Are We Overtreating Patients With T1a HER2+ Breast Cancer? An Analysis of the National Cancer Database.

INTRODUCTION: The potential benefit of systemic therapy in patients with T1a HER2+ cancers is not well understood, and no consensus guidelines exist. We sought to investigate practice patterns of chemotherapy use in this population. METHODS: From the National Cancer Database (2013-2018), we identified female patients with HER2+ cancers staged as cT1aN0 or pT1aN0 and stratified by receipt of chemotherapy. Using univariate and multivariable analyses we assessed the clinicopathologic features associated with the receipt of chemotherapy. We also compared rates of overall survival (OS). RESULTS: Of 5176 women with cT1aN0 HER2+ cancers, 88 (2%) received neoadjuvant chemotherapy. Younger age and hormone-receptor (HR) negative tumors were factors independently associated with receipt of neoadjuvant chemotherapy (all P < .001). Of 11,688 women with pT1aN0 HER2+ cancers, 5,588 (48%) received adjuvant chemotherapy. Rates of use increased over the analysis period from 39% in 2013 to 53% in 2018 (P < .001). Factors independently associated with receipt of adjuvant chemotherapy included younger age, having a poorly differentiated tumor, exhibiting lymphovascular invasion, undergoing adjuvant radiation (all P < .001). There were no differences in OS when comparing those who did and did not receive chemotherapy in either group. CONCLUSIONS: The use of chemotherapy in patients with HER2+ T1a cancers is increasing over time and is, as expected, more common among patients with unfavorable clinicopathologic features. Since no prognostic algorithm currently exists, more prospective data is needed to understand which of these patients may derive benefit from systemic therapy and which may safely avoid the morbidity of chemotherapy.

Utility of Oncotype DX in Male Breast Cancer Patients and Impact on Chemotherapy Administration: A Comparative Study with Female Patients.

BACKGROUND: Use of the Oncotype DX recurrence score (RS) has been widely adopted in women with early-stage hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER-) breast cancer (BC). Validation studies on the use of RS in male BC (MBC) are lacking. OBJECTIVE: The aim of this study was to identify the utilization of RS and association with chemotherapy recommendations in early-stage MBC compared with female BC (FBC). METHODS: Using the National Cancer Database (NCDB), a retrospective review was performed for patients with T1/T2, node-negative, HR+/HER2- BC between 2010 and 2014. Patients were stratified by demographics, tumor characteristics, RS, and chemotherapy use comparing MBC with FBC over the allotted time period. RESULTS: A total of 358,497 patients-3068 (0.8%) males and 355,429 (99.1%) females-met the inclusion criteria. A smaller proportion of MBC patients received RS testing compared with FBC patients (32% vs. 35%, p < 0.001). Male patients who had RS were younger, had T2 tumors, lymphovascular invasion, and private insurance. The distribution of RS was similar in both groups. Only 4% of MBC patients with low RS received adjuvant chemotherapy, compared with 4.9% of FBC patients. Overall chemotherapy rates were similar in MBC and FBC patients. CONCLUSIONS: Our results showed that RS has not been completely embraced in the management of MBC, although when performed in MBC, chemotherapy recommendations vary based on RS. Whether the use of RS affects the clinical outcomes of MBC is unknown. A prospective registry would help clarify and evaluate the impact of RS on clinical outcomes in MBC.

Changing practice patterns of adjuvant radiation among elderly women with early stage breast cancer in the United States from 2004 to 2014.

Randomized controlled trials (RCTs) have challenged the need for routine radiation therapy (RT) in women ≥ age 70 with favorable early stage breast cancer (BC) due to modest improvement in local control and no survival benefit. We studied practice patterns in RT among elderly women in the United States. We analyzed data from the National Cancer Database (NCDB) of women ≥age 70 diagnosed with T1 or T2 and N0 invasive BC treated with breast conservation surgery (BCS) between 2004 and 2014. Patients were divided into four groups: (1) no RT, (2) partial breast irradiation (PBI); (3) hypofractionation (HF); and (4) conventional whole breast RT (CWBI). Univariable and multivariable analyses (MVA) were performed to compare characteristics among the four RT groups. A subgroup analysis of women with favorable disease (T1N0 ER + HER2-) was also performed with similar statistical comparisons. Of the 66,126 meeting eligibility, 9,570 (14.5%) had PBI, 16,340 (24.7%) had HF, and 40,117 (60.7%) had CWBI. Only 99 patients (0.15%) had RT omitted. Omission of RT increased marginally from 0.04% in 2004 to 0.24% in 2014. MVA identified older age (OR 1.18, CI 1.08-1.28), more comorbidities (Charlson-Deyo Score of 1) (OR 3.36, CI 1.29-8.72), and no hormone therapy (OR 22.07, CI 5.79-84.07) as more likely to have RT omitted. The use of HF increased from 3.9% to 47.0%, P < .001 with a concomitant decrease in CWBI from 88% to 41%, P < .001. MVA identified older age, treatment location, and omission of chemotherapy as associated with HF. No significant differences from the larger cohort were found among the T1N0 subgroup analysis. Despite RCT evidence, omission of RT was rare in the United States, suggesting that more effective outreach methods to disseminate clinical guideline information may be needed.

Practice Changing Potential of TAILORx: A Retrospective Review of the National Cancer Data Base from 2010 to 2015.

BACKGROUND: Uncertainty regarding chemotherapy benefit among breast cancer patients with intermediate Oncotype Dx® recurrence scores (RS; 11-25) led to the TAILORx study. We evaluated chemotherapy use in patients with intermediate RS to determine practice change potential based on the TAILORx results. METHODS: National Cancer Data Base patients with hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative, N0 breast cancer were identified and were divided into three groups: Group A, ≤ 50 years of age (RS 11-15); Group B, ≤ 50 years of age (RS 16-25); and Group C, > 50 years of age (RS 11-25). Demographic and clinical factors were compared using Chi square tests and Poisson regression models to determine predictors of chemotherapy receipt. RESULTS: Overall, 37,087 patients met the inclusion criteria, with 6.3% in Group A and 11.7% in Group C having received chemotherapy that may have been avoided based on TAILORx. The majority of Group B (64.7%) did not receive chemotherapy, whereas TAILORx showed potential benefit from treatment. Chemotherapy use decreased over time for all intermediate RS patients. T2 tumors, high grade, and treatment before 2012 increased the likelihood of chemotherapy receipt among both groups. Younger patients with the lower intermediate RS (Group A) were more likely to receive chemotherapy if they had treatment at community or comprehensive centers, whereas moderate grade was also a significant factor to receive chemotherapy in Group B. Significant factors in older patients (Group C) were Black race, estrogen receptor-positive/progesterone receptor-negative, and moderate/high grade. CONCLUSIONS: The most potential impact of TAILORx findings on practice change is for patients ≤ 50 years of age with RS of 16-25 who did not receive chemotherapy but may benefit. These findings may serve as a baseline for future analysis of practice patterns related to TAILORx.

Quality of life and sexual well-being after nipple sparing mastectomy: A matched comparison of patients using the breast Q.

BACKGROUND: Nipple sparing mastectomy (NSM) is considered safe for select patients. Our objective was to examine quality of life (QOL) and satisfaction for NSM compared with skin sparing mastectomy (SSM). We aimed to evaluate these using the BREAST-Q. METHODS: After IRB approval, we analyzed patients who underwent NSM and reconstruction between July 2010-June 2015. NSM patients were matched with those after SSM based on age, race, and body mass index. Telephone interviews were prospectively conducted using the BREAST-Q Mastectomy Postoperative Module. Bivariate analysis and a paired samples t-test were performed. RESULTS: We identified 43 patients meeting our inclusion criteria with a response rate 60% (N = 26). NSM and SSM patients were matched well in age (P = 1.00), race (P = 1.00), and Body Mass Index (P = 0.99). There were no significant differences in stage, estrogen and progesterone status, HER2 expression, reconstruction type and radiation. Mean BREAST-Q scores did not vary between NSM and SSM in regards to satisfaction with breasts (P = 0.604), psychosocial well-being (P = 0.146), physical well-being (P = 0.121), and satisfaction with surgeon (P = 0.170). Sexual well-being was significantly higher in NSM patients (P = 0.011). CONCLUSION: NSM provides patients with favorable results in psychosocial, sexual, and physical well-being and overall satisfaction. Sexual well-being showed significant improvement for NSM.

Impact of Neoadjuvant Chemotherapy on Breast Cancer Subtype: Does Subtype Change and, if so, How? : IHC Profile and Neoadjuvant Chemotherapy.

BACKGROUND: Breast cancer subtype, as determined by the expression of estrogen receptor (ER) and progesterone receptor (PR), together defined as hormone receptor (HR) status, and the HER2/neu receptor (HER2), is important in predicting prognosis and guiding therapy. Knowledge regarding how tumors evolve during treatment and whether subtype is influenced by neoadjuvant chemotherapy (nCT) is limited. The purpose of this study was to compare the HR and HER2 status between core needle biopsy and residual tumor after surgery of breast cancer patients treated with nCT and to evaluate the impact of status change on therapeutic management. METHODS: After institutional review board approval, we performed a retrospective review of all patients with a diagnosis of breast cancer who received nCT and had their initial biopsy and post-nCT surgical specimens evaluated for tumor subtype between January 2009 and December 2014 at our institution. Immunohistochemistry (IHC) of ER, PR, HER2, and fluorescence in situ hybridization for HER2 expression, when indicated, was performed using identical technique and measured by a single pathologist who specializes in breast pathology. Pre- and post-nCT subtype was cross-tabulated to assess change. Standard diagnostic metrics were computed. RESULTS: Fifty-two patients with 54 cancers were identified to have their initial biopsy and post-nCT surgical specimens evaluated for tumor subtype in identical fashion. There was a complete pathologic response after nCT in 23 cancers (42.6%). Residual disease was noted in 31 cancers (57.4%). Five of these (16.1%) had a change in tumor subtype, of which four changes were based on IHC. HR status changed from positive to negative in two cases and from negative to positive in one case. HER2 status changed from positive to negative in one case and from negative to positive in one case. Subtype change led to treatment change in all five cases, with either the addition or discontinuation of adjuvant therapies. CONCLUSIONS: Patients with breast cancer may experience alterations in their tumor subtype after nCT. At our institution, this led to a change in adjuvant treatment in 100% of such patients. This implies that retesting receptor status of residual tumors after nCT should be routinely performed to tailor adjuvant therapy after nCT.

Is Age Trumping Genetic Profiling in Clinical Practice? Relationship of Chemotherapy Recommendation and Oncotype DX Recurrence Score in Patients Aged < 50 Years versus ≥ 50 Years, and Trends Over Time.

BACKGROUND: Oncotype DX (oDX) is used to predict recurrence and indicate response to chemotherapy in patients with early-stage breast cancer (BC). We evaluated the relationship between age (< 50 vs. ≥ 50 years), recurrence score (RS), chemotherapy use, and trends of oDX testing over time. METHODS: Using the National Cancer Database, we identified women with T1/T2, N0, estrogen receptor-positive BC from 2009 to 2014. We stratified patients by age (< 50 and ≥ 50 years) and RS (low: < 18; intermediate: 18-30; and high: > 30), and compared demographics, tumor characteristics, and chemotherapy recommendations. Management trends were also assessed. RESULTS: From 2009 to 2014, a total of 377,725 cases met the eligibility criteria for oDX testing; 115,052 (30.5%) patients had oDX, and 60,804 (16.1%) were < 50 years of age. The majority had low RS and T1N0 disease. Patients < 50 years of age were more likely to be recommended chemotherapy than those ≥ 50 years of age, regardless of RS (p ≤ 0.001), and were more likely to ultimately undergo chemotherapy (p < 0.001). When stratified by year, oDX utilization increased. There was a decreasing trend in chemotherapy recommendations in both the low- and intermediate-RS groups for both age groups (all p = 0.001), with no change in the high-RS group (< 50 years: p = 0.52; ≥ 50 years: p = 0.67). Univariate and multivariate analyses demonstrated that patients < 50 years of age and those with a higher RS were more likely to be recommended chemotherapy (p < 0.001). CONCLUSIONS: The testing of oDX in BC has significantly increased since first implemented. Results from additional studies such as TAILORx will clarify the current discordant practice patterns between low oDX RSs and adjuvant chemotherapy recommendations.

Immunotherapy for Breast Cancer is Finally at the Doorstep: Immunotherapy in Breast Cancer.

BACKGROUND: Although immunotherapy is making rapid inroads as a major treatment method for melanoma, lung, bladder, and hereditary colon cancer, breast cancer (BC) remains one of the tumors yet to experience the cellular immunology explosion despite the fact that heavy lymphocyte responses in breast tumors improve response to therapy and can predict for long-term survival. RESULTS: Immunotherapies in the form of monoclonal antibodies such as trastuzumab and pertuzumab have had an impact on HER2-positive breast cancer (HER2+BC) treatment through antibody-dependent cellular cytotoxicity. Current evidence suggests that checkpoint inhibitors and other cellular therapies are at the doorstep of improving outcomes in triple-negative BC (TNBC) and HER2+BC, especially when combined with standard therapies. CONCLUSIONS: Although this approach has benefitted small numbers of patients to date, numerous clinical trials are underway to define the relative role immunotherapy may play in the treatment of BC.

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.

The impact of preoperative magnetic resonance imaging and lumpectomy cavity shavings on re-excision rate in pure ductal carcinoma in situ-A single institution's experience.

BACKGROUND AND OBJECTIVES: The impact of preoperative magnetic resonance imaging (pMRI) and cavity shave margins (CSM) on re-excision rate (RR) in DCIS is unclear. We investigated whether either modality was associated with RR in DCIS. METHODS: This is a single-institution retrospective study of 295 women undergoing breast conservation surgery for pure DCIS (2010-2013). CSM were the systematic resection of 4-6 margins during lumpectomy whereas selective shave margins (SSM) were the selective resection of 1-3 margins. Patient demographics and clinical characteristics were abstracted. RR was analyzed according to the use of pMRI, SSM, or CSM with respect to three high-volume breast surgeons at our institution. RESULTS: RR was not associated with the use of pMRI (P = 0.87). Any shave margins (P = 0.05), DCIS size (P < 0.001), and DCIS grade (P = 0.14) associated with a lower RR. Of our high-volume surgeons, RR was lower for Surgeon A (P = 0.02). Multivariate analyses showed larger DCIS (OR 1.35, P = 0.005) and practices specific to surgeons B (OR 3.23, P = 0.04) and C (OR 3.57, P = 0.04) increased re-excision odds. CONCLUSIONS: SSM/CSM and pMRI use varied among surgeons. Our results suggested the routine use of CSM, not pMRI, could lower re-excision rate, which highlighted a quality improvement opportunity at our institution.

Evaluating the Risk of Upstaging HER2-Positive DCIS to Invasive Breast Cancer.

BACKGROUND: Overexpression of human epidermal growth factor 2 (HER2) in invasive breast cancer (IBC) is an independent poor prognostic factor. However, the significance of HER2 overexpression in ductal carcinoma in situ (DCIS) is not well defined. The current study assessed the correlation of HER2+ DCIS with the rate of upstaging to IBC on the final pathology. METHODS: The study retrospectively analyzed patients with the diagnosis of DCIS on core needle biopsy (CNB) at the authors' institution from 2009 to 2016. Data were analyzed using two-sample t tests. Multivariate analysis was performed using logistic regression. RESULTS: The study found that HER2+ DCIS had significantly higher rates of upstaging to IBC than HER2- DCIS (odds ratio [OR] 1.89; p = 0.012). In addition, triple-positive disease was more than two times more likely to be upstaged (OR 2.5; p = 0.01), whereas patients with estrogen (ER)-positive, progesterone (PR)-positive, and HER2- diseases were half as likely to be upstaged (OR 0.5; p = 0.04). Upstaging did not differ for patients with triple-negative disease (OR 0.89; p = 0.8). Additionally, patients with HER2+ DCIS were significantly younger regardless of ER/PR status (p = 0.03). The overexpression of HER2 in patients with an initial diagnosis of DCIS on CNB were twice as likely to have IBC on the final pathology as those who did not. CONCLUSION: The results suggest that overexpression of HER2 may serve as a biomarker for risk stratification of patients with DCIS and may help to guide treatment strategies in the future. For institutions in which HER2 testing may be performed on DCIS, patients should be counseled appropriately about the risk of upgrade to IBC.

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

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.

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.