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Study Description

Highly variable outcomes are observed in patients with estrogen receptor positive (ER+) breast cancer who undergo preoperative estrogen deprivation therapy with aromatase inhibitors (AI). In this study, 46 tumor and normal genomes and 31 exomes of participants selected from two clinical trials of neoadjuvant AI therapy on ER+ breast cancer were sequenced to identify somatic alterations that correlate with response to AI, to screen for therapeutic targets and to elucidate the genetic landscape of ER+ breast cancer. Of the significantly mutated genes, GATA3 mutations correlated with low post-treatment Ki67 and up-regulation of IGF1R mRNA. TP53 mutations associated with multiple markers of poor outcome and mutations in MAP3K1 associated with inferior clinical response. Mutations in MAP3K1 and MAP2K4 were mutually exclusive and positively associated with mutations in PIK3CA. The majority of tumors were multiclonal, as defined by distinct mutation clusters. A number of potential therapeutic targets were provided by both common and rare variants. Potential therapeutically relevant mutations of tryosine kinase included ERBB2, KIT, PDGFRA, DDR1, CSF1R, and MET.

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Study Inclusion/Exclusion Criteria

All tumors sequenced were classified as luminal A or B by PAM50 gene expression profiling. Tumor samples for whole genome sequencing were selected from two clinical trials of neoadjuvant aromatase inhibitor therapy:

  1. NCT00084396 - Neoadjuvant Letrozole in Treating Postmenopausal Women With Estrogen-Receptor Positive and/or Progesterone-Receptor Positive Stage II, Stage IIIA, or Stage IIIB Breast Cancer
    Inclusion Criteria
    For inclusion in the study, patients must fulfill all of the following criteria:
    1. Palpable and measurable infiltrating adenocarcinoma of the breast confirmed by core needle biopsy, previously untreated, at least T2 (greater than 2cm) by clinical or radiological parameters.
    2. Stage Clinical T2, T3, T4a, b, c, N0, 1 or 2, M0.
    3. ER positive and/or PR positive based on 10% or more nuclear staining of the invasive component of the tumor.
    4. Patient is eligible if they would benefit from preoperative therapy with an improvement in surgical outcomes defined as:
      • Marginal candidate for lumpectomy (lumpectomy feasible but patient at risk for positive margins or poor cosmetic outcome. Patient desires breast-conserving surgery if possible.
      • Ineligible for lumpectomy but modified radical mastectomy currently feasible. Patient desires breast-conserving surgery if possible and surgeon judges this would be possible if the primary tumor were smaller.
      • Inoperable, systemic therapy required for patient to become operableby modified radical mastectomy.
    5. Written informed consent must be obtained and documented.
    6. In the case of bilateral primaries, both tumors must have features consistent with eligibility criteria.
    7. Postmenopausal as defined as cessation of menstrual periods for at least one year, bilateral surgical oophorectomy or FSH and estradiol inthe postmenopausal range.
    8. The patient must have an ECOG performance status of 0-2.
    9. Patient is willing and able to provide biopsy material for research evaluation.
    10. Patient is willing to undergo breast surgery at the end the preoperative treatment period.
    Exclusion Criteria
    Any of the following is regarded as a criterion for exclusion from the study at the time of enrollment:
    1. Inflammatory carcinoma defined as peau d'orange affecting at least one third of the breast. Direct extension of the tumor to skin is not a contraindication.
    2. Metastatic breast cancer, excluding isolated ipsilateral superclavicular lymphadenopathy.
    3. The patient is unwilling to undergo breast surgery at the end the preoperative treatment period.
    4. Any reason that would make the patient unlikely to comply with study requirements (e.g. Confusion, infirmity, alcoholism, etc.)
    5. Unwillingness, or inability, to stop taking any drug known to affect sex hormone status (including hormone replacement therapy, phytoestrogenic herbal/alternatives/OTC remedies).
    6. Previous history of breast cancer treated with either radiation, chemotherapy, or hormonal agents. Prior history of other invasive malignancies is not an exclusion criteria, unless the disease is active and progressing at the time of protocol screening.
    7. Any severe concomitant disease that would preclude surgery or safe administration of the study drug, particularly severe liver dysfunction.
    8. Treatment with a non-approved or experimental drug during the 30 days prior to study initiation.
    9. Prior treatment with an aromatase inhibitor, tamoxifen, raloxifene or other antiestrogen/SERM.
    10. Concomitant anticancer treatments such as chemotherapy, immunotherapy/biological response modifiers and radiotherapy. Bisphosphonates are allowable if treatment is for osteoporosis.
  2. NCT00265759 - Exemestane, Letrozole, or Anastrozole in Treating Postmenopausal Women Who Are Undergoing Surgery for Stage II or Stage III Breast Cancer
    Inclusion Criteria
    For inclusion in the study, patients must fulfill all of the following criteria:
    1. Patient must have an ECOG/Zubrod performance status of ≤ 2.
    2. Patient must have T2-T4c, any N, M0 breast cancer, by clinical staging. NOTE: Primary tumor must be palpable and measure >2 cm by tape, ruler or caliper measurements in at least one dimension.
    3. Patient must be postmenopausal, verified by:
    4. Patient, as documented by the treating physician, is clinically staged as one of the following:
      • T4 a-c for whom modified radical mastectomy with negative margins is the goal
      • T2 or T3 for whom conversion from needing mastectomy to breast conservation is the goal
      • T2 for whom lumpectomy at first attempt is the goal.
    5. Patient has an ER+ tumor with an Allred score of 6, 7 or 8. Note: Patients with > 66.6% (two-thirds) of cells staining positive have a minimum Allred score of 6 and are eligible.
    6. Patient must have mammogram and ultrasound within 42 days prior to registration.
    7. If patient is a cancer survivor, all of the following criteria must be met:
      • Patient has undergone potentially curative therapy for all prior malignancies, ACOSOG Protocol Z1031 Z1031 A7 - 17
      • No evidence of any prior malignancies for at least 5 years with no evidence of recurrence (except for successfully treated cervical carcinoma in situ, lobular carcinoma in situ of the breast, contralateral DCIS treated with mastectomy or lumpectomy and radiation but without tamoxifen treatment, or non-melanoma skin cancer with no evidence of recurrence), and
      • Patient is deemed by their treating physician to be at low risk for recurrence from prior malignancies
    Exclusion Criteria
    A patient will NOT be eligible for inclusion in this study if any of the following criteria apply:
    1. Inflammatory breast cancer defined as clinically significant erythema of the breast and/or documented dermal lymphatic invasion (not direct skin invasion by tumor or peau d'orange without erythema).
    2. Prior treatment for invasive breast cancer, including radiation, endocrine therapy,chemotherapy or investigational agent. Patients whose diagnosis was established by incisional biopsy are not eligible.
    3. Patient has received hormone replacement therapy of any type, megestrol acetate, or raloxifene within one week prior to registration.
    4. Patient has distant metastasis (M1), excluding isolated ipsilateral supraclavicular node involvement.
    5. Patient does not agree to undergo mastectomy or lumpectomy after neoadjuvant aromatase inhibitor therapy.
    6. Patient is enrolled in another neoadjuvant clinical trial for treatment of the existing breast cancer.
    7. Cohort B only: Patient has undergone prior sentinel lymph node biopsy.

Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
Whole Genome Genotyping Illumina OmniExpress 1M Duo N/A N/A
Whole Genome Sequencing Illumina Genome Analyzer IIX N/A N/A
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Diseases/Traits Related to Study (MESH terms)
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