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

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614 General Poster Session (Board #11A), Sat, 8:00 AM-12:00 PM<br />

Quantitative HER2 measurement and PI3K mutation pr<strong>of</strong>ile in matched<br />

primary and metastatic breast cancer tissues. Presenting Author: Weidong<br />

Huang, Monogram Biosciences, South San Francisco, CA<br />

Background: HER2 status <strong>of</strong> primary breast cancer (PBC) is routinely used<br />

to determine systemic treatment for metastatic breast cancer (MBC)<br />

patients. Discordance rates <strong>of</strong> HER2 status between PBC and MBC range<br />

from 5.5% to 29% based on published meta-analyses. The clinical benefit<br />

<strong>of</strong> re-assessing HER2 in MBC tissues remains controversial. In this study,<br />

we measured quantitative HER2 expression in matched PBC and MBC<br />

tissues and correlated changes <strong>of</strong> HER2 with mutations in the catalytic<br />

domain <strong>of</strong> PI3 kinase(PIK3CA). Methods: Total HER2 protein expression<br />

(H2T) was quantified by the HERmark assay in 41 matched PBC and MBC<br />

formalin-fixed, paraffin-embedded specimens. PIK3CA mutation status in<br />

exons 9 (E545K and E542K) and 20 (H1047R) was determined using a<br />

validated pyrosequencing assay. Results: MBC samples included 5 lymph<br />

node, 13 viscera, 6 brain, and 17 s<strong>of</strong>t tissue lesions (N�41). 27 (66%)<br />

cases showed higher H2T in MBC than in matched PBC; and 14 (34%)<br />

cases had higher H2T in PBC than in matched MBC, indicating an overall<br />

increase <strong>of</strong> H2T in matched MBC lesions (fold change 0.25-17.57;<br />

p�0.005, paired Wilcoxon rank sum test). HER2 positive conversion<br />

(HERmark negative/equivocal in PBC, but positive in matched MBC) was<br />

found in 6 (15%) cases, while HER2 negative conversion (HERmark<br />

positive in PBC, but negative/equivocal in matched MBC) was seen in 2<br />

(5%) cases. HER2 status was unchanged in 33 (80%) cases. PIK3CA<br />

mutations were detected in 13 (32%) <strong>of</strong> PBC and 19 (46%) <strong>of</strong> MBC<br />

samples. Among the HER2 positive conversion cases, PIK3CA mutation<br />

was identified in 50% (3/6) PBC and 67% (4/6) MBC, compared to 0%<br />

(0/2, PBC or MBC) in the HER2 negative conversion cases. Among cases<br />

with unchanged HER2 status, PIK3CA mutation was observed in 30%<br />

(10/33) PBC and 42% (14/33) MBC. Conclusions: Quantitative HER2<br />

assessment revealed a 20% discordance in HER2 status between matched<br />

PBC and MBC tissues, with more frequent conversion from low HER2 in<br />

PBC to high HER2 in MBC. PIK3CA mutation was observed more frequently<br />

in patients who converted from HER2 negative PBC to HER2 positive MBC.<br />

These results suggest that re-assessment <strong>of</strong> biomarkers in MBC tissues may<br />

better inform the selection <strong>of</strong> therapeutic options for patients with MBC.<br />

616 General Poster Session (Board #11C), Sat, 8:00 AM-12:00 PM<br />

Can MRI accurately identify which patients with operable breast cancer will<br />

have a pathologic complete response after neoadjuvant therapy? Presenting<br />

Author: Carolyn Nessim, Sunnybrook Odette Cancer Centre, University <strong>of</strong><br />

Toronto, Toronto, ON, Canada<br />

Background: With the introduction <strong>of</strong> targeted therapy based on tumor<br />

subtypes, an increasing number <strong>of</strong> patients that receive neoadjuvant<br />

chemotherapy achieve a pathologic complete response (pCR). Previous<br />

studies have shown that the accuracy <strong>of</strong> MRI is poor at predicting the<br />

response to neoadjuvant chemotherapy in locally advanced and <strong>of</strong>ten<br />

non-resectable breast cancers, where the rate <strong>of</strong> pCR is low. The purpose <strong>of</strong><br />

this study is to evaluate MRI’s ability to predict a pCR in operable breast<br />

cancers after neoadjuvant therapy. Methods: All patients enrolled in the<br />

NSABP B-40, B-41, FB-5 and FB-6 protocols in a single tertiary care<br />

centre, that had an MRI done before and after neoadjuvant therapy were<br />

reviewed. A radiologist, blinded to the pathology results, interpreted the<br />

pre- and post- treatment MRI’s and made a prediction as to whether or not<br />

patients would have a pCR. In this study, a true negative was defined as a<br />

reading <strong>of</strong> a complete response on MRI that was confirmed as a pCR on final<br />

pathology. pCR was defined as having no residual invasive or in situ disease<br />

in the breast. Results: 129 women with a median age <strong>of</strong> 51 years were<br />

identified. 90% had invasive ductal carcinoma; 8% had invasive lobular.<br />

58% were ER�, 21% were triple negative and 21% were Her2�. 16% <strong>of</strong><br />

patients had a pCR. 25% <strong>of</strong> patients had no residual invasive cancer in the<br />

breast. pCR rates for ER� tumors was 5%, triple negative 37%, and Her2�<br />

26%. 19% <strong>of</strong> patients that had a pCR had a total mastectomy. The<br />

sensitivity and specificity <strong>of</strong> MRI for predicting residual disease were 88%<br />

and 52% respectively. The positive predictive value was 90% and the<br />

negative predictive value was 46% with an accuracy <strong>of</strong> 82%. Conclusions:<br />

MRI has limited value for determining which patients had a pCR after<br />

neoadjuvant chemotherapy, even in operable breast cancers. When residual<br />

disease is suspected on MRI, it is unlikely that a pCR has been<br />

achieved. Surgical excision following neoadjuvant therapy remains the gold<br />

standard to identify which patients have achieved a pCR. Other modalities<br />

will need to be used in order to accurately determine which patients would<br />

be eligible for studies evaluating non operative management following<br />

neoadjuvant therapy.<br />

Breast Cancer—HER2/ER<br />

35s<br />

615 General Poster Session (Board #11B), Sat, 8:00 AM-12:00 PM<br />

Long-term follow-up (FU) <strong>of</strong> patients with durable complete response<br />

(DCR) after chemotherapy (CT) and trastuzumab (T) for HER2-altered<br />

(HER2�) metastatic breast cancer (MBC). Presenting Author: Giuseppe<br />

Gullo, St Vincent’s University Hospital, Dublin, Ireland<br />

Background: Durable CT-induced complete response (DCR) <strong>of</strong> MBC is<br />

reported only anecdotally. The addition <strong>of</strong> monoclonal antibody T to<br />

conventional CT results in significant increase in response rates and<br />

prolonged survival for patients (pts) with HER2� MBC. Though CRs are<br />

reported in most phase II and III clinical trials <strong>of</strong> CT�T, there is lack <strong>of</strong> data<br />

about clinical features and long-term outcome <strong>of</strong> these pts. Methods: We<br />

retrospectively reviewed all pts with HER2� MBC treated at our Institutions<br />

with any CT�T and identified cases who achieved DCR. HER2<br />

positivity was defined as 3�score at immunohistochemistry and/or amplification<br />

at FISH test. DCR was defined as a CR according to RECIST 1.0<br />

criteria lasting �36 months. Results: We identified 13 pts with HER2�<br />

MBC who met criteria for DCR following CT�T. Their characteristics are:<br />

median age: 56yrs (range 30-65), stage at diagnosis: M0 54%/M1 46%,<br />

histology: ductal 84%/mixed ductal-lobular 8%/unknown 8%, tumour<br />

grade: G3 54%/G2 23%/unknown 23%, oestrogen receptors (ER): neg<br />

62%/pos 38%, sites <strong>of</strong> metastatic disease: liver only 54%/other visceral<br />

15%/bone and s<strong>of</strong>t tissues only 31%, chemotherapy regimen:<br />

taxane�carboplatin 54%/single-agent taxane 23%/docetaxel�lapatinib<br />

15%, capecitabine 8%. Metastatic disease was biopsy-proven in 54% <strong>of</strong><br />

pts. All pts received maintenance T. Median follow-up (FU) is 6.5 yrs (range<br />

3.0-11.6). Median duration <strong>of</strong> T was 59 months (17-121). At database<br />

cut-<strong>of</strong>f date 12 pts (92%) are alive. Five pts (38%) had disease relapse (3<br />

on maintenance T, 2 after T discontinuation), 2 <strong>of</strong> whom had radical<br />

surgery. In 8 pts (62%) disease has not relapsed (characteristics: all<br />

1st-line therapy, ER negative 75%, liver only distant disease 75%).<br />

Conclusions: This is the largest series to our knowledge analyzing long-term<br />

FU <strong>of</strong> HER2� MBC pts with DCR following CT�T. DCR pts appear to have<br />

prolonged survival and a substantial subgroup <strong>of</strong> them have no further<br />

disease relapse. These pts are usually treated in the 1st-line setting, have<br />

more frequently ER-negative disease and liver-only metastases. We are<br />

currently investigating the molecular pr<strong>of</strong>ile <strong>of</strong> this subset <strong>of</strong> pts.<br />

617 General Poster Session (Board #11D), Sat, 8:00 AM-12:00 PM<br />

Neuromedin U: A potential predictive biomarker for HER2-targeted drugs.<br />

Presenting Author: Sweta Rani, School <strong>of</strong> Pharmacy and Pharmaceutical<br />

Sciences and Molecular Therapeutics for Cancer Ireland, Trinity College<br />

Dublin, Dublin, Ireland<br />

Background: Not all HER2-positive breast cancer patients respond to<br />

HER2-targeted drugs and some, who initially respond, subsequently<br />

relapse. There is a need to identify biomarkers for improved patient<br />

selection. Here we aimed to identify gene expression changes associated<br />

with response to HER2-targeted drugs. Methods: To identify mRNA changes<br />

associated with resistance, whole genome microarrays were used to pr<strong>of</strong>ile<br />

conditioned medium (CM) from HER2-positive cell lines (SKBR3,<br />

HCC1954) and their lapatinib (L)-resistant variants (SKBR3-LR , HCC1954-<br />

LR ). Neuromedin U (NmU) over-expression, identified in this way, was<br />

confirmed in the L-resistant cells and corresponding CM by qPCR and<br />

ELISA. Pooled data from 21 published expression datasets (n�3489<br />

patients) was mined to relate NmU mRNA to tumour subtype and patients’<br />

outcome. NmU cDNA and siRNAs were used to over-express and knockdown<br />

expression <strong>of</strong> NmU, respectively, prior to assessing it’s association<br />

with response to L, Trastuzumab (T) and Neratinib (N). Results: Analysis <strong>of</strong><br />

the tumour data showed NmU expression to be particularly associated with<br />

poor outcome for patients with HER2-positive tumours (p�0.000005). In<br />

cell lines, we identified NmU mRNA and protein to be at significantly<br />

higher levels in L-resistant cells and corresponding CM, compared to that <strong>of</strong><br />

L-sensitive SKBR3 and HCC1954. This trend was observed for T-resistant<br />

and N-resistant SKBR3 cells (SKBR3T , SKBR3N ) and their CM, compared<br />

to sensitive parent SKBR3 cells and CM. NmU cDNA over-expression in<br />

SKBR3 and HCC1954 increased resistance to L, T and N. Knock-down <strong>of</strong><br />

NmU endogenous levels in SKBR3-LR and innately L-resistant MDA-MB-<br />

361 and T47D sensitised these cells to L, T and N. Further analysis <strong>of</strong> our<br />

NmU over-expressing and knock-down cells indicated NmU to also be<br />

associated with increased motility, invasion and anoikis resistance.<br />

Conclusions: NmU expression is prognostic <strong>of</strong> poor outcome in HER2positive<br />

breast tumours. In cell line models, NmU over-expression is<br />

associated with resistance to L, T and N. Taken together, we propose NmU<br />

as a possible prognostic and predictive biomarker for HER2-positive<br />

cancers, with potential also as a co-target to help circumvent resistance to<br />

these drugs. [SFI: 08/SRC/B1410]<br />

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