Annual Meeting Proceedings Part 1 - American Society of Clinical ...

549^ General Poster Session (Board #2G), Sat, 8:00 AM-12:00 PM
A prospective clinical utility study of the impact of the 21-gene recurrence
score assay (Oncotype DX) in estrogen receptor positive (ER�) node
negative (pN0) breast cancer in academic Canadian centers. Presenting
Author: James Ashley Davidson, British Columbia Cancer Agency (Fraser
Valley Centre), Surrey, BC, Canada
Background: The Oncotype DX 21-gene Recurrence Score assay (RS) can
potentially predict the magnitude of chemotherapy benefit in patients with
stage I-II, node-negative, ER� disease who will be treated with tamoxifen
for 5 years. While use in the United States has grown significantly since its
introduction, it is not yet routinely ordered by oncologists in most parts of
Canada. The primary purpose of this study was to measure the impact of the
Oncotype DX test on the physician’s treatment recommendation in ER�
pN0 breast cancer in British Columbia. Methods: After providing informed
consent, patients and medical oncologists completed respective pre-RS
questionnaires indicating their treatment preferences and level of confidence
and a decisional conflict scale (patients only). At a subsequent visit,
after the RS result was known and discussed, the patient and oncologist
completed a second set of questionnaires. The proportion of physician
treatment recommendations that changed from baseline to follow-up (post
RS) were calculated with 95% confidence interval (CI). A prospective
health economic (HE) analysis was also performed. Results: From May
2010 to July 2011, two participating BCCA centres enrolled 156 patients.
Of the 150 for whom successful RS assay results were obtained, physicians
changed their chemotherapy recommendation in 45 cases (30%; 95% CI
22.8-38.0%); either to add (10%; 95% CI 5.7-16.0%) or omit (20%; 95%
CI 13.9-27.3%) adjuvant chemotherapy. As a secondary end-point, in 84
cases (56%; 95% CI 47.7-64.1%) there was a change in either the
planned chemo and/or endocrine therapy recommendation. There was an
overall significant improvement in physician confidence post RS (p �
0.001). Patient decisional conflict also significantly decreased following
the RS assay (p � 0.001). The HE analysis is ongoing and will be presented
separately. Conclusions: Within the context of a publicly funded health care
system, the RS assay significantly affects adjuvant treatment recommendations
in ER� node negative breast cancer, in addition to reducing patient
decisional conflict.
551 General Poster Session (Board #3B), Sat, 8:00 AM-12:00 PM
Safety of everolimus for women over 65 years of age with advanced breast
cancer (BC): 12.5-mo follow-up of BOLERO-2. Presenting Author: Kathleen
I. Pritchard, Sunnybrook Odette Cancer Centre, University of Toronto,
Toronto, ON, Canada
Background: Postmenopausal women with estrogen-receptor–positive (ER� )
BC who relapse/progress on a nonsteroidal aromatase inhibitor (NSAI) are
usually treated with the steroidal AI exemestane (EXE); but there is no
currently approved treatment for this indication. The BOLERO-2 trial
showed that adding everolimus (EVE), an oral inhibitor of mammalian
target of rapamycin (mTOR), to EXE significantly improved clinical benefit
beyond that of EXE alone (Hortobagyi et al, SABCS 2011, Abstract S3-7).
As many women with advanced BC are elderly, the tolerability profile of EVE
� EXE in this population is of interest. Methods: BOLERO-2 is a phase III,
randomized, trial comparing EVE (10 mg once daily) vs placebo (PBO),
both plus EXE (25 mg once daily) in postmenopausal women with advanced
ER� BC progressing or recurring after NSAIs. Safety data with a focus on
elderly patients are reported at 12.5 mo median follow-up. Results:
Baseline disease characteristics, age, and prior cancer therapy were well
balanced between treatment arms (N � 724). At 12.5 months’ median
follow-up, the addition of EVE to EXE significantly improved progressionfree
survival in patients �65 (HR � 0.37; P � .05) or �65 years of age (HR
� 0.56; P � .05). Adverse events (AEs) of special interest (all grades)
occurring more frequently with EVE vs PBO (overall study population)
included stomatitis (66.6% vs 11.3%), infections (50.4% vs 25.2%), rash
(44.0% vs 8.4%), pneumonitis (18.7% vs 0.4%), and hyperglycemia
(15.4% vs 2.5%). Elderly EVE-treated patients (�65 years) had similar or
marginally lower incidence of stomatitis (52.1%), rash (32.3%), pneumonitis
(14.6%), and hyperglycemia (12.5%) compared with the overall
population. Grade 3/4 AEs in patients �70 years of age (n � 161) reported
only among patients receiving EVE (n � 118) included fatigue (10.2%),
anemia (10.2%), hyperglycemia (8.5%), stomatitis (7.6%), dyspnea
(6.8%), pneumonitis (5.1%), neutropenia (3.4%), and hypertension (3.4%).
Conclusions: Adding EVE to EXE was well tolerated in the overall population
and in elderly patients with advanced BC; grade 3/4 AEs were uncommon
and manageable. Overall, AEs were consistent with the known safety profile
of EVE.
Breast Cancer—HER2/ER
19s
550 General Poster Session (Board #3A), Sat, 8:00 AM-12:00 PM
CYP2D6 genotype and adverse effects as indicators of plasma endoxifen in
breast cancer patients taking tamoxifen. Presenting Author: Bavanthi
Balakrishnar, Westmead Hospital, University of Sydney, Sydney, Australia
Background: Tamoxifen is a prodrug. Its principal active metabolite endoxifen
is a product of cytochrome P450 2D6 (CYP2D6) metabolism. The
CYP2D6 gene is highly polymorphic with a number of relatively common
reduced function alleles. The aim of this study was to determine whether
plasma endoxifen levels were reflected by CYP2D6 genotype or adverse
effects in individuals taking tamoxifen. Methods: Plasma endoxifen was
measured by High Performance Liquid Chromatography / Mass Spectroscopy
in 90 breast cancer patients taking 20mg tamoxifen per day. Ten
CYP2D6 single nucleotide polymorphisms were assessed to designate four
putative CYP2D6 functional categories: ultra-rapid (UM), extensive (EM),
intermediate (IM) and poor (PM) metabolizers. CYP2D6 inhibitor use and
adverse effects were documented. The study was part of an ongoing
Australian trial of tamoxifen dose escalation. Results: There was marked
variation in plasma endoxifen levels across the cohort (mean 27.6 nM, SD
14.3). Endoxifen levels were significantly associated with metabolizer
categories (p�0.001, r� -0.44), but were not distinctive between categories.
For example, in the EM category (n�46) endoxifen levels ranged from
3.8-72.2 nM (mean 32.6 nM) with levels in the lowest quartile (3.8-19.7
nM) substantially overlapping the PM category (n�11); 6.1-24.7 nM.
Consistent with an impact of non-CYP2D6 genotype related factors on
endoxifen levels, endoxifen was significantly lower in 18 patients taking
CYP2D6 inhibitor medications (p�0.005). There was no association
between endoxifen levels and vasomotor symptoms or other adverse effects
of tamoxifen. Conclusions: Endoxifen levels were highly variable in patients
taking standard dose tamoxifen, and not predicted by CYP2D6 genotype or
adverse effects. Therapeutic monitoring of endoxifen levels may be a useful
approach to assess tamoxifen activity.
552 General Poster Session (Board #3C), Sat, 8:00 AM-12:00 PM
Prospective comparison of recurrence score and independent central
pathology assessment of prognostic tools in early breast cancer (BC): Focus
on HER2, ER, PR, Ki-67 results from the phase III WSG-Plan B trial.
Presenting Author: Oleg Gluz, West German Study Group, Moenchengladbach,
Germany
Background: Use of multi-gene real-time PCR (RT-PCR) based assays e.g.
Recurrence Score (RS) and single markers (grade, uPA/PAI-1, ER/PR,
HER2, KI-67) is currently controversially discussed in early BC. Here, we
present the final WSG-planB trial correlation analysis of risk assessment
tools and first prospective comparison of independent central pathology
IHC/FISH assessment and RT-PCR for single markers. Methods: Plan B trial
(n�2,448 randomized for 6xTC vs. 4xEC-4xDOC in locally HER2- BC). RS
has been used as selection criterion for cht omission in HR� BC (if RS�11
in pN0 or pN1). uPA/PAI-1 was optionally obtained. Grade, ER/PR, HER2
(IHC/FISH), Ki-67 were evaluated by the independent trial pathologist in
all tumors. Results: From 04/09 to 11/11, 3196 patients have been
recruited and 2448 randomized. RS distribution in 2551 HR� tumors:
0-11 (18%), 12-25 (60%), �25 (22%). In 354 pN0-1 patients, cht was
omitted based on low risk RS (88% compliance). Central grade for n�3038
and IHC/FISH results are currently available in n�1476. Moderately
significant correlations were only found between RS and both central grade
(rs�0.313; p�0.001) as well as Ki-67 (rs�0.374; p�0.001) and a weak
one for uPA/PAI-1, particularly due to poor correlations within the RS group
�26. In 1476 locally HER2- cases, n�9 were found as 3� and/or FISH�
by central analysis. In 6 HR�/HER2� cases, RS revealed 2 positive, 2
equivocal and 2 negative results. In 7 cases positive for HER2 by RT-PCR
central pathology revealed 4 negative results. 24 locally HR� cases are
assessed as HR- in central pathology (2%). Among these, 6 were ER
positive by RT-PCR. Final correlation analyses will be presented at the
meeting. Conclusions: These first prospective data demonstrate that highrisk
status according to RS is predictive of high risk by other factors, but the
converse is not true. Regarding controversial HER2 and HR status by
RT-PCR and IHC/FISH, we found few cases with false-negative or positive
RT-PCR results in HER2- BC by local pathology. However, these discrepancies
could potentially have a substantial impact on clinical patient
management.
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