Patient case: 70-year-old female with breast cancer; genetic feature: AURKA amplification

Clinical trial: Genetic Analysis in Blood and Tumor Samples From Patients With Advanced or Metastatic Estrogen Receptor Positive and HER2 Negative Breast Cancer Receiving Palbociclib and Endocrine Therapy

Summary: This research trial studies genetic profiles in blood and tumor samples from patients with estrogen receptor positive and HER2 negative breast cancer that has spread to other places in the body who are receiving palbociclib and endocrine therapy. Examine the genetic changes associated with the cancer and comparing the genetic material from the cancer tissue with the genetic material found in the blood may help doctors to develop customized treatment for breast cancer.

Detailed description: PRIMARY OBJECTIVES:
  I. Identify novel genomic variants and pathways associated with early progression (progression within 12 months) among women with advanced hormone positive breast cancer treated with palbociclib and endocrine therapy.
  SECONDARY OBJECTIVES:
  I. To assess whether time to progression differs with respect to SNAIL expression and other markers of EMT.
  II. To assess whether time to progression differs with respect to genetic alterations known to be associated with endocrine monotherapy resistance (e.g. ESR1 mutations/fusions, AKT, HER2, estrogen receptor [ER]alpha, etc.).
  III. To tabulate the number of patients who have targetable mutations found in the baseline tumor and assess their subsequent treatment regimen following progression on palbociclib and endocrine therapy.
  IV. To assess whether time to progression differs with respect to biomarkers associated with the CD44high/CD24/low/ERlow cancer stem cell-like phenotype, ERalpha downregulation and resistance to endocrine therapy and palbociclib [expression of total and phosphorylated AURKA, breast cancer stemness biomarkers (CD44, CD24, ALDH1) EMT transcription factors (SMAD5, SOX2), cyclin E, cyclin A and phosphorylated retinoblastoma (Rb)].
  V. To generate patient derived xenograft (PDX)s from the baseline tumor biopsy (Rochester only) test novel endocrine therapy combinations in PDXs generated from the baseline tumor biopsy.
  TERTIARY OBJECTIVES:
  I. To compare and contrast the spectrum of ESR1 mutations identified in tissue, circulating cell free deoxyribonucleic acid (DNA) (cfDNA), and circulating tumor cell (CTC) derived DNA.
  II. To compare and contrast the actionable genomic alterations found in cfDNA or CTC derived DNA that are not found in tumor tissue.
  III. To assess whether genetic alterations known to be associated with endocrine monotherapy resistance is seen in cfDNA and CTC derived DNA.
  IV. To examine shifts in the populations of epithelial like CTCs and stem cell like CTCs during the course of endocrine therapy with palbociclib.
  V. To assess CTC expression of ER, HER2, and other markers of endocrine resistance.
  VI. To explore the proteomics of ER-positive breast cancer and identify biomarkers associated with early progression and neutropenia.
  OUTLINE:
  Patients undergo collection of blood at baseline and on day 1 of each treatment cycle. Patients also undergo tumor biopsy at baseline and 2 months. Biopsy samples are analyzed for genetic profile via next generation sequencing and ribonucleic acid (RNA) sequencing. Biopsy samples are also used for the generation of xenograft mice model.
  After completion of study, patients are followed up for 3 years.

Eligibility: Inclusion Criteria:
  -  PRE-REGISTRATION INCLUSION CRITERIA
  -  Women who have disease that is amenable to biopsy and agree to undergo a standard of care core biopsy of recurrent or metastatic breast cancer, and to collect additional core samples for research purposes
  -  Patients must satisfy one of the following criteria for prior therapy:
  -  First line setting: No prior endocrine therapy in the metastatic setting with no more than one prior line of chemotherapy in the advanced/metastatic setting
  -  Second line setting: Progression on one prior line of endocrine based therapy monotherapy either in the adjuvant or advanced/metastatic setting. Either one or two prior lines of chemotherapy in the advanced setting are allowed
  -  Note: Patients receiving bisphosphonate or denosumab therapy prior to registration may continue at the same intervals used prior to study registration
  -  First line therapy setting only: Palbociclib and letrozole is recommended for locally advanced or metastatic breast cancer
  -  Second line therapy setting only: Palbociclib and fulvestrant is recommended (after progression on first line endocrine therapy) for metastatic breast cancer
  -  Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria or bone only disease are eligible.
  -  Note: Those patients with both non-measurable disease and bone metastases are eligible
  -  Note: Patients are not allowed to begin a new systemic anti-cancer therapy during pre-registration with the exception of bisphosphonate or denosumab; palliative radiation is allowed during pre-registration
  -  No current evidence of visceral crisis or lymphangitic spread
  -  History of central nervous system metastasis are allowed provided they have been treated (i.e., surgery, radiation, and/or radiosurgery) =< 12 weeks prior to registration and have stable neurologic function, including no requirement for medication(s) to control symptoms for at least 2 weeks; Note: patients with known leptomeningeal disease are not eligible
  -  Women who are premenopausal must agree to begin or continue an LHRH agonist (goserelin preferred)
  -  NOTE: A woman is considered premenopausal if menses has occurred in the last 12 months prior to preregistration and both serum and follicle stimulating hormone (FSH) levels are not in the laboratory?s reference range for postmenopausal females
  -  Eastern Cooperative Oncology Group (ECOG) performance status: 0, 1, or 2
  -  Able to swallow oral formulation of drugs
  -  Signed and dated informed consent document for study participation
  -  Willing to submit tissue for required correlative research
  -  REGISTRATION INCLUSION CRITERIA
  -  Histologic confirmation from the pre-registration biopsy of either locally advanced or metastatic breast cancer that is ER-positive and HER2 -negative
  -  Note: ER-positive disease is defined as >= 10% nuclear staining; HER2-negative disease per 2013 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines, one of the following must apply:
  -  0 or 1+ by immunohistochemistry (IHC) and not amplified by in situ hybridization (ISH)
  -  0 or 1+ by IHC and ISH not done
  -  2+ by IHC and not amplified by ISH or
  -  IHC not done and not amplified by ISH
  -  Absolute neutrophil count (ANC) >= 1500/mm^3
  -  Platelet count >= 100,000/mm^3
  -  Hemoglobin >= 9.0 g/dL
  -  Total bilirubin =< 1.5 x upper limit of normal (ULN), (=< 3 x ULN if Gilbert?s disease)
  -  Aspartate transaminase (AST) =< 3 x ULN (=< 5 x ULN if liver metastases present)
  -  Creatinine =< 1.5 x ULN
  -  Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
  -  Recovered from all toxicities from all prior anticancer therapies
  Exclusion Criteria:
  -  PRE-REGISTRATION EXCLUSION CRITERIA
  -  History of metastatic ER negative or HER2 positive breast cancer
  -  Prior treatment in the metastatic setting with everolimus, or any agent whose mechanism of action is to inhibit the PI3K-mTOR pathway
  -  Uncontrolled intercurrent illness including, but not limited to:
  -  Ongoing or active infection
  -  Symptomatic congestive heart failure
  -  Unstable angina pectoris
  -  Uncontrolled symptomatic cardiac arrhythmia
  -  Uncontrolled hypertension (defined as blood pressure > 160/90)
  -  Other active second malignancy other than non-melanoma skin cancers =< 3 years of pre-registration; Note: a second malignancy is not considered active if all treatment for that malignancy is completed and the patient has been disease-free for =< 3 years prior to pre-registration
  -  Prior hematopoietic stem cell or bone marrow transplantation =< 3 years of pre-registration
  -  Known hypersensitivity to palbociclib, letrozole, fulvestrant, goserelin (if applicable) or to any of their excipients
  -  Known to be pregnant and planning to continue nursing
  -  REGISTRATION EXCLUSION CRITERIA
  -  No tumor identified on biopsy or insufficient tumor cells to obtain ER or HER2 status
  -  Any of the following therapies prior to registration:
  -  Chemotherapy =< 2 weeks
  -  Immunotherapy =< 2 weeks
  -  Biologic therapy =< 2 weeks
  -  Monoclonal antibodies =< 2 weeks
  -  Radiation therapy =< 2 weeks
  -  Anti HER2 or other ?targeted? therapy =< 2 weeks
  -  The following patients are not eligible
  -  Pregnant women
  -  Nursing women
  -  Women of childbearing potential who are unwilling to employ adequate contraception

Relevance to patient case: not relevant