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

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549^ General Poster Session (Board #2G), Sat, 8:00 AM-12:00 PM<br />

A prospective clinical utility study <strong>of</strong> the impact <strong>of</strong> the 21-gene recurrence<br />

score assay (Oncotype DX) in estrogen receptor positive (ER�) node<br />

negative (pN0) breast cancer in academic Canadian centers. Presenting<br />

Author: James Ashley Davidson, British Columbia Cancer Agency (Fraser<br />

Valley Centre), Surrey, BC, Canada<br />

Background: The Oncotype DX 21-gene Recurrence Score assay (RS) can<br />

potentially predict the magnitude <strong>of</strong> chemotherapy benefit in patients with<br />

stage I-II, node-negative, ER� disease who will be treated with tamoxifen<br />

for 5 years. While use in the United States has grown significantly since its<br />

introduction, it is not yet routinely ordered by oncologists in most parts <strong>of</strong><br />

Canada. The primary purpose <strong>of</strong> this study was to measure the impact <strong>of</strong> the<br />

Oncotype DX test on the physician’s treatment recommendation in ER�<br />

pN0 breast cancer in British Columbia. Methods: After providing informed<br />

consent, patients and medical oncologists completed respective pre-RS<br />

questionnaires indicating their treatment preferences and level <strong>of</strong> confidence<br />

and a decisional conflict scale (patients only). At a subsequent visit,<br />

after the RS result was known and discussed, the patient and oncologist<br />

completed a second set <strong>of</strong> questionnaires. The proportion <strong>of</strong> physician<br />

treatment recommendations that changed from baseline to follow-up (post<br />

RS) were calculated with 95% confidence interval (CI). A prospective<br />

health economic (HE) analysis was also performed. Results: From May<br />

2010 to July 2011, two participating BCCA centres enrolled 156 patients.<br />

Of the 150 for whom successful RS assay results were obtained, physicians<br />

changed their chemotherapy recommendation in 45 cases (30%; 95% CI<br />

22.8-38.0%); either to add (10%; 95% CI 5.7-16.0%) or omit (20%; 95%<br />

CI 13.9-27.3%) adjuvant chemotherapy. As a secondary end-point, in 84<br />

cases (56%; 95% CI 47.7-64.1%) there was a change in either the<br />

planned chemo and/or endocrine therapy recommendation. There was an<br />

overall significant improvement in physician confidence post RS (p �<br />

0.001). Patient decisional conflict also significantly decreased following<br />

the RS assay (p � 0.001). The HE analysis is ongoing and will be presented<br />

separately. Conclusions: Within the context <strong>of</strong> a publicly funded health care<br />

system, the RS assay significantly affects adjuvant treatment recommendations<br />

in ER� node negative breast cancer, in addition to reducing patient<br />

decisional conflict.<br />

551 General Poster Session (Board #3B), Sat, 8:00 AM-12:00 PM<br />

Safety <strong>of</strong> everolimus for women over 65 years <strong>of</strong> age with advanced breast<br />

cancer (BC): 12.5-mo follow-up <strong>of</strong> BOLERO-2. Presenting Author: Kathleen<br />

I. Pritchard, Sunnybrook Odette Cancer Centre, University <strong>of</strong> Toronto,<br />

Toronto, ON, Canada<br />

Background: Postmenopausal women with estrogen-receptor–positive (ER� )<br />

BC who relapse/progress on a nonsteroidal aromatase inhibitor (NSAI) are<br />

usually treated with the steroidal AI exemestane (EXE); but there is no<br />

currently approved treatment for this indication. The BOLERO-2 trial<br />

showed that adding everolimus (EVE), an oral inhibitor <strong>of</strong> mammalian<br />

target <strong>of</strong> rapamycin (mTOR), to EXE significantly improved clinical benefit<br />

beyond that <strong>of</strong> EXE alone (Hortobagyi et al, SABCS 2011, Abstract S3-7).<br />

As many women with advanced BC are elderly, the tolerability pr<strong>of</strong>ile <strong>of</strong> EVE<br />

� EXE in this population is <strong>of</strong> interest. Methods: BOLERO-2 is a phase III,<br />

randomized, trial comparing EVE (10 mg once daily) vs placebo (PBO),<br />

both plus EXE (25 mg once daily) in postmenopausal women with advanced<br />

ER� BC progressing or recurring after NSAIs. Safety data with a focus on<br />

elderly patients are reported at 12.5 mo median follow-up. Results:<br />

Baseline disease characteristics, age, and prior cancer therapy were well<br />

balanced between treatment arms (N � 724). At 12.5 months’ median<br />

follow-up, the addition <strong>of</strong> EVE to EXE significantly improved progressionfree<br />

survival in patients �65 (HR � 0.37; P � .05) or �65 years <strong>of</strong> age (HR<br />

� 0.56; P � .05). Adverse events (AEs) <strong>of</strong> special interest (all grades)<br />

occurring more frequently with EVE vs PBO (overall study population)<br />

included stomatitis (66.6% vs 11.3%), infections (50.4% vs 25.2%), rash<br />

(44.0% vs 8.4%), pneumonitis (18.7% vs 0.4%), and hyperglycemia<br />

(15.4% vs 2.5%). Elderly EVE-treated patients (�65 years) had similar or<br />

marginally lower incidence <strong>of</strong> stomatitis (52.1%), rash (32.3%), pneumonitis<br />

(14.6%), and hyperglycemia (12.5%) compared with the overall<br />

population. Grade 3/4 AEs in patients �70 years <strong>of</strong> age (n � 161) reported<br />

only among patients receiving EVE (n � 118) included fatigue (10.2%),<br />

anemia (10.2%), hyperglycemia (8.5%), stomatitis (7.6%), dyspnea<br />

(6.8%), pneumonitis (5.1%), neutropenia (3.4%), and hypertension (3.4%).<br />

Conclusions: Adding EVE to EXE was well tolerated in the overall population<br />

and in elderly patients with advanced BC; grade 3/4 AEs were uncommon<br />

and manageable. Overall, AEs were consistent with the known safety pr<strong>of</strong>ile<br />

<strong>of</strong> EVE.<br />

Breast Cancer—HER2/ER<br />

19s<br />

550 General Poster Session (Board #3A), Sat, 8:00 AM-12:00 PM<br />

CYP2D6 genotype and adverse effects as indicators <strong>of</strong> plasma endoxifen in<br />

breast cancer patients taking tamoxifen. Presenting Author: Bavanthi<br />

Balakrishnar, Westmead Hospital, University <strong>of</strong> Sydney, Sydney, Australia<br />

Background: Tamoxifen is a prodrug. Its principal active metabolite endoxifen<br />

is a product <strong>of</strong> cytochrome P450 2D6 (CYP2D6) metabolism. The<br />

CYP2D6 gene is highly polymorphic with a number <strong>of</strong> relatively common<br />

reduced function alleles. The aim <strong>of</strong> this study was to determine whether<br />

plasma endoxifen levels were reflected by CYP2D6 genotype or adverse<br />

effects in individuals taking tamoxifen. Methods: Plasma endoxifen was<br />

measured by High Performance Liquid Chromatography / Mass Spectroscopy<br />

in 90 breast cancer patients taking 20mg tamoxifen per day. Ten<br />

CYP2D6 single nucleotide polymorphisms were assessed to designate four<br />

putative CYP2D6 functional categories: ultra-rapid (UM), extensive (EM),<br />

intermediate (IM) and poor (PM) metabolizers. CYP2D6 inhibitor use and<br />

adverse effects were documented. The study was part <strong>of</strong> an ongoing<br />

Australian trial <strong>of</strong> tamoxifen dose escalation. Results: There was marked<br />

variation in plasma endoxifen levels across the cohort (mean 27.6 nM, SD<br />

14.3). Endoxifen levels were significantly associated with metabolizer<br />

categories (p�0.001, r� -0.44), but were not distinctive between categories.<br />

For example, in the EM category (n�46) endoxifen levels ranged from<br />

3.8-72.2 nM (mean 32.6 nM) with levels in the lowest quartile (3.8-19.7<br />

nM) substantially overlapping the PM category (n�11); 6.1-24.7 nM.<br />

Consistent with an impact <strong>of</strong> non-CYP2D6 genotype related factors on<br />

endoxifen levels, endoxifen was significantly lower in 18 patients taking<br />

CYP2D6 inhibitor medications (p�0.005). There was no association<br />

between endoxifen levels and vasomotor symptoms or other adverse effects<br />

<strong>of</strong> tamoxifen. Conclusions: Endoxifen levels were highly variable in patients<br />

taking standard dose tamoxifen, and not predicted by CYP2D6 genotype or<br />

adverse effects. Therapeutic monitoring <strong>of</strong> endoxifen levels may be a useful<br />

approach to assess tamoxifen activity.<br />

552 General Poster Session (Board #3C), Sat, 8:00 AM-12:00 PM<br />

Prospective comparison <strong>of</strong> recurrence score and independent central<br />

pathology assessment <strong>of</strong> prognostic tools in early breast cancer (BC): Focus<br />

on HER2, ER, PR, Ki-67 results from the phase III WSG-Plan B trial.<br />

Presenting Author: Oleg Gluz, West German Study Group, Moenchengladbach,<br />

Germany<br />

Background: Use <strong>of</strong> multi-gene real-time PCR (RT-PCR) based assays e.g.<br />

Recurrence Score (RS) and single markers (grade, uPA/PAI-1, ER/PR,<br />

HER2, KI-67) is currently controversially discussed in early BC. Here, we<br />

present the final WSG-planB trial correlation analysis <strong>of</strong> risk assessment<br />

tools and first prospective comparison <strong>of</strong> independent central pathology<br />

IHC/FISH assessment and RT-PCR for single markers. Methods: Plan B trial<br />

(n�2,448 randomized for 6xTC vs. 4xEC-4xDOC in locally HER2- BC). RS<br />

has been used as selection criterion for cht omission in HR� BC (if RS�11<br />

in pN0 or pN1). uPA/PAI-1 was optionally obtained. Grade, ER/PR, HER2<br />

(IHC/FISH), Ki-67 were evaluated by the independent trial pathologist in<br />

all tumors. Results: From 04/09 to 11/11, 3196 patients have been<br />

recruited and 2448 randomized. RS distribution in 2551 HR� tumors:<br />

0-11 (18%), 12-25 (60%), �25 (22%). In 354 pN0-1 patients, cht was<br />

omitted based on low risk RS (88% compliance). Central grade for n�3038<br />

and IHC/FISH results are currently available in n�1476. Moderately<br />

significant correlations were only found between RS and both central grade<br />

(rs�0.313; p�0.001) as well as Ki-67 (rs�0.374; p�0.001) and a weak<br />

one for uPA/PAI-1, particularly due to poor correlations within the RS group<br />

�26. In 1476 locally HER2- cases, n�9 were found as 3� and/or FISH�<br />

by central analysis. In 6 HR�/HER2� cases, RS revealed 2 positive, 2<br />

equivocal and 2 negative results. In 7 cases positive for HER2 by RT-PCR<br />

central pathology revealed 4 negative results. 24 locally HR� cases are<br />

assessed as HR- in central pathology (2%). Among these, 6 were ER<br />

positive by RT-PCR. Final correlation analyses will be presented at the<br />

meeting. Conclusions: These first prospective data demonstrate that highrisk<br />

status according to RS is predictive <strong>of</strong> high risk by other factors, but the<br />

converse is not true. Regarding controversial HER2 and HR status by<br />

RT-PCR and IHC/FISH, we found few cases with false-negative or positive<br />

RT-PCR results in HER2- BC by local pathology. However, these discrepancies<br />

could potentially have a substantial impact on clinical patient<br />

management.<br />

Visit abstract.asco.org and search by abstract for the full list <strong>of</strong> abstract authors and their disclosure information.

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