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

500 Oral Abstract Session, Sun, 8:00 AM-11:00 AM
Impact of concurrent (CON) and sequential (SEQ) radiotherapy (RT) with
adjuvant aromatase inhibitors (AI) in early-stage breast cancer (EBC): NCIC
CTG MA.27. Presenting Author: Abdullah Khalaf Altwairgi, NCIC Clinical
Trials Group, Queen’s University, Kingston, ON, Canada
Background: Optimal timing of administration of adjuvant (adj) RT and AI in
EBC is unknown. Methods: MA.27 was a phase III RCT of exemestane to
anastrozole in postmenopausal women with hormone receptor positive EBC
(Goss et al. Cancer Res. 70(24, Suppl):75s, 2010). The final trial database
was used for this retrospective analysis. Median follow-up was 4.1 years.
MA.27 patients received CON-AI [any overlap with AI; 4233 (57%)
patients], SEQ-AI [RT preceded AI, no overlap with AI; 1010 (14%)
patients] and No RT [AI only; 2128 (29%) patients]. Outcome measures for
this analysis were: event free survival (EFS; time to locoregional or distant
disease recurrence, new primary BC, or death from any cause), locoregional
recurrence (LRFS), distant recurrence (DDFS) and overall survival (OS). RT
groups were compared univariately (uni) with stratified log-rank tests, and
multivariately (multi) with step-wise stratified Cox regression adjusted by
stratification factors: nodal status, adj chemotherapy (chemo), celecoxib,
aspirin, and trastuzumab. Results: 7371 eligible women received AI; were
included in the analysis; and 71% (5243) received adj RT. CON-AI and
SEQ-AI groups were comparable by median age (63 v 63), proportion T1
tumours (75% v 75 %), and mastectomy rate (10% v 11%). The frequency
of axillary dissection for CON-AI and SEQ-AI was 48% v 44%, proportion
N0 was 73% v 69%, and proportion receiving adj chemo 29% v 41%.
CON-AI had similar uni results to SEQ-AI: EFS, HR�0.86, p�0.20; LRFS,
HR�0.82, p�0.51; DDFS, HR�0.92, p�0.59; and OS, HR�1.04,
p�0.80. In multi analyses, CON-AI had better EFS than SEQ-AI patients
[stratified HR of CON-AI to SEQ-AI 0.78 (0.66 – 0.91), p�0.001]; as well,
age�70 (p�0.0001), ECOG PS�1 (p�0.0001), L-sided tumours
(p�0.02), T2-T4 (p�0.0001), N2/N3 (p�0.0001), and no adj chemo
(p�0.01) had significantly shorter EFS. There was no multi difference
between CON-AI and SEQ-AI for LRFS (p�0.50), DDFS (p�0.72), or OS
(p�0.85). Conclusions: Patients receiving CON-AI had significantly better
EFS than SEQ-AI suggesting timing of administration of AI and RT may
affect patient outcomes. Further research is necessary to confirm these
findings.
502 Oral Abstract Session, Sun, 8:00 AM-11:00 AM
Adjuvant therapy with zoledronic acid (AZURE-BIG 01/04): The influence
of menopausal status and age on treatment effects. Presenting Author:
Helen Marshall, CTRU, Leeds, United Kingdom
Background: The AZURE trial evaluated the use of zoledronic acid (ZOL) in
addition to standard adjuvant therapy in patients with stage II/III breast
cancer. Although analysis of the primary endpoint in the total study
population showed no significant effects on disease outcomes, prespecified
subgroup analyses identified significant benefit in both invasive
disease-free survival (IDFS) and overall survival (OS) in women �5years
postmenopause (Coleman et al. NESM. 2011;365:1396–1405). Here we
evaluate the treatment modifying effects of both menopausal status and
age. Methods: 3360 patients were randomized to receive standard (neo)
adjuvant systemic therapy �/- ZOL 4mg iv every 3-4 weeks for 6 doses,
then at reduced frequency to complete 5 years treatment. Results: ZOL had
no overall effect on IDFS or OS at a median follow-up of 59 months.
Pre-specified subgroup analyses showed significant heterogeneity of treatment
effect (chi2 1 �7.91; p�.0049) on IDFS between those who were �5
years post-menopause (n�1041; adjusted HR� 0.75; 95% CI 0.59-0.96,
p�0.02) and all other (pre, peri and unknown status) menopausal groups
(n�2318; adjusted HR� 1.15; 95% CI 0.97-1.36, p�0.11). The treatment
interaction between the two menopausal groups was related to
differences in first extra-skeletal IDFS events (chi2 1 � 14.00, p�0.0002),
rather than first recurrence in bone (chi2 1 � 0.14, p�0.70). In women
aged �40, a significant worsening in extra-skeletal IDFS events was seen
(HR � 1.68; 95% CI � 1.14-2.47, p�.008). Although the ZOL effect on
IDFS improved by age from a negative effect in younger patients (�40) to a
beneficial effect for those aged 54 and over (chi2 1(trend) � 5.96,
p�0.015, using Cox model analysis to test for an interaction effect
between age, menopausal status and treatment for IDFS (using age 55 as a
cut-off) showed that the age effect is reversed by menopausal status, with
this model providing a significantly better fit (chi2 2 � 22.8, p�.00001)
than the aforementioned linear model. Conclusions: These results suggest
menopausal status is more informative than age in the selection of patients
for treatment with ZOL. In women aged �40, ZOL may increase extraskeletal
recurrence.
Breast Cancer—HER2/ER
501 Oral Abstract Session, Sun, 8:00 AM-11:00 AM
Effect of osteoporosis in postmenopausal breast cancer patients randomized
to adjuvant exemestane or anastrozole: NCIC CTG MA.27. Presenting
Author: Lois E. Shepherd, NCIC Clinical Trials Group, Queen’s University,
Kingston, ON, Canada
Background: NCIC CTG MA.27 compared adjuvant steroidal [exemestane
(E)] and non-steroidal [anastrozole (A)] aromatase inhibitors (AIs) and
showed neither to be superior in breast cancer outcomes. AIs are known to
increase the risk of osteoporosis. We examined the effects of baseline or
subsequent self reported osteoporosis on disease outcomes. Methods:
MA.27 enrolled 7,576 women. Event free survival (EFS) was the primary
endpoint. Distant disease-free-survival (DDFS) was a secondary outcome.
MA.27 permitted bisphosphonates to prevent or treat osteopenia or
osteoporosis unless prohibited by enrollment to one of two cohorts in a bone
substudy. Osteoporosis was considered present for this analysis if reported
at baseline or prior to relapse or breast cancer death. Multivariate stratified
Cox regression was used to examine the effects of trial therapy, osteoporosis,
baseline patient and tumour characteristics on EFS; DDFS; bone only
relapse; bone concurrent with other relapse; and non-bone recurrence.
Bone marrow recurrence (N�8) was excluded. Results: Osteoporosis was
reported at baseline by 654 of 7576 (8.6%) women, and prior to relapse by
an additional 661 women. EFS events occurred in 693/7576 (9.15%).
Osteoporosis was significantly associated with better EFS [HR 0.81 (95%
CI 0.66-0.99), p�0.04] with no difference in multivariate HR of E vs A:
1.02, 95% CI 0.88-1.19, p�0.77. Women experienced 313 (4.1%) DDFS
events. Osteoporosis was associated with better DDFS [HR 0.71 (95% CI
0.51-0.98), p�0.04], adjusted HR of E to A: 0.94 (95% CI of 0.75-1.17),
p�0.56. Both EFS and DDFS interactions of osteoporosis with trial therapy
were not significant (p�0.05). Osteoporosis was not significantly associated
with the site of relapse. Conclusions: Osteoporosis had a significant
prognostic association with improved EFS and DDFS in women treated with
AIs. We plan to investigate the use of bisphosphonates, raloxifene treatment
prior to randomization, and markers of bone resorption with outcome.
503 Oral Abstract Session, Sun, 8:00 AM-11:00 AM
Whole genome sequencing to characterize luminal-type breast cancer.
Presenting Author: Matthew James Ellis, Department of Internal Medicine,
Division of Oncology, and Siteman Cancer Center, Washington University
Medical Center, St. Louis, MO
Background: To correlate clinical features of estrogen receptor positive
breast cancer with somatic mutations, massively parallel sequencing
(MPS) was applied to tumor and normal DNAs accrued from patients
treated with neoadjuvant aromatase inhibitors (AI). Methods: MPS was
applied to 77 baseline tumor biopsy samples from the preoperative
letrozole trial (JACS 2009: 208, 906) and the Z1031 trial (JCO 2011: 29,
2342) followed by targeted sequencing in another 240 trial samples.
Standard statistical approaches were used to compare mutation status and
clinical parameters and pathway-based correlation was used to assess
interactions between signaling perturbations induced by gene mutations
and response to neoadjuvant AI. Results: Eighteen genes were significantly
mutated above background. Aside from PIK3CA mutations, the list is
dominated by loss-of-function mutations in tumor suppressor genes. Five
(RUNX1, CBFP, MYH9, MLL3 and SF3B1) have been previously linked to
benign and malignant hematopoietic disorders. Clinical correlation revealed
that TP53 mutation was associated with PAM50 LumB status,
high-grade histology and high proliferation rates whereas loss-of-function
mutations in MAP3K1 associate with PAM50 lumA status, low proliferation
rates, and low grade histology. Mutations in GATA3 were associated with
greater suppression of proliferation upon AI treatment suggesting mut-
GATA3 may predict endocrine response. Notably, mutations in MAP3K1
were more common in PIK3CA mutant cases, suggesting cooperation.
Pathway analysis demonstrated that rare MAP2K4 mutations produce
similar pathway perturbations as MAP3K1 mutation, a logical finding since
MAP2K4 is a substrate for MAP3K1. Signaling network patterns driven by
lncRNA MALAT1 mutations were associated with multiple poor clinical
outcome features. Rare mutations in druggable kinases included two in the
kinase domain of HER2. Conclusions: Tumor heterogeneity in luminal-type
breast cancer is driven by specific patterns of somatic mutations, however
most druggable or potentially prognostic mutations are infrequent. Prospective
clinical trials based on these findings will require comprehensive
genome sequencing approaches and large scale investigations.
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