Monitoring Response to Neoadjuvant Chemotherapy in HER2 Negative Breast Cancer Using High-speed MR Spectroscopic Imaging

The primary objective of the study is to assess the correlation of serial high-speed MRSI of
[tCho] with pCR following NAC in women with HNBC. The endpoint is the pCR.

Hypothesis 1: Changes in [tCho] early during NAC (from 24 hours after the start of the first
cycle until the start of the 2nd cycle of NAC) are predictive of pathologic response (using
quantitative metrics of Residual Cancer Burden (RCB)1 and/or CPS+EG score 2 and radiologic
response (change in lesion size on DCE-MRI).

Hypothesis 2: Decreases in [tCho] within the tumor precede decreases in tumor volume on
DCE-MRI, thus enabling earlier discrimination between responders from non-responders. The
primary objective of the study is to assess the correlation of serial high-speed magnetic
resonance spectroscopic imaging (MRSI) of [tCho] with pCR following NAC for HNBC. The
secondary objective is to compare the time course of [tCho] on serial high-speed MRSI and
tumor volume on serial DCE-MRI for predicting early NAC treatment response in HNBC.

Subjects' participation will start approximately 2 weeks before initiation of neoadjuvant
therapy and end after surgery.

Patients will undergo up to 5 MRI scans in total as 2 are clinical MRIs and 3 are research
scans. The clinical pretreatment MRI scan and a post treatment MRI scan are standard and will
be ordered at the discretion of the treating provider.The post treatment MRI is done after
clinical response and before surgery. This helps guide the surgeon about what amount of
tissue should be removed at surgery. The minimum time between clinical and research MRI scans
is 24 hours.

The 3 research MRIs will be performed on a 3T Siemens scanner equipped with 16 channel
Hologic breast coil. Breast anatomy will be imaged using a bilateral localizer, an axial T
2-weighted turbo-spin-echo scan, and a fat-suppressed T1-weighted sagittal gradient echo
scan. Dynamic non-fat-suppressed T1-weighted axial 3D GRE scans are collected before and with
20s delay at four time points after Gd-HP-DO3A administration (total scan time: 7.5 min).
Subtraction images are created using the pre-contrast image as the mask. A diffusion weighted
multi-slice EPI scan will be performed to compute apparent diffusion coefficient (ADC) maps
online (total scan time: 3:14 min). An axial low-resolution multi-slice multi-echo gradient
echo scan will be performed to compute field maps for slice and laterality specific
auto-shimming. Spectroscopic imaging will be performed using 3D PEPSI.

The MR measurement protocol will be performed at 3 time points: (1) prior to treatment
typically several days before NAC (ideally 24h before NAC) (MRSI, DW-MRI, DCE-MRI), (2) 20-52
hours after the beginning of the first cycle of NAC (MRSI, DW-MRI), and (3) between the first
and second cycle of NAC (MRSI, DW-MRI, DCE-MRI).

Surgery will be performed within 3 to 12 weeks of last chemotherapy. RCB will be obtained
from the final pathologic findings.

Inclusion Criteria:

- Have a biopsy proven HER2 negative (by IHC or FISH) breast cancer per standard
clinical criteria (per ASCO-CAP guidelines). Although patients with hormone-receptor
positive (ER+ and/or PR+) disease will be included, patients with tumor features
indicative of luminal A intrinsic sub-type will be excluded from this study. Excluding
features are:

- Patients with Grade 1 breast cancers, as assessed by local standard criteria,
will be excluded from participation.

- Patients with strongly ER AND PR positive breast cancer, defined as >75% positive
staging for BOTH markers by IHC, will be excluded from participation.

- Stage of disease that is appropriate for standard NAC (any combination of T2 to T4, N0
to N3 that would comprise stage IIA to IIIB disease). Patients with inflammatory
carcinoma or stage IIIC disease who are deemed inoperable at the outset, but
appropriate for NAC are excluded in this study since there is no guarantee they can be
converted to operability following NAC; thus precluding assessment of pCR.

- Medically fit for NAC as per good clinical practice and per the treating physician's
judgment.

- Age > or = to 18 years AND able to provide informed consent.

- Women of childbearing potential must be willing and able to use effective means of
contraception. A female of childbearing potential is any woman who has not undergone a
hysterectomy or bilateral oophorectomy or has not had menses at any time in the
preceding 12 consecutive months.

- Able to undergo standard clinical MRI exams PLUS additional 30 minutes longer (total
scan time is 50 to 60 minutes).

Exclusion Criteria:

- Pregnant or lactating women.

- Body contains foreign items posing an issue of MRI safety, such as intra-ocular
metallic foreign bodies, MRI incompatible devices such as pacemakers and cochlear
implants, and other MRI incompatible devices.

- Obesity (Body Mass Index [BMI] > 40) or inability to fit into the standard MRI gantry.

- Suffer from back pain, claustrophobia, seizures, panic disorder and/or other medical
disorders severe enough that would prevent them from completing a standard clinical
MRI study (30 min) + 30 mins for the research scans. If applicable, patients may take
a mild anxiolytic (e.g., lorazepam) if deemed appropriate by their treating physician.

- Patients with stage IV disease (gross metastasis or documented M1 disease) and stage
of disease excluded above.