Study to Identify Molecular Mechanisms of Clinical Resistance to Chemotherapy in Triple Negative Breast Cancer Patients

Mechanisms of resistance have been studied for many years in various experimental models.
However, many drugs that are highly effective in experimental models at overcoming
resistance have been either ineffective or marginally active in preliminary clinical
studies. Thus after decades of study, most reviews of anti-cancer drug resistance still
focus largely on experimental models, which may not reflect resistance in humans. However,
recent studies have demonstrated that clinical resistance occurs in primary and metastatic
tumors that may have undergone significant molecular evolution due to treatment effects and
the selection of clones as recently shown in breast cancer.

Triple negative breast cancer is a subtype that carries a poor prognosis and a high
incidence of early metastatic recurrence. Furthermore, no target therapy is efficacious up
to now in this subtype. Thus, identification of mechanisms of resistance to available
therapies and prediction of tumoral response to various treatments could help in the
management of patients affected by this particularly aggressive type of breast cancer.

The goals of this study are two-fold. First, to build a biobank of blood and tissue
specimens, prior to starting chemotherapy and at a determined time-point (surgery or
progression of disease), from patients undergoing the chemotherapeutic treatments in the
neoadjuvant and metastatic settings. Second, to use cutting-edge molecular techniques
available in several Quebec research centers, to carefully compare these pre and post
treatment samples to identify "molecular factors of resistance". The discovery of these
factors will help oncologists in triaging patients to receive the most beneficial therapy by
recognizing when not to give particular treatment and will be essential for reducing the
potential for harmful side effects and for avoiding the extremely high cost of modern
treatments when they can be predicted to be ineffective.

Inclusion Criteria:

Neoadjuvant setting

1. Histologically confirmed diagnosis of adenocarcinoma of the breast

2. Patient candidate for neoadjuvant chemotherapy (taxane-based)

3. Triple negative (ERnegative, PRnegative and Her2negative as defined by local
standards)

4. Normal coagulation profile; including INR/ PTT ≤ 1.5 x ULN.

5. ECOG 0,1 or 2

6. Provide written consent after the investigational nature, study design, risks and
benefits of the study have been explained.

7. Able to adhere to the study visit schedule and other protocol requirements.

Metastatic setting

1. Patients with histologically confirmed primary adenocarcinoma of the breast

2. Metastatic (stage IV) disease at initial diagnosis or following previous diagnosis of
primary breast cancer

3. At least one metastatic site accessible for biopsy.

4. ER-negative, PgR negative and HER2 negative as per local standards

5. Scheduled to receive chemotherapy for triple negative metastatic breast cancer.

6. Measurable disease (at least one unidimensionally measurable lesion)

7. Normal coagulation profile; including INR/ PTT ≤ 1.5 x ULN.

8. ECOG 0,1 or 2

9. Life expectancy of 12 or more weeks.

10. Provide written consent after the investigational nature, study design, risks and
benefits of the study have been explained.

11. Able to adhere to the study visit schedule and other protocol requirements

Exclusion Criteria:

Neoadjuvant setting

1. Positive for ER, PR or Her2 as defined by local standards

2. Clinical or radiological evidence of metastatic disease

3. Inadequate or unusable tissue as the only tissue available for biopsy

4. Other non-malignant systemic disease to preclude treatment with chemotherapy regimen
or prevent follow-up

5. Diagnosis of inflammatory breast cancer

6. Known infection with HIV or hepatitis

Metastatic setting

1. Patients with ER+, PR+ or HER2+ tumors demonstrated by local standards

2. Inadequate or unusable tissue as the only tissue available for biopsy

3. Other non-malignant systemic disease to preclude treatment with standard chemotherapy
regimen or prevent follow-up

4. Abnormal coagulation profile

5. The planned concurrent administration of therapies (e.g. palliative radiotherapy)
that target metastatic sites accessible for biopsy

6. Known infection with HIV or hepatitis