Neoadjuvant Endocrine Therapy in Hormone Receptor-Positive HER2-Negative Node-Negative Breast Cancer Patients to Assess Responses and Mechanisms of Endocrine Resistance

STUDY RATIONALE: Patients with HR+ HER2- node-negative breast cancers generally undergo
surgical resection upfront, followed by adjuvant chemotherapy, if needed, in addition to
adjuvant endocrine therapy. Because endocrine therapy is primarily delivered in the
postoperative setting, the ability to assess the tumor response to this treatment modality is
lost and very difficult to assess. This study offers the unique opportunity to assess the
responsiveness of breast tumors to endocrine therapy while the tumors are still in vivo by
treating patients with endocrine therapy before surgery and assessing molecular changes with
treatment. By comparing pre- and post-treatment levels of molecular markers in individual
tumors, the team expects to identify predictors of responsiveness to existing agents and
identify new candidate therapeutic targets.

PRIMARY OBJECTIVE: The primary objective is to determine the frequency of increased HER
family of receptor tyrosine kinases protein expression in tumors, following treatment with
neoadjuvant endocrine therapy and their correlation with Ki-67 tumor responses. The team will
measure cancer cell protein levels of growth factor receptors of the HER family before and
after neoadjuvant endocrine therapy. The data will be used to inform a future randomized
trial of combined endocrine and the most promising anti-HER targeted therapy.

Inclusion Criteria:

- Female; age ≥18 years.

- Pathologically proven diagnosis of invasive breast cancer, clinically stage I-II.

- Clinically lymph node negative, confirmed by clinical exam and/or ultrasound imaging.

- Estrogen- and/or progesterone-receptor-positive tumor, defined ≥1% positively staining
cells by immunohistochemistry, according to the current ASCO/CAP guidelines.

- HER2/neu must be negative by immunohistochemistry (IHC) or fluorescence in situ
hybridization (FISH).

- ECOG performance status 0-2.

- Pretreatment evaluations (minimum diagnostic workup) within 28 days prior to study

- Qualify for anti-endocrine treatment (per medical oncologist).

- Informed consent provided.

- If history of contralateral breast cancer, patient completed all treatment two years
prior

- No treatment for this breast cancer or any malignancy within two years (except
non-melanomatous skin cancer, carcinoma in situ of the cervix and contralateral breast
cancer)

- Using adequate methods of contraception; negative pregnancy test.

- No strong CYP2D6 inhibitors.

- Adequate organ function with baseline lab values.

- Absolute neutrophil count (ANC) ≥ 1500/µL.

- Hemoglobin (Hb) ≥ 9g/dL.

- Platelet count ≥ 100,000/µL.

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3x upper
limit of normal (ULN).

- Serum bilirubin within ≤ 1.5 x ULN.

Exclusion Criteria:

- AJCC clinical T4, N1-3 or M1, breast cancer.

- Synchronous non-breast malignancy (exceptions include non-melanomatous skin cancer,
carcinoma in situ of the cervix).

- Purely noninvasive breast cancer (i.e., ductal carcinoma in situ, lobular carcinoma in
situ).

- Men with breast cancer.

- Medical, psychiatric or other condition that would prevent the patient from receiving
the protocol therapy or providing informed consent.

- Pregnant or lactating women.