Anti-HER2 CD4+ T-Helper Type 1 Immune Response is Superior to Breast MRI for Assessing Response to Neoadjuvant Therapy in Patients with HER2-Positive Breast Cancer.

BACKGROUND: In human epidermal growth factor 2-positive breast cancer (HER2+BC), neoadjuvant chemotherapy and anti-HER2-targeted therapy (nCT) achieves a complete pathologic response (pCR) in 40-67% of patients. Posttreatment magnetic resonance imaging (pMRI) is considered the gold standard, with high specificity but lower sensitivity for assessing response. The authors previously determined that anti-HER2Th1 immune response is associated with pathologic response after nCT in HER2+BC patients. This study contrasted pMRI with anti-HER2Th1 response for assessing pCR in HER2+BC. METHODS: A retrospective review of HER2+BC patients at the authors' institution was performed. Original pMRI reports were collected, and images were reviewed by a breast radiologist blinded to pCR and immune response. The post-nCT imaging-based tumor response was assessed by Response Evaluation Criteria in Solid Tumors. The anti-HER2Th1 response was determined by ex vivo stimulation of peripheral blood mononuclear cells with six major histocompatibility complex (MHC) class 2-derived HER2 peptides via enzyme-linked immunospot (ELISPOT). Posttreatment MRI and anti-HER2Th1 responses were cross-tabulated with pCR. Standard diagnostic metrics were computed. RESULTS: For 30 patients, pMRI and anti-HER2Th1 immune response were measured, with 13 patients (43.3%) achieving pCR. The mean anti-HER2Th1 response in pCR was 167 (range 53-418), and

NSQIP Analysis of Axillary Lymph Node Dissection Rates for Breast Cancer: Implications for Resident and Fellow Participation.

INTRODUCTION: Management of the axilla in invasive breast cancer (IBC) has shifted away from more radical surgery such as axillary lymph node dissection (ALND), towards less invasive procedures, such as sentinel lymph node biopsy. Because of this shift, we hypothesize that there has been a national downward trend in ALND procedures, subsequently impacting surgical trainee exposure to this procedure using the ACS-NSQIP database to evaluate this. METHODS: Women with IBC were identified in the ACS-NSQIP database from 2007 to 2014. Procedures including ALND were identified using CPT codes. This number was divided by total cases, given a varying number of participating institutions each year. Next, cases involving resident participation were identified and divided by training level: junior (post graduate year-[PGY] 1-2), senior (PGY 3-5) and fellow (PGY ≥ 6). Two tailed z tests were used to compare proportions, with significance determined when p < 0.05. RESULTS: A total of 128,372 women were identified with IBC with 36,844 ALND. ALND rates decreased by an average of 2.43% yearly from 2007 to 2014. Resident participation significantly drops in 2011, from 49.3% before to 29.4% after (p < 0.01). Junior residents experienced a significant decrease in participation rate (43.3%-32.2%, p < 0.05). Senior residents and fellows experienced an upward trend in their participation, although not significant (51.2%-56.3%, p = 0.35, and 5.6%-11.6%, p = 0.056, respectively). CONCLUSIONS: Using the ACS-NSQIP database, we demonstrate the downward trend in rate of ALND for IBC with subsequent decrease in resident participation. Junior residents experienced a significant decrease in their participation with no significant change for senior or fellow-level trainees. Awareness of this trend is important when creating future surgical curriculum changes for general surgery and fellowship training programs.

Restoring anti-oncodriver Th1 responses with dendritic cell vaccines in HER2/neu-positive breast cancer: progress and potential.

HER2/neu is expressed in the majority of in situ breast cancers, but maintained in 20-30% of invasive breast cancer (IBC). During breast tumorigenesis, there is a progressive loss of anti-HER2 CD4(pos) Th1 (anti-HER2Th1) from benign to ductal carcinoma in situ, with almost complete loss in IBC. This anti-HER2Th1 response can predict response to neoadjuvant therapy, risk of recurrence and disease-free survival. Vaccines consisting of HER2-pulsed type I polarized dendritic cells (DC1) administered during ductal carcinoma in situ and early IBC can efficiently correct anti-HER2Th1 response and have clinical impact on the disease. In this review, we will discuss the role of anti-HER2Th1 response in the three phases of immunoediting during HER2 breast cancer development and opportunities for reversing these processes using DC1 vaccines alone or in combination with standard therapies. Correcting the anti-HER2Th1 response may represent an opportunity for improving outcomes and providing a path to eliminate escape variants.

Restoring Lost Anti-HER-2 Th1 Immunity in Breast Cancer: A Crucial Role for Th1 Cytokines in Therapy and Prevention.

The ErbB/B2 (HER-2/neu) oncogene family plays a critical role in the development and metastatic spread of several tumor types including breast, ovarian and gastric cancer. In breast cancer, HER-2/neu is expressed in early disease development in a large percentage of DCIS lesions and its expression is associated with an increased risk of invasion and recurrence. Targeting HER-2 with antibodies such as trastuzumab or pertuzumab has improved survival, but patients with more extensive disease may develop resistance to therapy. Interestingly, response to HER-2 targeted therapies correlates with presence of immune response genes in the breast. Th1 cell production of the cytokines interferon gamma (IFNγ) and TNFα can enhance MHC class I expression, PD-L1 expression, augment apoptosis and tumor senescence, and enhances growth inhibition of many anti-breast cancer agents, including anti-estrogens and HER-2 targeted therapies. Recently, we have identified that a loss of anti-HER-2 CD4 Th1 in peripheral blood occurs during breast tumorigenesis and is dramatically diminished, even in Stage I breast cancers. The loss of anti-HER-2 Th1 response is specific and not readily reversed by standard therapies. In fact, this loss of anti-HER-2 Th1 response in peripheral blood correlates with lack of complete response to neoadjuvant therapy and diminished disease-free survival. This defect can be restored with HER-2 vaccinations in both DCIS and IBC. Correcting the anti-HER-2 Th1 response may have significant impact in improving response to HER-2 targeted therapies. Development of immune monitoring systems for anti-HER-2 Th1 to identify patients at risk for recurrence could be critical to improving outcomes, since the anti-HER-2 Th1 response can be restored by vaccination. Correction of the cellular immune response against HER-2 may prevent recurrence in high-risk patients with DCIS and IBC at risk of developing new or recurrent breast cancer.