Functional Precision Oncology to Predict, Prevent, and Treat Early Metastatic Recurrence of TNBC (TOWARDS-II)

This is an interventional treatment trial for Breast Cancer Recurrent Read More

Step 1: Pre-tumor Collection Eligibility Participant Inclusion Criteria

• Subject aged ≥ 18 years.
• Subject has Stage I-III disease.

• Histologically or cytologically confirmed invasive breast carcinoma that is triple negative (TNBC) or hormone receptor (HR)-low/Her2 negative

  --TNBC is defined as:

  • HER2 expression 0 or 1+ on immunohistochemistry (IHC) or non-amplified (defined as HER2/CEP17 ratio <2 or copy number <6) on fluorescence in situ hybridization (FISH). If HER2 expression is 2+ on IHC, negative HER2 expression must be confirmed by FISH. Pathologic diagnosis of TNBC (negative HER2 status by cytogenetics, <1% of cells stained positive for estrogen receptor (ER) by IHC, and <1% of cells stained positive for progesterone receptor (PR) by IHC).

    --HR-low/Her2(-) is defined as:

  • HER2 expression 0 or 1+ on IHC or non-amplified (defined as HER2/CEP17 ratio <2 or copy number <6) on fluorescence in situ hybridization (FISH). If HER2 expression is 2+ on IHC, negative HER2 expression must be confirmed by FISH.1-10% of cells stained positive for ER by IHC, and/or 1-10% of cells stained positive for PR by IHC).
• Primary tumor OR local lymph node metastasis that is ≥ 1.5 cm. Patients with inflammatory breast cancer are eligible. Patients with multifocal or multicentric breast cancer are eligible so long as ALL tumors meet eligibility criteria.
• Patient is considered for preoperative cytotoxic chemotherapy per standard of care or in the context of a separate, ongoing clinical trial.
• Patient has not received any prior therapy for her breast cancer.
• Willing and capable (per treating investigator's assessment) to undergo baseline tumor material collection from the primary tumor or lymph node metastasis.

• Patient can safely undergo tumor collection:

  • The tumor is reasonably accessible to tumor collection
  • The tumor is amenable to tumor collection (e.g. does not abut neurovascular structures)
  • If the patient receives anticoagulation, anticoagulation can be safely withheld to accommodate for tumor material acquisition
  • The patient does not have a medical condition that would render tumor acquisition a high-risk procedure (e.g. tumor material acquisition from lung metastases in a patient with emphysema)
• Life expectancy of ≥ 12 months as assessed by the treating investigator.
• ECOG Performance Status ≤ 2.

• Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

  • Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have estradiol and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
  • Women ≥ 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
• Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines.

Step 2: Tumor Modeling and Tumor Material Testing Participant Inclusion Criteria

• Patient continues to meet step 1 registration criteria.
• Successful acquisition of a solid tumor biopsy sample containing ≥ 20% tumor content.
• Sample from tumor collection is the type of sample that is feasible for PDX or organoid development as determined by the investigator.

Physician Inclusion Criteria

• Physician is the treating medical oncologist for a patient who meets all of the inclusion criteria and none of the exclusion criteria.
• Willing and able to answer the physician questionnaires at the protocol required time points.
• Willing and able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines.

Participant Exclusion Criteria

• Radiographically evident metastatic breast cancer
• ER and/or PR expression >10% on immunohistochemistry
• Her2(+) and/or Her2-amplified breast cancer. HER2 expression 3+ on IHC or amplified (defined as HER2/CEP17 ratio ≥2 or copy number >6) on fluorescence in situ hybridization (FISH). If HER2 expression is 2+ on IHC, reflex FISH must be performed to determine eligibility.
• Patient has bilateral breast cancer

• Patient received any anti-cancer therapy or any investigational therapy prior to study entry and collection of tumor.

  --Treatment includes: neoadjuvant therapy, radiation therapy, chemotherapy, bisphosphonates for an indication other than osteopenia/osteoporosis, and/or hormonal therapy administered for the currently diagnosed primary breast cancer prior to study entry. Hormonal therapy for a prior diagnosis of a hormone receptor-positive breast cancer us allowed.

• The diagnosis of another malignancy, unless the patient is considered disease-free for ≥5 years before study entry. Patients are eligible if diagnosed and treated for carcinoma in situ of the cervix, melanoma in situ, colon cancer in situ, ductal carcinoma in situ, and basal and/or squamous cell carcinoma of the skin, early stage papillary thyroid cancer, and other low risk malignancies per investigator discretion.
• Prior history of local or locally advanced hormone receptor positive (ER and/or PR expression >10% on immunohistochemistry) and Her2 positive or negative breast cancer is allowed so long as patients have completed all treatments with curative intent (except adjuvant medical non-chemotherapy treatments, e.g. adjuvant endocrine therapy with any hormonal agent) AND an interval of 6 months has elapsed between completion of these treatments and histologic diagnosis of eligible breast cancer AND all other eligibility criteria are otherwise met.

• The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

  • Myocardial infarction (<6 months prior to enrollment), unstable angina, congestive heart failure (> New York Heart Association Classification Class IIB) or a serious cardiac arrhythmia requiring medication.
  • Renal or liver disease that prohibits the patient from receiving at least single-agent full recommended dose chemotherapy.

• Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions:

  • Cardiovascular disorders:

    • Congestive heart failure New York Heart Association Class III or IV, unstable angina pectoris, serious cardiac arrhythmias.
    • Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic events, or thromboembolic event (eg, deep venous thrombosis, pulmonary embolism) within 3 months before the first dose.
    • QTc prolongation defined as a QTcF > 500 ms.
    • Known congenital long QT.
    • Left ventricular ejection fraction < 55%.
    • Uncontrolled hypertension defined as ≥ 160/100 as assessed from the mean of three consecutive blood pressure measurements taken over 10 minutes.
  • Any other condition that would, in the Investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, [subjects may not receive the drug through a feeding tube], social/ psychological issues, etc.)
• Medical, psychiatric, cognitive, or other conditions that may compromise the subject's ability to understand the subject information, give informed consent, comply with the study protocol or complete the study.