Characterization of Circulating Tumor Cells (CTC) From Patients With Metastatic Breast Cancer Using the CTC-Endocrine Therapy Index

Patients with estrogen receptor (ER) positive metastatic breast cancer (MBC) starting their
first line of endocrine therapy (ET) only have a 30-50% chance of receiving clinical
benefit. For the other 50-70% of patients, ET is ineffective and these patients should
probably be treated with chemotherapy, as is done for ER negative patients. More
importantly, in nearly every clinical trial of ET in ER positive, MBC patients, between
15-30% of enrolled patients progress in the first 2-3 months, regardless of whether they are
receiving first or later lines of ET. Currently there is no validated method to identify
which ER positive MBC patients will be refractory to ET. Therefore, almost all ER positive
patients are treated with serial endocrine therapies before switching to chemotherapy. The
investigators propose that a subset of these patients would be better served with
chemotherapy, in spite of its increased toxicity profile, rather than delaying chemotherapy
during a several month trial of ineffective, albeit less toxic, ET.

To try and predict benefit from or resistance to ET, an index (the CTC-ETI) has been created
that takes into account the number of CTC (which is prognostic) as well as the phenotype of
the CTC, based on the hypothesis that relative levels of ER and Bcl-2 (high=benefit) and
HER2 and Ki67 (high=resistance) are predictive of ET responsiveness or resistance. Although
the preliminary data demonstrate the ability to detect, enumerate, and characterize CTC
utilizing the CellSearch® System, the purpose of the current study is to establish proof of
principle that these 4 markers can be used to generate a CTC-ETI which can be performed at
baseline from patients enrolled at different centers, and that baseline CTC-ETI predicts
relative outcome for patients with ER positive MBC starting a new ET, and can be monitored
in such patients during ET. Successful completion of this study will set the stage for a
larger, definitive study designed to demonstrate the clinical utility of a "refined" CTC-ETI
in patients with ER positive, HER2 negative MBC.

Inclusion Criteria:

- Signed informed consent.

- Women who are 18 years or older.

- Patients must have estrogen receptor (ER) positive, HER2 negative metastatic breast
cancer (MBC) with at least one non-irradiated distant site of metastasis.

- ECOG performance status of 0-2.

- Patients must have currently progressive metastatic disease according to RECIST v1.1
criteria, AND

- They have progressed on at least one previous line of endocrine therapy (ET) for
their metastatic disease (but are not currently progressing on fulvestrant), OR;

- They show evidence of disease progression during or within 12 months of the end
of adjuvant ET.

- Patient is about to start a new line of ET for their metastatic disease

- Patient is willing and able to undergo standard of care imaging studies (same
imaging/staging modality being used at each evaluation), which are anticipated to be
performed prior to the initiation of therapy and subsequently every 3 months.

- Patient agrees to the collection and testing of their blood and is willing and able
to provide approximately 40mL blood draw(s) at:

- Baseline (prior to the initiation of new ET), and;

- Subsequently at 1, 2, 3 and 12 months after the initiation of therapy, and/or;

- Time of disease progression.

Exclusion Criteria:

- Patients with local regional recurrence only or brain only metastasis.

- Patients who are progressing on current fulvestrant therapy (patients who have had
fulvestrant therapy in the past and were subsequently treated with other therapies or
those who are starting fulvestrant as their next line of ET are eligible for the
study).

- Patients who are or will be taking other unapproved (i.e. not cleared/approved by the
FDA) anti-neoplastic therapies concurrently are not eligible (exception: ET with
everolimus is acceptable).

- Patients with concomitant malignancies or previous malignancies within the last 5
years, with exception of adequately treated basal or squamous cell carcinoma of the
skin or carcinoma in situ of the cervix.

- Unable to provide informed consent or high risk that patient may not comply with
protocol requirements (i.e. due to health and/or participation in other research
studies).