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

82s Breast Cancer—Triple-Negative/Cytotoxics/Local Therapy
TPS1134 General Poster Session (Board #35C), Sat, 8:00 AM-12:00 PM
Phase II neoadjuvant trial with carboplatin and eribulin mesylate in
patients with triple-negative breast cancer. Presenting Author: Sara E.
Barnato, Northwestern University, Chicago, IL
Background: Several neoadjuvant trials have been conducted in triple
negative breast cancer (TNBC) with platinum agents with pathologic
complete response (pCR) ranging from 16%-32%. Eribulin mesylate, a
nontaxane microtubule dynamics inhibitor, has clinical activity as monotherapy
in breast cancer and other solid tumors. A recent phase I trial found
the combination of eribulin mesylate with carboplatin was well tolerated
and showed activity in advanced solid tumors. The recommended dose for
future trials was eribulin mesylate 1.1 mg/m2 and carboplatin AUC6. We
proposed a neoadjuvant phase II trial with the combination of carboplatin
and eribulin in patients with TNBC. Methods: This is a non-randomized,
open-label, multi-center, phase II clinical trial of eribulin and carboplatin
enrolling histologically-confirmed TNBC patients. Our primary endpoint is
to determine the pCR in TNBC patients treated with the combination of
carboplatin and eribulin. Secondary endpoints include determination of
the clinical response rate, toxicity evaluation and measurement of stem cell
and TLE3 as a biomarker of response to eribulin therapy. To obtain an alpha
of 0.10 and a power of 0.90, a sample size of 30 patients is required to
detect a pCR rate ��30%. 10 of the planned 30 patients have been
enrolled to date. Treatment will be given every 3 weeks for a total of 4 cycles
of therapy. There will be an initial safety run-in to evaluate the appropriate
dose of eribulin in this population. The first 10 patients will receive eribulin
at 1.4 mg/m2 (intravenously over 2-5 minutes) followed by carboplatin
AUC�6 (intravenously over 30 minutes). After the 10th patient has been
enrolled, the study will be temporarily suspended pending review; toxicity
will be assessed for these first 10 patients (cycle 1 only) to assess whether
this dose of eribulin will be used for the remaining patients or if a reduction
to a dose of 1.1 mg/m2 will be required. Definitive surgery will be performed
3-8 weeks after completion of therapy, which will conclude the duration of
the study. Clinical Trial Registry Number NCT01372579.
TPS1136 General Poster Session (Board #35E), Sat, 8:00 AM-12:00 PM
ANZ1001 SORBET: Study of estrogen receptor beta and efficacy of
tamoxifen, a single arm, phase II study of the efficacy of tamoxifen in
triple-negative but estrogen receptor beta-positive metastatic breast cancer.
Presenting Author: Kelly-Anne Phillips, Peter MacCallum Cancer
Centre, Melbourne, Australia
Background: Targeted therapies are needed for triple negative breast cancer
(BC). ER� is expressed in at least 20% of triple negative BCs. ER� binds
estrogen and tamoxifen with a similar affinity to ER�. ER�has 5 isoforms
but only ER�1 is fully functional. ER� expression has been shown to be
significantly associated with improved distant disease free survival and
better overall survival in tamoxifen treated ER� negative patients in
retrospective studies. This “proof of principle” study will determine the
efficacy of tamoxifen in patients with triple negative but ER� positive
metastatic BC. Methods: This single arm phase II study, being conducted by
the Australia and New Zealand Breast Cancer Trials Group, has a Simon’s 2
stage optimal design. The primary end-point is objective response rate
(complete and partial responses). Progression free survival and clinical
benefit rate will also be assessed. Eligibility criteria include histologically or
cytologically confirmed metastatic triple negative BC (ER and PR absent,
HER2 ISH negative or IHC 0 or 1) and measureable disease as per RECIST
1.1. Consenting patients undergo central ER� testing and confirmation of
triple negative status on a metastatic biopsy sample. ER� positive patients
(ER�1 nuclear staining with Allred score �4) are offered trial participation.
To date 12 potentially eligible patients have been screened for ER�; 4 had
Allred score �4 (although 2 of these subsequently proved to be ineligible
for the trial), 7 had Allred scores �4 and 1 result is pending. Consenting
patients receive tamoxifen 20mg per oral daily until disease progression,
unacceptable toxicity or withdrawal of consent. If there are �2 responses in
the first stage of 28 patients, an additional 38 patients will be accrued.
Tamoxifen will be considered worthy of further research if there are �6
responses in the total 66 patients recruited. Current accrual is 1.
Registered on ANZCTR (12610000506099).
TPS1135 General Poster Session (Board #35D), Sat, 8:00 AM-12:00 PM
A phase III, randomized trial of docetaxel plus carboplatin (TP) versus
epirubicin plus cyclophosphamide followed by docetaxel (EC-T) as adjuvant
treatment for triple-negative, early-stage breast cancer in Chinese
patients. Presenting Author: Peng Yuan, Cancer Hospital, Chinese Academy
of Medical Sciences, Beijing, China
Background: Triple-negative [estrogen receptor (ER)-/progesterone receptor
(PR)-/HER2-] breast cancer (TNBC) accounts for about 15% of all breast
cancers and is associated with very poor prognosis. A combination of
anthracycline and taxanes represents the most commonly used adjuvant
chemotherapy for TNBC patients. BRCA1, a protein responsible for repair
upon DNA damage, is often dysfunctional in TNBC. As a result, TNBC is
often sensitive to DNA-damaging agents (e.g., cisplatin and carboplatin). A
phase II study of docetaxel plus carboplatin as neoadjuvant treatment for
TNBC achieved promising response rate (Chang, CANCER, 2010). Encouraged
by this important finding, we are currently conducting a phase III trial
to examine docetaxel plus carboplatin as adjuvant chemotherapy in
patients with early-stage TNBC (registration number at www.ClinicalTrials.
gov: NCT 01150513). Methods: All participants received radical mastectomy
or breast-conserving surgery for pT1-3N0-2 breast cancer. All cancers
were negative for ER, PR, HER2/Neu. All participants had adequate organ
function and performance status. The age ranged from 18 to 70 years.
Patients randomly received a TP regimen (docetaxel 100 mg/m2 plus
carboplatin AUC�6 on day 1, 21 days a cycle for 6 cycles) or a EC-T
regimen (epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 on d1,
21 days a cycle for 4 cycles; followed by docetaxel 100 mg/m2 on d1, 21
days a cycle for 4 cycles). Adjuvant radiotherapy was permitted in both
arms. The primary endpoint is disease-free survival (DFS). Secondary
endpoints included adverse event and quality of life (QoL). The study
planned to recruit 500 subjects over a period of 5 years, with 5-year
follow-up (once every 6 months). Target hazard ratio is 0.86 (5 year DFS of
74.0% vs. 71.0%). The estimated power is 0.80; 1-sided type 1 error was
set at 0.05). The study was activated in June 2010 with enrollment of 110
subjects.
TPS1137 General Poster Session (Board #35F), Sat, 8:00 AM-12:00 PM
Neoadjuvant bevacizumab with weekly nab-paclitaxel plus carboplatin
followed by doxorubicin plus cyclophosphamide (AC) for triple-negative
breast cancer. Presenting Author: Jessica N. Snider, University of Tennessee
Health Science Center, Memphis, TN
Background: Triple negative breast cancer (TNBC) predominantly clusters
with “basal like” subtype on genomic profiling. Over-expression of Secreted
Protein Acidic and Rich in Cysteine (SPARC) has been observed in basal
like breast cancer (Charaffe-Jaufrett et al. Oncogene 2006; 2273-84).
Endothelial transcytosis of nab- paclitaxel occurs via albumin- gp60
receptor-caveolin 1 interaction. SPARC entraps the albumin resulting in
higher intratumoral accumulation, which may explain the increased efficacy
of nab-paclitaxel (Desai et al. Translational Oncology 2009; 59-63).
Exploiting this mechanism and the dysfunctional BRCA mediated DNA
repair in basal tumors, we hypothesize that nab-paclitaxel � the DNA
damaging drug carboplatin would produce high response rates in TNBC.
Adding bevacizumab may enhance efficacy by blocking angiogenesis. In
TNBC, pathologic complete remission (pCR) to neo-adjuvant therapy
correlates with better disease-free survival (DFS). We hypothesize that high
pCR rates can be achieved for patients with TNBC with this combination
translating to an improved DFS than seen historically. Methods: Patients
with palpable and operable TNBC � 2 cm are eligible for this single stage
phase II trial. pCR (defined as the absence of invasive tumor cells) in the
breast is the primary end point, while pCR in the breast � axillary nodes
and pCR � near pCR (residual tumor � 5mm) in the breast are secondary
end points. 57 evaluable patients are needed, assuming a pCR rate of 25%
vs. 40% for the null and alternate hypotheses respectively. 34 patients
have been accrued to date. Patients receive carboplatin AUC 6 day 1 and
nab-paclitaxel 100mg/m2 days 1, 8 and 15 of a 28 day cycle for 4 cycles
and then dose dense AC for 4 cycles. Bevacizumab is given at 10mg/kg Q 2
weeks with chemotherapy for the first 6 cycles. Surgery and radiation are
per institutional standards. Bevacizumab is continued postoperatively to
complete 1 year of treatment. A core biopsy for collection of fresh tumor
tissue is required prior to the start of study treatment. Blood is collected at
baseline, and after 4 and 8 cycles for biomarker analysis. Gene expression
profiling will be undertaken for correlation with response.
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