Inclusion Criteria:

1. Males or females 18 years or older at the time of consent.

2. ECOG performance status of 0-2 within 21 days of study registration.

3. Histologically or cytologically confirmed adenocarcinoma of the breast with locally
recurrent or metastatic disease. NOTE: locally recurrent disease must not be amenable
to surgery or radiation with curative intent.

4. Measurable or evaluable disease according to RECIST v1.1 within 35 days prior to
study registration.

5. Disease must be amenable to biopsy (image-guided or via direct visualization of
superficial lesions) with minimal risk to the patient. NOTE: Patients with disease
limited to the lung and/or pleura are excluded.

6. Disease must be HER2+ as defined by IHC 3+ or FISH ratio > 2.0.

7. Resistant to trastuzumab as defined as (1) progression within 12 months of completing
adjuvant/neoadjuvant trastuzumab or (2) progression on trastuzumab administered for
metastatic disease.

8. Prior treatment with lapatinib or investigational HER2 targeted therapies is allowed
but not required. There are no limits on the number of regimens or other prior
anti-HER2 therapies patients have received.

9. LVEF ≥ Lower Limit of Normal based on MUGA or ECHO within 35 days prior to study
registration

10. Females of childbearing potential and males must be willing to use an effective
method of contraception from the time consent is signed until 6 months after
treatment discontinuation. Methods of contraception include hormonal birth control
(oral contraceptives, patch, injection, vaginal ring or implant), two barrier methods
of birth control, abstinence and/or other methods as determined by the treating
physician.

11. Females of childbearing potential must have a negative pregnancy test within 14 days
prior to registration for protocol therapy.

NOTE: Females are considered of child bearing potential unless they are surgically
sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral
oophorectomy) or they are postmenopausal (> 12 months since last menses).

Laboratory values must be obtained within 21 days of study registration:

12. Absolute neutrophil count (ANC) ≥ 1.5 K/mm3

13. Platelets ≥ 100 K/mm3

14. Hemoglobin (Hgb) ≥ 9.0 g/dL (may be transfused)

15. Serum creatinine < 3.0 mg/dL

16. Total Bilirubin ≤ 1.5 x ULN

17. AST/SGOT ≤ 2.5 x ULN. If liver metastases is present, AST ≤ 5 x ULN

18. ALT, SGPT ≤ 2.5 x ULN. If liver metastases is present, ALT ≤ 5 x ULN

Exclusion Criteria:

19. No Investigational therapy within 4 weeks of study registration

20. No hormonal therapy within 2 weeks of study registration

21. No cytotoxic chemotherapy within 2 weeks of study registration.

22. No prior treatment with GRN163L

23. No prior history of severe reaction to trastuzumab, as determined by the treating
physician.

24. No history of clinically significant cardiac dysfunction, including:

Current uncontrolled hypertension (systolic >150 mmHg and/or diastolic >100
mmHg), or unstable angina History of symptomatic CHF (Grade >3 by NCI CTCAE or Class
>II by NYHA criteria [see Appendix IV]) or serious cardiac arrhythmia requiring
treatment within 12 months of study registration, with the exceptions of atrial
fibrillation and paroxysmal supraventricular tachycardia History of myocardial
infarction within 6 months of study registration

25. No history of cerebrovascular accident within 12 months of study registration

26. No active CNS metastases. Patients with previously treated CNS metastases who do not
require chronic steroids or anticonvulsants are eligible.

27. Prior radiation therapy must not have involved > 25% of bone marrow due to potential
myelosuppression with GRN163L. See bone marrow chart in Appendix III

NOTE: Radiation therapy within 2 weeks of study registration is not allowed.

28. Females must not be breastfeeding.

29. No clinically significant active infection, as determined by the treating
physician