Peoples. Our target study population is high-risk HER2-positive breast cancer patients. High-risk HER2-positive breast cancer patients are defined as: • Those with HER2-positive breast cancer, regardless of hormone receptor status, who receive neoadjuvant therapy with an approved regimen that includes trastuzumab and at least four cycles (12 weeks) of taxane-containing chemotherapy, and fail to achieve a pCR. • Those with HER2-positive breast cancer, regardless of hormone receptor status, who undergo surgery as a first intervention and are found to have ≥ 4 positive lymph nodes. • Those with HER2-positive, hormone receptor negative breast cancer who undergo surgery as a first intervention and are found to have 1-3 positive lymph nodes. Following surgery, patients will be screened and HLA-typed (consent #1). Nelipepimut-S is a CD8-eliciting peptide vaccine that is restricted to HLA-A2+ or HLA-A3+ or HLA-A24+ or HLA-A26+ patients (approximately 80% of the US population). HLA-A2+/ /A3+/A24+/orA26+ patients who meet all other eligibility criteria will be randomized to receive trastuzumab + nelipepimut-S/GM-CSF or trastuzumab + GM-CSF alone (consent #2). The trastuzumab will be administered to all patients consistent with current standard of care. Patients randomized to the nelipepimut-S/GM-CSF arm will receive vaccinations of nelipepimut-S (1000 μg) and GM-CSF (250 μg) administered intradermally every three weeks for six total vaccinations, 30-120 minutes after completion of trastuzumab infusion. With prior approval from the Principal Investigator, the vaccine may be administered 15 minutes after completion of the trastuzumab 15 Protocol: 2014-0443 Version 2.1 Version Date: 11 April 2016 infusion. The first vaccination will be given with the third dose of maintenance trastuzumab administered as monotherapy (Appendix B) optimally, but may be given with later maintenance doses of trastuzumab, provided there are at least six remaining doses of trastuzumab to overlap with the primary vaccine series (PVS). Patients randomized to the GM-CSF alone arm will receive inoculations of GM-CSF (250 μg) administered in an identical manner to those receiving nelipepimut-S/GM-CSF. Patients will be blinded as to whether they are receiving nelipepimut-S/GM-CSF or GM-CSF alone. Upon completion of the PVS, booster inoculations (same dose and route) will be administered every six months x 4 (Appendix B). The first booster inoculation will occur 6 months ± 2 weeks after the completion of the PVS with subsequent boosters timed every six months + 2 weeks. Boosters will therefore occur at the following time points after completion of the PVS: 6 months ± 2 weeks, 12 months ± 2 weeks, 18 months ± 2 weeks and 24 months ± 2 weeks. Booster inoculations will occur for patients randomized to receive nelipepimut-S/GM-CSF as well as patients randomized to receive GM-CSF alone, and will consist of the same treatment drugs and dosing (i.e. nelipepimut-S/GM-CSF patients will be boosted with nelipepimut-S/GM-CSF while GM-CSF alone patients will be boosted with GM-CSF alone). Patient blinding will be maintained throughout the study.