Patient case: 35-year-old female with Breast cancer. Genetic variant: NRAS Amplification. Other conditions: None.

Clinical trial: The p53 Breast Cancer Trial

Summary: This is a multicenter, open labeled, phase 2 clinical trial, where patients are stratified to one of two treatment groups based on upfront TP53 mutation status; i.e. TP53 mutated vs. TP53 wt disease, and treated with dose-dense cyclphosphamide. Furthermore, patients included are stratified based on tumor stage; i.e. locally advanced breast cancer (M0 disease) or metastatic breast cancer (M1 disease). All participating cancer centers will prospectively include patients with breast cancer fulfilling the inclusion criteria.
  If patients do not respond to the experimental treatment as outlined in the protocol, treatment with dose-dense cyclophosphamide will be terminated, and further cancer treatment will continue at the treating oncologist's discretion. The response data for all patients who have received at least one chemotherapy course will be included in the final efficacy analysis.
  Tumor tissue, blood samples and radiology data will be collected before therapy starts, if therapy needs to be changed, and for patients with locally advanced breast cancer: at surgery. Response data will be evaluated closely during treatment, with clinical assessment of tumor size every two weeks for patients with locally advanced breast cancer and by radiology every eight weeks for patients with metastatic breast cancer. Evaluation of side effects/tolerance will be performed at every clinical visit, i.e. every two weeks for all patients included in the p53 trial.

Detailed description: Stage IV breast cancer (distant metastases) remains a non-curable condition; thus, treatment is considered palliative. However, many patients may live for years with their metastatic disease with a reasonably good quality of life. As for locally advanced primary breast cancers in need of primary medical therapy, lack of responsiveness to regular chemotherapy is associated with a poor prognosis, with a high risk of relapse and, subsequent, breast cancer death. TP53 mutations have been shown to predict a poor response to anthracyclines, a group of cytotoxic agents which is extensively used and which is in general efficacious in breast cancer. Notably, dose-intensification with cyclophosphamide has been found to significantly improve the response rate in TP53 mutated primary breast cancers. Our preliminary experience indicates that the use of dose-dense cyclophosphamide monotherapy every 2nd week with G-CSF support is well tolerated. As for patients with metastatic disease for whom the alternative would be to receive continuous chemotherapy at 3-weekly intervals the hypothesis is that cyclophosphamide given at 2-weekly intervals over a limited time period, followed by a "treatment holiday" among responders should be associated with a non-inferior quality of life all-over. As for patients with TP53 mutated locally advanced breast cancers where standard chemotherapy fails, the hypothesis is that cyclophosphamide dose dense treatment may be an effective treatment option downstaging the tumor prior to surgery.

Eligibility: Inclusion Criteria:
  -  Locally advanced breast cancers in need of pre-surgical chemotherapy or metastatic breast cancer for whom conventional therapy has failed (see below)
  -  Resistance to endocrine therapy: Metastatic disease: either as i) estrogen and progesterone negative tumor, or ii) harboring an estrogen and / or progesterone positive tumor where regular endocrine therapies have failed and where the treating physician finds further endocrine therapy not indicated. LABC in need of pre-surgical therapy, in practice most patients will be selected for chemotherapy and not endocrine therapy, except older patients with tumors expressing strong hormone receptor staining. Here, the inclusion criteria should be patients for whom the treating physician selected primary chemotherapy instead of endocrine therapy based on clinical assessment.
  -  In the metastatic setting, patients enrolled should have been exposed to and developed resistance to at least one conventional regimen containing a taxane. Exposure to anthracyclines prior to inclusion is accepted, but is not mandatory for patients with TP53 mutated cancers. For patients with TP53 wt tumors it is mandatory that an anthracycline regimen has been used previously. Taxanes should have been applied in the metastatic setting; alternatively, patients relapsing within 2 years subsequent to adjuvant chemotherapy may be considered resistant to the drugs applied in the adjuvant setting. This relates also to patients who could not receive proper taxane therapy due to side effects or other medical reasons. As for respon-se, patients should have a lack of clinical benefit (SD, PR or CR) or acquired resistance (progression after an initial response) in metastatic breast cancer.
  -  For patients harboring locally advanced breast cancer; previous chemotherapy treatment should have contained a taxane. Anthracyclines are not considered mandatory (see above) in case the tumor reveals a TP53 mutation (similar to metastatic cancers). Further, the patient should have obtained a non-optimal response to the conventional regimen(s) given; i.e. lack of objective response (PR or CR) for locally advanced breast cancer.
  -  The primary tumor or at least one metastatic lesion must be available for biopsy collection at protocol inclusion. Notably; for patients with primary metastatic breast cancer, TP53 status should be determined in a metastatic deposit; tissue from the primary tumor may not substitute (this relates both to patients with synchronous and metachronous metastatic disease).
  -  Patients must have clinically and/or radiographically documented measurable breast cancer according to RECIST.
  -  WHO performance status 0-1
  -  Known tumor ER, PGR and HER2 status in the current situation, i.e. archival and historic breast cancer tissue can not be used for patients with relapse of the disease. However, patients can be included regardless of hormone receptor and HER2 status; in case such information lacks at inclusion, it may be analysed on the biopsy retrospectively.
  -  Age >18 years
  -  Radiology studies (CT thorax/abdomen and bone scintigraphy/bone scan) and ecco cor must be performed within 28 days prior to registration.
  -  Before patient registration, written informed consent must be given according to national and local regulations.
  -  Blood test requirements:
  -  Neutrophils > 1.0 x 109/L
  -  Platelets > 75 x 109/L
  -  Bilirubin < 20 µmol/L.
  -  Serum creatinine < 1.5 x ULN
  Exclusion Criteria:
  -  Co-morbidity that, based on the assessment of the treating physician, may preclude the use of cyclophosphamide at actual doses.
  -  Psychological, familial, sociological or geographical condition(s) potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
  -  Pregnant or lactating patients can not be included.
  -  Clinical evidence of serious coagulopathy. Prior arterial/venous thrombosis or embolism does not exclude patients from inclusion, unless patient is considered unfit by study oncologist.
  -  Active cystitis (to be treated upfront)
  -  Active bacterial infections
  -  Urinary obstruction
  -  Known hypersensitivity towards cyclophosphamide or pegfilgrastim, their metabolites and other ingredients in the drug administration formulation.
  -  Patient not able to give an informed consent or comply with study regulations as deemed by study investigator.

Relevance to patient case: not relevant