Low Mre11 Complex Expression Identifies a Subset of Triple Negative Breast Cancer With Excellent...

Volume 90 � Number 1S � Supplement 2014 Oral Scientific Sessions S69

outcome and limited long-term toxicity. Roughly 15-20% of patients who

are refractory to DA R-EPOCH may experience primary refractory disease

that may be salvageable with radiation therapy.

Author Disclosure: C.C. Pinnix: None. J. Westin: None. M. Ahmed:

None. V. Reed: None. J. Romaguerra: None. Y. Oki: None. M. Rodri-

guez: None. L. Fayad: None. F. Hagemeister: None. L. Kwak: None. L.

Medeiros: None. T. Francesco: None. R. Davis: None. H.H. Chuang:

None. R.E. Davis: None. B. Dabaja: None.

146Impact of Approximated Biological Subtype on LocoregionalRecurrence in Women With Node-Negative Breast Cancer TreatedWith MastectomyJ. Setton, M. Morrow, B. Lok, K. Krause, S. Chun, X. Pei, B. McCormick,

S.N. Powell, and A.Y. Ho; Memorial Sloan-Kettering Cancer Center, New

York, NY

Purpose/Objective(s): Although postmastectomy radiation therapy

(PMRT) is not routinely indicated in patients with N0 disease, randomized

studies of regional nodal irradiation such as the EORTC 22922 and NCIC

MA-20 trials have included high risk node-negative patients. In order to

identify a subset of patients with locoregional recurrence (LRR) frequent

enough to warrant PMRT, we examined the risk of LRR in women with

node-negative breast cancer treated with mastectomy without adjuvant

radiation therapy, according to approximated biological subtype and

clinicopathologic factors.

Materials/Methods: From an institutional database of 7789 consecutive

Stage I-III invasive breast cancer cases treated from 1997 to 2007, we

identified 1569 who underwent total mastectomy with sentinel and/or

axillary lymph node dissection, and were found to have pathologic N0 or

N0(i+) disease. Patients who received PMRT or neoadjuvant chemo-

therapy were excluded. Locoregional recurrence was defined as invasive

tumor recurring in the ipsilateral chest wall or regional lymph nodes

either as a first breast cancer event or simultaneously with distant

recurrence. Cases were categorized into four approximated biological

subtypes: luminal A/B (N Z 1008), luminal HER2 (N Z 133), HER2 (N

Z 93), and triple negative (N Z 250). The incidence of LRR was esti-

mated using the Kaplan-Meier method. Cox regression analysis was used

to investigate clinicopathologic factors for association with LRR (sub-

type, LVI, age 2 cm vs � 2 cm, grade 3 vs 1-2, N0[i+] vs N0). Factors

with p � 0.10 in univariate analysis were included in the multivariate

model.

Results: The median age was 52 and median follow-up was 61 months

(range, 1-178 months). Adjuvant chemotherapy and/or hormonal therapy

were delivered to 63% and 68% of all patients, respectively. Patients with

triple negative subtype were more likely to receive chemotherapy than

those with luminal A/B subtype (78% vs 57%, p Z 0.01). Among patients

with HER2 or luminal HER2 disease, 33% received adjuvant trastuzumab.

The overall 5-year rate of LRR was 2.2% (95% CI Z 1.4-3.0%). In uni-

variate analysis, biological subtype (p < 0.001), LVI (p Z 0.046), and

grade 3 histology (p Z 0.02) were significantly predictive of LRR, while

age2cm (p Z 0.3), and nodal isolated tumor cells (p Z 0.11) were not. In

multivariate analysis, only biological subtype remained predictive of

increased LRR. The 5-year rates of LRR for patients with luminal A/B,

luminal HER2, HER2, and triple negative disease were 0.9% (0.3-1.5%),

3.3% (0.0%-7.0%), 5.2% (0.3%-10.1%), and 6.0% (2.9-9.1%),

respectively.

Conclusions: In this series of N0 patients - in whom a majority received

chemotherapy – we were unable to identify a subgroup whose 5-year risk

of LRR was high enough to warrant PMRT, even among patients with

unfavorable biological subtype or multiple adverse risk factors.

Author Disclosure: J. Setton: None. M. Morrow: None. B. Lok: None.

K. Krause: None. S. Chun: None. X. Pei: None. B. McCormick: None.

S.N. Powell: None. A.Y. Ho: None.

147Low Mre11 Complex Expression Identifies a Subset of TripleNegative Breast Cancer With Excellent OutcomesG.P. Gupta, Y.H. Wen, M. Akram, K. Krause, E. Brogi, S.N. Powell,

A.Y. Ho, and J.H.J. Petrini; Memorial Sloan-Kettering Cancer Center, New

York, NY

Purpose/Objective(s): The Mre11 complex is an initiator of the DNA

damage response, and has been implicated as a tumor suppressor in breast

cancer. Disruption of the Mre11 complex results in marked hypersensi-

tivity to DNA damaging agents. We investigated whether expression of this

ubiquitous nuclear protein complex is disrupted in triple negative (ER-/

PR-/HER2-) breast cancer (TNBC), and whether there is any association

with clinical outcomes.

Materials/Methods: Tissue microarrays were constructed from 271 pa-

tients with non-metastatic TNBC (ER/PR < 1%; HER2 0/1+, or HER2 2+/

FISH not amplified) who underwent surgical resection of their primary

tumor at our institution between 2002 and 2007. Exclusion criteria were <

1 cm primary tumor size, prior breast radiation, inflammatory breast

cancer, and neoadjuvant chemotherapy. Immunohistochemistry (IHC) was

performed using rabbit polyclonal anti-sera generated against human

Mre11 (1:3000) and human Nbs1 (1:3000). Tumors were classified as low-

expressors of the Mre11 complex if < 10% of cancer cells had detectable

nuclear protein expression of Mre11 and/or Nbs1 relative to background

staining levels. Lack of immunoreactivity was confirmed by repeating the

IHC using whole tissue sections in a subset of Mre11 complex low-

expressors. Fisher’s exact test was used for correlation with clinicopath-

ological features, and log-rank and Cox proportional hazards were used for

survival analyses.

Results: Two hundred fifty-six of the 271 TNBCs were evaluable for

Mre11 and/or Nbs1 expression by IHC. Twenty-three (9.0%) of these

tumors were Mre11 complex low-expressors. Mre11 complex expression

did not correlate with any significant differences in clinicopathological

features (age, menopausal status, tumor size, grade, LVI, or nodal

involvement). Median follow-up for the cohort was 52 months: 84% of

the patients received adjuvant chemotherapy and 61% radiation therapy.

Low Mre11 complex expression was associated with improved overall

survival (5 year OS 100% vs 77%, P Z 0.013), with a hazard ratio of

0.32 (95% CI Z 0.13 to 0.79). Similar trends were also observed for

locoregional recurrence and distant metastasis-free survival. A multi-

variate model for low Mre11 expression, tumor size, and lymph node

involvement demonstrates a trend towards favorable prognostic associ-

ation of low Mre11 expression with overall survival (HR Z 0.18; p Z0.09).

Conclusions: A subset of TNBC expresses significantly reduced levels of

the Mre11 complex by IHC, and is associated with improved overall

survival in a cohort of patients frequently treated with adjuvant therapy.

Given the known functions of Mre11 in the DNA damage response, we

propose that low Mre11 complex expression may define a subset of TNBC

that is hypersensitive to DNA damaging therapy and is associated with

excellent patient outcomes.

Author Disclosure: G.P. Gupta: None. Y.H. Wen: None. M. Akram:

None. K. Krause: None. E. Brogi: None. S.N. Powell: None. A.Y. Ho:

None. J.H.J. Petrini: None.

148Significance of Phospho(Ser73)-K8 Expression in Women WithBreast Cancer of Triple Negative PhenotypeR. Garg,1 N. Housri,2 S. Kongara,2 H. Wu,2 D. Schiff,2 M. Moran,3

V. Karantza,2 and B. Haffty2; 1Rutgers New Jersey Medical School,

Newark, NJ, 2Rutgers Cancer Institute of New Jersey, New Brunswick, NJ,3Yale University School of Medicine, New Haven, CT

Purpose/Objective(s): Basal-like carcinoma of the breast tends to be

linked with more aggressive progression and poorer prognosis. Lack of