SPY-1

Official Title

Spy 1 in patients with triple negative breast cancer receiving dose dense AC x 4 followed by dose dense taxol x 4 given every 2 weeks in combination with carboplatin at 6 AUC every 4 weeks.

Summary:

Patients with triple negative breast cancer will be treated with a novel chemotherapy regimen in the adjuvant setting which adds carboplatin to a standard anthracycline and taxol based regimen.   Patient's tumor will be tested for a novel protein expression regulator, Spy-1.  Levels of Spy-1 and Spy-1-mediated genes will be tested for correlation with poor response to therapy, even in the presence of wild-type p53.   This may determine the efficacy of targeting this pathway for novel therapeutic design as well as utilizing this pathways as a prognostic marker for this population of patients.

Trial Description

Primary Outcome: 

  • Identification of correlation of Spy-1 expression and response to chemotherapy. 
  • Progression free and overall survival at 5 years.

Secondary Outcome:  

  • Hematologic and neurological toxicity with chemotherapy regimen during chemotherapy administration.

Triple negative breast cancer (TNBC) comprises 10-15% of breast cancer patients.  This patient population is defined as those that were negative for estrogen, progesterone and HER2neu. In a recent review [1] likelihood of relapse was increased in this group (HR2.6; 95%CI 2.0-3.5); p<0.0001) and death HR3.2; 95%CI 2.3-4.5;<0.0001 within 5 years of diagnosis but not thereafter.  Risk of distant recurrence peaked at approximately 3 years and declined rapidly thereafter. 

We are also aware that the TNBC group tends to reflect a younger patient population.  Mean age 53 vs 57.7 in the non-TNBC group ;<0.0001. 

A frustration is evident in the TNBC patient population as well as those caring for this population in the lack of effective treatment options.  In our other patient populations we see significant benefit from the addition of hormonal agents and herceptin. Chemotherapy is the only treatment option currently left to this group of women and has tended to fail a significant percentage of women with this unfortunate pathology.

A large number of molecular and immunohistochemical  profiles have been developed to explore the molecular signature of TNBC. While few utilized full genome arrays, the expression of myoepithelial/basal markers and a host of molecular changes including TP53 gene mutations and an amplification of MYC are among this characterized profile.[2] 

There are ongoing efforts to develop more targeted treatment approaches for TNBCs. For example, PARP-1 inhibitors are a novel agent that have developed to treat this poor risk patient population.  PARP-1 inhibitors are thought to be critical enzyme in DNA repair and cell proliferation.  They are involved in non-BRCA-dependent DNA repair pathways and upregulated in most TNBC.  PARP inhibition reduces DNA repair capabilities, including repair of chemotherapy induced damage.[3] 

The addition of this novel treatment to carboplatin offered a significant improvement in median progression free and overall survival. Further exploration of potential targeted therapies to eliminate the use of cytotoxic approaches with this patient population is under investigation, additionally markers to both address prognosis and early response to treatment is also critically needed. 

Rationale for Chemotherapy Regimen:

  • Rational for Dose Dense Doxorubicin/ Cyclosphosphamide/ Paclitaxel (AC/T)
    Dose Dense AC followed by Paclitaxel was established as standard of care by the Citron trial.  In this trial, it was demonstrated that four cycles of AC given every 2 weeks followed by paclitaxel given every 2 weeks significantly improved patients disease free survival.  This has become standard of care in much of the United States.
  • There is also evidence of benefit to the use of anthracycline based chemotherapy in patients that are triple negative measured by disease free and overall survival

Rationale for the Addition of Carboplatin:

  • A signal suggesting benefit for the addition of platinums to TNBC has been noted increasingly in the literature.  Torrissi et al reported a neoadjuvant study in which patients who had TNBC received epirubicin, cisplatin and infusional fluorouracil.
  • In this patient population patients received epirubicin 25 mg/m2 day 1 and 2, cisplatin 60 mg/m2 day 1 and fluorouracil continuous infusion days 1 - 21 for four courses.  Thirty patients were treated.  Pathologic CR was obtained in 40% (95%CI 22.7-59.4%)
    Sikov et al report a protocol used weekly paclitaxel with every four week carboplatin adjuvant setting for patients. 
  • Fifty-five patients were enrolled.  Median age was 54.  There were no episodes of febrile neutropenia, and only two episodes of grade 3 peripheral neuropathy.  Overall the pCR rate was 45%.  Higher pCR rates occurred in patients with TNBC (67% vs 12% if ER positive and HER2 negative; p=0.02).  Patients received Carboplatin 6 AUC every 4 weeks plus paclitaxel 80 mg/m2 over one hour every week +/- for 16 weeks, traztuzumab for HER2 positive patients.

Rationale for testing for Spy-1

  • Spy1 or Speedy, is a novel cell cycle regulator functioning by both directly activating the cyclin dependent kinases (CDKs), CDK2 and CDK1 as well as inhibiting the action of the CDK inhibitors
    p27 and p21
  • Spy1 is activated downstream of pathways implicated in TNBCs, MAPK and MYC [13-15]. Spy1 is known to override response to cytotoxic therapy [13,14] as well as overriding p53 mediated responses [17,18]. Spy1 protein levels are elevated in a number of human breast carcinomas and over expression in mouse models induces rapid mammary tumorigenesis [14]. Exciting recent data from our laboratories demonstrate that persistent levels of Spy1 protein appears to be involved in actively promoting breast cancer cell progression to a triple negative phenotype however to date expression levels of Spy1 in TNBCs has not been explored in human samples.

We will measure Spy1 protein/mRNA levels in patient samples collected prior to treatment, along with levels Spy1 affectors and effectors (phospho-MAPK, MYC, activity of CDK2 and CDK1 and levels of p27 and p21) using both immunohistochemistry to obtain localization data as well as western blot analysis and Q-RT-PCR to obtain quantified data on protein and expression levels. Additionally we will sequence over the p53 gene to correlate p53 status with our obtained clinical and molecular data. In addition to the patient samples collected we have approximately 100 TNBC patient samples banked, which will also be added to this analysis. We will also collect samples from ER positive, luminal A breast cancers to compare the expression levels of these pathways in this subset of more responsive tumours.

Furthermore, we know that 40% of the TNBC patients will relapse in a relatively short interval.  For these cases, we will retest the patients at the time of relapse to test for changes that occur in the Spy1/MAPK/MYC/p53 signaling pathways following chemotherapy. 

Hence we will determine whether Spy1 and/or Spy1 related proteins are implicated in TNBCs and we will correlate the levels and activity of these pathways with response to treatment in this patient population. It is our hypothesis that levels of Spy1 and Spy1-mediated genes will correlate positively with poor response to therapy, even in the presence of wild-type p53. This may determine the efficacy of targeting this pathway for novel therapeutic design, as well as utilizing this pathway as a prognostic marker for this population of patients.

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Resources

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