant (85.3% vs 80.4%, respectively; HR=0.65, P=.18). EFS was similar in the
HER2-positive arm treated with chemotherapy
alone and the HER2-negative control arm over the first 18 months, but showed a divergence in favor of
HER2-negative patients over a longer period of
time. Adverse events from the 2 therapy regimens, including cardiac toxicity, were within acceptable
limits.
These data support the use of trastuzumab with chemotherapy as a standard treatment option in women
with HER2-positive LABC. Professor Gunter von Minckwitz presented results of an integrated
meta-analysis of 6402 patients with primary breast cancer receiving neoadjuvant anthracyclinetaxane therapy with or without trastuzumab.12 The integrated meta-analysis was based on individual data
from the studies that were included.
The analysis defined pCR as no invasive residual disease in the excised tissue of breast and axillary
lymph nodes. For HER2-positive patients, the pCR
rate nearly doubled in patients treated with trastuzumab plus chemotherapy compared with patients
treated with chemotherapy alone. (41.1%
vs 22.7%, respectively; P<.001) patients treated with trastuzumab were excluded from the analysis,
duration of treatment (> 18 weeks
vs 8-12 weeks) was also a significant contributor to increase of pCR rates over time. Patient
characteristics associated with a high probability of pCR
were: young age, small tumor size, node-negative disease, negative hormone-receptor status, positive
HER2 status, and histologic tumor grade.
Screening and Molecular Image of Breast Cancer
FUNCTIONAL/MOLECULAR IMAGING
Breast imaging can provide several types of information. Screening information allows the detection of
cancer in asymptomatic individuals. Diagnostic information can improve patient outcome by improving
selection for breast conserving surgery, refining the definition of tumor extent and thereby reducing
reexcision rates, synchronously identifying contralateral
cancer, and decreasing the rate of local recurrence. Treatment response information can monitor the
effectiveness of a specific therapy, and help in
determining when a switch to a different treatment regimen is appropriate. Different imaging modalities
vary in how effective they are in supplying these various types of information. Presentations at the 2008
SABCS reviewed the current status of several forms of functional/molecular imaging; that is, imaging
that relies on in vivo tumor biology rather than anatomic measurements of the tumor. This includes
established technologies (magnetic resonance imaging
[MRI] and positron emission tomography [PET] imaging), as well as new approaches to imaging
currently under development (dynamic molecular imaging and optical tomography).
Magnetic resonance imaging (MRI)
Monica Morrow, MD, from Memorial Sloan- Kettering Cancer Center presented an overview of the
evidence related to the use of MRI for diagnostic
imaging.31 There is no question that MRI finds cancers that are not detected by physical examination,
mammography, or ultrasound, and it has
always been assumed that finding these MRI-detected cancers had a clinical benefit for the
patients.However, this assumption may not be valid. For
example, in comparing surgical outcomes in breast conserving surgery between patients who received
an MRI compared with those who did not, there were no significant differences in the rate of conversion
from
breast conservation to mastectomy or in the percentage of patients with positive margins after first
excision.32 This is especially noteworthy because the
selection of women to receive MRIs is generally biased towards those who would be expected to benefit,
for example, younger women, those with dense
breasts, patients with lobular carcinoma, or those who had a difficult mammogram. These findings
drawn from retrospective studies have been confirmed in the first retrospective study to look at this
question, which reported no significant difference in reoperation rates within 6 months in patients who
received MRIs compared with those who did not.33
MRIs have also shown no benefit in the detection of contralateral cancer. A recent study by Solin and
colleagues34 showed no difference in the incidence of contralateral cancer at a median follow-up of 8
years in patients who received MRIs compared with those who did not. This study also showed no
difference in LR rates between these 2 groups (3% vs 4%, respectively;
P=.51). In all published series, patients with lobular cancer were not at higher risk for local recurrence,
even though more disease was apparent
on MRI with lobular carcinoma compared with invasive ductal carcinoma
Dr Morrow concluded that neither short-term surgical outcomes nor long-term local control or
contralateral cancer rates are improved with MRI, suggesting a questionable patient benefit associated
with the increased mastectomy
rate found with MRI. There are, however, instances where MRI is of value. This includes: wise occult
disease in internal mammary nodes or at
distant sites. Routine systemic staging is not indicated for asymptomatic early-stage breast cancer,
where the incidence of distant metastases is low and the chance of false positives is very high. In
addition, for the type of low-volume axillary disease that we can detect easily with sentinel lymph node
biopsy in earlyknown or suspected BRCA1/2 carriers not undergoing
mastectomy; presentation as axillary adenopathy with occult primary; assessment of response to
neoadjuvant chemotherapy; and in a situation where physical examination, mammography, and
ultrasound produce significantly discrepant results.
Positron emission tomography (PET)
In PET, a positron-emitting radiopharmaceutical (usually fluorodeoxyglucose [FDG]) is injected into the
patient. FDG is a tracer of glucose metabolism in
metabolically active cells. A scanner collects the pairs of photons that come out of a positron emission
and uses these data to reconstruct an image of tracer concentration in quantitative terms. In recent
years, PET has been used in combination with CT to allow the simultaneous measurement of anatomic
and functional images in the same imaging session. A review of the current status of PET imaging was
presented by David Mankoff, MD, PhD, from the
University of Washington in Seattle.35 The current clinical applications for FDG PET in breast cancer are
for staging of recurrent or metastatic breast cancer and for treatment response assessment. In
single-center trials, the sensitivity of FDG PET for systemic staging in recurrent/ metastatic breast cancer
has ranged from 85% to 93%, with reasonable specificity that has been improved by the addition of CT
One of the areas in which FDG PET has been especially helpful is in the detection of mediastinal lymph
node metastases,
even in cases that are CT-negative. FDG PET can also be helpful in the detection of lytic bone
metastases, but may not be as useful for sclerotic lesions. An emerging clinical application where FDG
PET will be very helpful is in the staging of locally advanced breast cancer, where it can identify other
Chemotherapy: Update
Taxanes in adjuvant chemotherapy
The taxane drugs, which block cell cycle progression by stabilizing microtubules, were originally
developed for use as cross-over therapy in patients who failed to respond to standard chemotherapy
regimens containing
doxorubicin/epirubicin and cyclophosphamide. They are now routinely used in combination with these
drugs as adjuvant treatment for patients with node-positive primary breast cancer.
SABCS showed results from a first-generation trial investigating the efficacy of docetaxel in a specific
subgroup of intermediate risk patients, and 2 studies presented results from second-generation trials
designed to optimize dosing of docetaxel for node-positive patients with operable breast cancer.
Hormonal Therapy: Update
Because of their demonstrated efficacy in the prevention of both recurrences and new primaries, as well
as their favorable side-effect profiles compared with
chemotherapy, increasing interest has focused on the use of hormonal agents for systemic adjuvant
therapy in hormone-receptor–positive women. The “gold” standard in this category is the selective
estrogen response
modifier, tamoxifen. For postmenopausal women, the third-generation aromatase inhibitors (AIs) have
compared favorably with tamoxifen in terms of survival outcomes, but present a very different side-effect
profile.
Several studies presented at the 31st Annual San Antonio Breast Cancer Symposium (SABCS)
presented outcomes of randomized trials comparing tamoxifen and AIs, examined quality of life (QoL)
measurements associated with the 2 drug regimens, and investigated whether the addition of an agent
that interacts with the human epidermal growth factor receptor 2 (HER2)
pathway can increase the clinical efficacy of an AI.
Comparing tamoxifen with AIs
Tamoxifen Exemestane Adjuvant Multinational (TEAM) prospective randomized phase 3 trial in
hormone- sensitive postmenopausal women with earlystage breast cancer.1 This study was originally
designed to compare tamoxifen as monotherapy with the AI exemestane as monotherapy, but the study
design was later amended to evaluate sequential therapy with 2.5
to 3 years of tamoxifen followed by exemestane compared with exemestane as monotherapy for 5
years.
The analysis presented by Dr Jones focused on tamoxifen vs exemestane as monotherapy at 2.75
years, which marked the average time of crossover to exemestane. In comparison with the tamoxifen/
exemestane arm, the
exemestane only arm showed a trend towards improved disease-free survival (DFS) (hazard ratio
[HR]=0.89; adjusted log rank P=.12) and a significant improvement in relapse-free survival (RFS)
(HR=0.85; P=.05) and
time to distant metastasis (TDM) (HR=0.81; P<.03).
Because early discontinuation from tamoxifen occurred at a high rate, a separate analysis looked at
endpoints only in preswitch patients who were verified to be in compliance with their drug regimens. This
analysis
showed a significant benefit in DFS for patients in the exemestane arm (HR=0.83, adjusted log rank
P=.02) Gynecologic adverse events, hot flashes, and thromboembolic events were significantly more
common in the tamoxifen/ exemestane arm, while patients receiving exemestane alone were more likely
to experience hypertension and musculoskeletal events, including arthralgia, arthritis, and osteoporosis.
There were no significant differences between treatment groups in cardiac
events or reported fractures.
Results of a meta-analysis of studies involving monotherapy with the third-generation AIs anastrozole,
exemestane, or letrozole compared with tamoxifen were reported by James Ingle, MD, from the
Aromatase Inhibitors Overview Group.2 For this analysis, cohort 1 contained studies in which all drugs
were given as monotherapy for 5 years, and used results
from the ATAC and BIG 1-98/IBCSG 18-98 trials. Cohort 2 contained studies in which AIs were given in
sequential therapy after 2 or 3 years of tamoxifen, and used results from the GABG/ARNO, IES/BIG
2-97,ITA, and ABCSG VIII trials. Cohort 1 included 9856 patients at an average follow-up time of 5.9
years.
Patients receiving AIs for 5 years showed a superior benefit in recurrence rate compared with patients
receiving tamoxifen at follow-up times of 5 years
(9.6% vs 12.6%) and 8 years (15.3% vs 19.2%) (logrank 2 P<.00001.)
There were no significant differences between treatment groups in breast
cancer mortality, death without recurrence, or any death. Cohort 2 included 9015 patients at an average
follow-up time of 3.9 years. Again, there was a significant benefit in recurrence rates associated with
using AIs. Patients switching to AIs showed lower recurrence rates compared with patients receiving
tamoxifen alone at 5 years (5.0% vs 8.1%) and 8 years (12.0% vs
16.1%) (log rank 2 P<.00001)
Compared with patients who switched to an AI for the last 3 to 5 years, patients receiving tamoxifen
alone had significantly higher rates of breast cancer mortality and death from any cause, and a trend
towards higher death
without recurrence. However, the absolute difference in mortality rates was low (1.6% at 6 years for
breast cancer mortality, 0.7% for death without recurrence, and 2.2% for any death). In particular, there
was minimal association of any treatment strategy with nonbreast- cancer–related death, suggesting
that the regimens are generally safe. In both cohorts, there appeared to be little benefit in extending
treatment beyond 5 years, questioning the value of longer AI therapy.
QoL issues associated with hormonal therapy
Although most trials are now showing a fairly consistent picture of improved clinical outcomes with AIs
com pared with tamoxifen as adjuvant therapy, these drug modalities have very different adverse event
profiles.
Thus, although recurrence rates or survival might be improved with AIs, drug compliance might be
affected by QoL issues, especially given the extended treatment periods that are used for hormonal
therapies.Janine van Nes, on behalf of the TEAM trial, presented results of a QoL study on a subset of
742 patients participating in this trial.3 QoL was assessed at 1 year and 2 years after randomization,
using the European Organization for Research and Treatment of Cancer (EORTC) QLQ C30 and the
EORTC BR23 questionnaires supplemented with Functional Assessment of
Cancer Therapy Endocrine Subscale (FACT-ES). The QLQ C30 assesses functional skills, symptoms,
and global health status. The BR23 was especially formulated for breast cancer patients; for this study,
questions related to chemotherapy symptoms (eg, hair loss) were excluded. There were no significant
differences in global health status/QoL between different treatment times, treatment arms, or in the
interaction between treatment time and treatment. Patients receiving tamoxifen showed improved
emotional and sexual functioning and decreased fatigue, dyspnea, and insomnia compared
with patients receiving tamoxifen and exemestane, while patients receiving both drugs showed
improvement in future perspective and arm symptoms
compared with patients receiving tamoxifen alone. The only clinically relevant difference between the 2
treatment groups was increased insomnia in the groups receiving both drugs vs the group receiving
tamoxifen
alone
Shozo Ohsumi, MD, PhD, and colleagues from the NHO Shikoku Cancer Center in Matsuyama, Japan,
initiated a study assessing health-related QoL and psychological distress in patients from the NSAS
BC03 trial.4 For
this trial, recurrence-free postmenopausal breast cancer patients who had received tamoxifen for 1 to 4
years after surgery were randomized to continue tamoxifen or to switch to anastrozole for the remainder
of a 5-year
period. Patients were asked to complete patient-administered
instruments—FACT-B (breast cancer scale),FACT-ES (endocrine symptom scale), and CES-D(Center
for Epidemiological Studies Depression scale)—
at baseline (randomization) and at 3 months, 1 year, and 2 years after randomization.
The total scores in FACT-G and FACT-ES and the scores of the FACT-G physical well-being subscale
were significantly better in the tamoxifen group compared with the anastrozole group (P=.042, .038,
and .005, respectively). Total scores in FACT-B were marginally better in the tamoxifen group. There
were no significant differences in scores from the CES-D scales or in
other subscales of any of the FACT instruments. Several individual items in the FACT-ES scale showed
significant differences between the 2 treatment groups. Hot flashes and vaginal discharge were worse in
the
tamoxifen group, while dizziness, diarrhea, and headache were worse in the anastrozole group. These
results indicate that patients continuing on tamoxifen
may have a slightly better health-related QoL than patients switching to anastrozole.
Combining a HER2 pathway inhibitor with an AI
Current endocrine therapies for metastatic breast cancer are limited by de novo or subsequent acquired
resistance. Because cross-talk between growth factor and steroid receptor pathways has been
implicated in
this endocrine resistance, Stephen Johnston, MD, and colleagues initiated the EGF30008 trial to see if
the addition of lapatinib to the AI letrozole would improve outcomes in postmenopausal women with
hormonereceptor–
positive metastatic breast cancer.5 Lapatinib is a small molecule tyrosine kinase inhibitor that competes
with ATP for binding to specific tyrosine residues in the intracellular catalytic kinase domain of the HER2
molecule, inhibiting the downstream reactions in the pathway. Dr Johnston presented the first results
from the EGF30008 trial at the 31st Annual SABCS.
The trial included 1286 patients randomized to oncedaily treatment with lapatinib and letrozole or
letrozole and placebo. Of the total, 219 patients were HER2- positive by immunohistochemistry or FISH.
Median
progression-free survival (PFS) in this subgroup was significantly increased in the patients receiving
lapatinib plus letrozole compared with patients receiving
letrozole alone (8.2 months vs 3 months, respectively; HR=0.71, P=.019) There was no significant
difference between treatment arms in the HER2negative patient group. The benefit of adding lapatinib was confirmed for the HER2-positive patients by
multivariate analysis using a pre-planned Cox regression, with age, ECOG status, and serum baseline
HER2 extracellular domain measurement as covariates. Overall response rate was also significantly
increased in the HER2-positive population receiving lapatinib plus
letrozole vs letrozole alone, but there was no difference between treatment arms in the HER2-negative
patients.The combination of drugs was well tolerated. The results of this study demonstrate that
lapatinib can significantly
improve the clinical efficacy of letrozole in patients with known HER2-positive,
hormone-receptor–positive metastatic breast cancer.
Targeted Therapy: Update
Advances in systemic therapy over the last 40 years have significantly improved outcomes for breast
cancer patients as a whole, but we are still in the beginning stages of being able to optimize treatment
for individual
patients. This task centers on 2 questions: who should receive therapy, and which therapy will give the
best results. The initial question is especially problematic in patients with minimal disease (T1a,bN0M0),
many of whom have an excellent prognosis and would do well with local therapy alone. The second
question requires an understanding of complex biochemical
pathways by which individual cells might respond to a particular drug. A number of presentations at the
2008 SABCS addressed 1 or both of these questions.
HER2 STATUS IN EARLY-STAGE DISEASE
HER2 is correlated with poorly differentiated tumors, a high proliferation rate, and poor outcomes.
Ronjay Rakkhit,MD, from the University of TexasM.D. Anderson Cancer Center presented results from a
study looking at
HER2 positivity as a prognostic factor in 965 patients with T1a,bN0M0 breast cancer at a median
follow-up time of 74 months.18 Of these patients, 77% were hormone- receptor positive, 13% were triple
negative (TN),
and 10% were HER2-positive. Patients were excluded from the study if they had received chemotherapy
or trastuzumab. A validation set of 350 cases with the same inclusion criteria and a similar median
follow-up time was
obtained from collaborators at other institutions. Both RFS and distant recurrence-free survival (DRFS)
were significantly worse in patients with HER2-positive disease (P<.0001). After adjustment for
hormonereceptor
status, age at diagnosis, tumor grade, and tumor stage, HER2 status remained a significant prognostic
indicator in this patient group, with a HR of 2.68
for RFS (P=.0002) and 5.30 for DRFS (P=.0002). A preliminary analysis of the cases from the other
institutions showed a significant difference in 5-year RFS
(87.4% for HER2-positive vs 97% for HER2-negative, P=.043) but not for 5-year DRFS (92.3% and
97.0%, respectively; P=.449). However, this second
analysis was based on only 10 events, compared with 106 events in the M.D. Anderson group. These
data suggest that patients with early-stage, node-negative breast cancer, who are HER2 positive, may
have a
poor prognosis, and should be considered for treatment with anti-HER2 therapies.
PREDICTORS OF RESPONSE
TO ANTHRACYCLINES
The anthracyclines have proven to be powerful additions to the chemotherapy armamentarium, but they
can have severe side effects. Thus, markers for treatment response to anthracycline therapy would be
of considerable value. HER2 and topoisomerase-2 (TOPO2) have been implicated in response to
anthracyclines in previous studies, but the results have been mixed. These genes are located on
chromosome 17, which also contains other genes associated with breast cancer, including BRCA1 and
TP53. In addition,
polysomy 17 is a frequent event in breast cancer cells. John M.S. Bartlett, PhD, from the Endocrine
Cancer Group at Edinburgh University presented the results of a study examining HER2 amplification,
TOPO2 amplification and deletion, Ki67, and chromosome 17 polysomy as prognostic and predictive
markers in the UK National Epirubicin Adjuvant Trial (NEAT).19 This trial compared the efficacy of
epirubicin followed by CMF compared with CMF alone.Of the patients randomized in the NEAT study,
819 patients in the CMF arm and 806 patients in the CMF plus epirubicin arm were available for this
study. In this patient group, HER2 amplification or 3+ positivity and TOPO2deletion were strongly
prognostic for poor RFS and OS (P<.001), but no individual marker showed a significant predictive value
for response to
anthracycline treatment. On the other hand, polysomy 17 had a significant treatment interaction
(HR=0.59, P=.04), and patients with tumors polysomic for chromosome 17 had significantly greater
benefit from
anthracycline This raises the possibility that the unifying predictive marker for anthracycline response
may be polysomy 17, rather than HER2 or TOPO2, perhaps as an indication of chromosome nstability.
The authors also suggest that previous studies examining the usefulness of HER2 and TOPO2,
some of which reported a strong association between these markers and anthracycline response, may
have been underpowered
Addressing this possibility, Angelo Di Leo, MD, PhD, and coworkers from the
HER2-TOPO2Meta-Analysis Study Group conducted a meta-analysis of phase 3 trials examining
anthracycline-based therapy with CMF in
early-stage breast cancer patients with available primary tumor samples. The studies included were the
Belgian 3-arm trial, the Canadian NCIC CTG trial, the Danish DBCG trial, and the UK NEAT trial. The
planned interim analysis presented at the 2008 SABCS included 1944 patients.20 The results of the
meta-analysis show that HER2 and TOPO2have a modest and statistically
borderline value in predicting sensitivity to anthracyclines.
A caveat attached to this study is the lack of reproducibility in TOPO2scores by FISH in 30.8% of cases
submitted to a central lab for verification. In
addition, the patient groups used for this analysis were highly heterogeneous with regard to systemic
therapies and patient/tumor characteristics. Importantly, thisanalysis currently includes only about
one-third of the
eligible patients from the UK NEAT trial (590/1625). The final analysis for this study will be done when
the remainder of these patients are incorporated. Since HER2 and TOPO2showed no treatment
interaction with anthracyclines in the Bartlett study, it is likely that the final analysis will show a reduction
in the
already borderline value of HER2 and TOPO2for the prediction of anthracycline response.