PIM kinase inhibitor AZD1208 in conjunction with Th1 cytokines potentiate death of breast cancer cellsin vitrowhile also maximizing suppression of tumor growthin vivo when combined with immunotherapy.

PIM kinases are over-expressed by a number of solid malignancies including breast cancer, and are thought to regulate proliferation, survival, and resistance to treatment, making them attractive therapeutic targets. Because PIM kinases sit at the nexus of multiple oncodriver pathways, PIM antagonist drugs are being tested alone and in conjunction with other therapies to optimize outcomes. We therefore sought to test the combination of pharmacological PIM antagonism and Th1-associated immunotherapy. We show that the pan PIM antagonist, AZD1208, when combined in vitro with Th1 cytokines IFN-γ and TNF-α, potentiates metabolic suppression, overall cell death, and expression of apoptotic markers in human breast cancer cell lines of diverse phenotypes (HER-2pos/ERneg, HER-2pos/ERpos and triple-negative). Interestingly, AZD1208 was shown to moderately inhibit IFN-γ secretion by stimulated T lymphocytes of both human and murine origin, suggesting some inherent immunosuppressive activity of the drug. Nonetheless, when multiplexed therapies were tested in a murine model of HER-2pos breast cancer, combinations of HER-2 peptide-pulsed DCs and AZD1208, as well as recombinant IFN-γ plus AZD1208 significantly suppressed tumor outgrowth compared with single-treatment and control groups. These studies suggest that PIM antagonism may combine productively with certain immunotherapies to improve responsiveness.

Disseminated cancer cells in breast cancer: Mechanism of dissemination and dormancy and emerging insights on therapeutic opportunities.

Metastatic spread in breast cancer patients is the major driver of cancer-related deaths. A unique subset of cells disseminated from pre-invasive or primary tumor lesions are recognized as the main seeds for metastatic outgrowth. Disseminated cancer cells (DCCs) can migrate to distant organs and settle in a dormant state for a prolonged period until they emerge to overt metastases. Understanding the biology of breast cancer cells dissemination, dormancy and reactivation to form overt metastases has become an important focus. In this review, we discuss the recent advancements of molecular pathways involving breast cancer cell dissemination, role of chemokine-chemokine receptor networks in DCCs migration, DCCs phenotypic heterogeneity and unique genes signatures in tumor dormancy, microenvironmental regulation and specific niches that favors DCCs homing and dormancy. In addition, we also discuss recent findings relating to the role of immune response on DCC dissemination and dormancy. With recent advances in the field of immunotherapy/targeted therapy and its beneficial effects in cancer treatment, this review will focus on their impact on DCCs, reversal of stemness, tumor dormancy and metastatic relapse.

The presentation of brain metastases in melanoma, non-small cell lung cancer, and breast cancer and potential implications for screening brain MRIs.

PURPOSE: This study assessed the presentation and institutional outcomes treating brain metastases (BM) of breast cancer (BC), non-small cell lung cancer (NSCLC), and melanoma origin. METHODS: Patients with brain metastases treated between 2014 and 2019 with primary melanoma, NSCLC, and BC were identified. Overall survival (OS) was calculated from dates of initial BM diagnosis using the Kaplan-Meier method. RESULTS: A total of 959 patients were identified including melanoma (31%), NSCLC (51%), and BC (18%). Patients with BC were younger at BM diagnosis (median age: 57) than NSCLC (65) and melanoma patients (62, p < 0.0001). Breast cancer patients were more likely to present with at least 5 BM (27%) than NSCLC (14%) and melanoma (13%), leptomeningeal disease (23%, 6%, and 6%, p = 0.0004) and receive whole brain radiation therapy (WBRT) (58%, 37%, and 22%, p < 0.0001). There were no differences in surgical resection (24%, 24%, and 29%, p = 0.166). Median OS was shorter for BC patients (9.9, 10.3, and 13.7 months, p = 0.0006). CONCLUSION: Breast cancer patients were more likely to be younger, present with advanced disease, require WBRT, and have poorer OS than NSCLC and melanoma patients. Further investigation is needed to determine which BC patients are at sufficient risk for brain MRI screening.

Evolving management of HER2+ breast cancer brain metastases and leptomeningeal disease.

Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer are at a particularly high risk of breast cancer brain metastasis (BCBM) and leptomeningeal disease (LMD). Improvements in systemic therapy have translated to improved survival for patients with HER2-positive BCBM and LMD. However, the optimal management of these cases is rapidly evolving and requires a multidisciplinary approach. Herein, a team of radiation oncologists, medical oncologists, neuro-oncologists, and breast surgeon created a review of the evolving management of HER2-positive BCBM and LMD. We assess the epidemiology, diagnosis, and evolving treatment options for patients with HER2-positive BCBM and LMD, as well as the ongoing prospective clinical trials enrolling these patients. The management of HER2-positive BCBM and LMD represents an increasingly common challenge that involves the coordination of local and systemic therapy. Advances in systemic therapy have resulted in an improved prognosis, and promising targeted therapies currently under prospective investigation have the potential to further benefit these patients.

Th1 cytokine interferon gamma improves response in HER2 breast cancer by modulating the ubiquitin proteasomal pathway.

HER2 breast cancer (BC) remains a significant problem in patients with locally advanced or metastatic BC. We investigated the relationship between T helper 1 (Th1) immune response and the proteasomal degradation pathway (PDP), in HER2-sensitive and -resistant cells. HER2 overexpression is partially maintained because E3 ubiquitin ligase Cullin5 (CUL5), which degrades HER2, is frequently mutated or underexpressed, while the client-protective co-chaperones cell division cycle 37 (Cdc37) and heat shock protein 90 (Hsp90) are increased translating to diminished survival. The Th1 cytokine interferon (IFN)-γ caused increased CUL5 expression and marked dissociation of both Cdc37 and Hsp90 from HER2, causing significant surface loss of HER2, diminished growth, and induction of tumor senescence. In HER2-resistant mammary carcinoma, either IFN-γ or Th1-polarizing anti-HER2 vaccination, when administered with anti-HER2 antibodies, demonstrated increased intratumor CUL5 expression, decreased surface HER2, and tumor senescence with significant therapeutic activity. IFN-γ synergized with multiple HER2-targeted agents to decrease surface HER2 expression, resulting in decreased tumor growth. These data suggest a novel function of IFN-γ that regulates HER2 through the PDP pathway and provides an opportunity to impact HER2 responses through anti-tumor immunity.

Capecitabine and stereotactic radiation in the management of breast cancer brain metastases.

BACKGROUND: Little is known about the safety and efficacy of concurrent capecitabine and stereotactic radiotherapy in the setting of breast cancer brain metastases (BCBM). METHODS: Twenty-three patients with BCBM underwent 31 stereotactic sessions to 90 lesions from 2005 to 2019 with receipt of capecitabine. The Kaplan-Meier method was used to calculate overall survival (OS), local control (LC), and distant intracranial control (DIC) from the date of stereotactic radiation. Imaging was independently reviewed by a neuro-radiologist. RESULTS: Median follow-up from stereotactic radiation was 9.2 months. Receptor types of patients treated included triple negative (n = 7), hormone receptor (HR)+/HER2- (n = 7), HR+/HER2+ (n = 6), and HR-/HER2+ (n = 3). Fourteen patients had stage IV disease prior to BCBM diagnosis. The median number of brain metastases treated per patient was 3 (1 to 12). The median dose of stereotactic radiosurgery (SRS) was 21 Gy (range: 15-24 Gy) treated in a single fraction and for lesions treated with fractionated stereotactic radiation therapy (FSRT) 25 Gy (24-30 Gy) in a median of 5 fractions (range: 3-5). Of the 31 stereotactic sessions, 71% occurred within 1 month of capecitabine. No increased toxicity was noted in our series with no cases of radionecrosis. The 1-year OS, LC, and DIC were 46, 88, and 30%, respectively. CONCLUSIONS: In our single institution experience, we demonstrate stereotactic radiation and capecitabine to be a safe treatment for patients with BCBM with adequate LC. Further study is needed to determine the potential synergy between stereotactic radiation and capecitabine in the management of BCBM.

Trastuzumab Emtansine (T-DM1) and stereotactic radiation in the management of HER2+ breast cancer brain metastases.

BACKGROUND: Due to recent concerns about the toxicity of trastuzumab emtansine (T-DM1) with stereotactic radiation, we assessed our institutional outcomes treating HER2-positive breast cancer brain metastases (BCBM) with T-DM1 and stereotactic radiation. METHODS: This is a single institution series of 16 patients with HER2-positive breast cancer who underwent 18 stereotactic sessions to 40 BCBM from 2013 to 2019 with T-DM1 delivered within 6 months. The Kaplan-Meier method was used to calculate overall survival (OS), local control (LC), distant intracranial control (DIC), and systemic progression-free survival (sPFS) from the date of SRS. A neuro-radiologist independently reviewed follow-up imaging. RESULTS: One patient had invasive lobular carcinoma, and 15 patients had invasive ductal carcinoma. All cases were HER2-positive, while 10 were hormone receptor (HR) positive. Twenty-four lesions were treated with stereotactic radiosurgery (SRS) to a median dose of 21 Gy (14-24 Gy). Sixteen lesions were treated with fractionated stereotactic radiation (FSRT) with a median dose of 25 Gy (20-30Gy) delivered in 3 to 5 fractions. Stereotactic radiation was delivered concurrently with T-DM1 in 19 lesions (48%). Median follow up time was 13.2 months from stereotactic radiation. The 1-year LC, DIC, sPFS, and OS were 75, 50, 30, and 67%, respectively. There was 1 case of leptomeningeal progression and 1 case (3%) of symptomatic radionecrosis. CONCLUSIONS: We demonstrate that stereotactic radiation and T-DM1 is well-tolerated and effective for patients with HER2-positive BCBM. An increased risk for symptomatic radiation necrosis was not noted in our series.

Breast cancer subtype predicts clinical outcomes after stereotactic radiation for brain metastases.

PURPOSE: We investigated the prognostic ability of tumor subtype for patients with breast cancer brain metastases (BCBM) treated with stereotactic radiation (SRT). METHODS: This is a retrospective review of 181 patients who underwent SRT to 664 BCBM from 2004 to 2019. Patients were stratified by subtype: hormone receptor (HR)-positive, HER2-negative (HR+/HER2-), HR-positive, HER2-positive (HR+/HER2+), HR-negative, HER2-positive (HR-/HER2+), and triple negative (TN). The Kaplan-Meier method was used to calculate overall survival (OS), local control (LC), and distant intracranial control (DIC) from the date of SRT. Multivariate analysis (MVA) was conducted using the Cox proportional hazards model. RESULTS: Median follow up from SRT was 11.4 months. Of the 181 patients, 47 (26%) were HR+/HER2+, 30 (17%) were HR-/HER2+, 60 (33%) were HR+/HER2-, and 44 (24%) were TN. Of the 664 BCBMs, 534 (80%) received single fraction stereotactic radiosurgery (SRS) with a median dose of 21 Gy (range 12-24 Gy), and 130 (20%) received fractionated stereotactic radiation therapy (FSRT), with a median dose of 25 Gy (range 12.5-35 Gy) delivered in 3 to 5 fractions. One-year LC was 90%. Two-year DIC was 35%, 23%, 27%, and 16% (log rank, p = 0.0003) and 2-year OS was 54%, 47%, 24%, and 12% (log rank, p < 0.0001) for HR+/HER2+, HR-/HER2+, HR+/HER2-, and TN subtypes, respectively. On MVA, the TN subtype predicted for inferior DIC (HR 1.62, 95% CI 1.00-2.60, p = 0.049). The modified breast-Graded Prognostic Assessment (GPA) significantly predicted DIC and OS (both p < 0.001). CONCLUSIONS: Subtype is prognostic for OS and DIC for patients with BCBM treated with SRT.

Management of brain metastases in breast cancer: a review of current practices and emerging treatments.

PURPOSE: Breast cancer brain metastases (BCBM) are becoming an increasingly common diagnosis due to improved systemic control and more routine surveillance imaging. Treatment continues to require a multidisciplinary approach managing systemic and intracranial disease burden. Although, improvements have been made in the diagnosis and management of BCBM, brain metastasis patients continue to pose a challenge for practitioners. METHODS: In this review, a group of medical oncologists, radiation oncologists, radiologists, breast surgeons, and neurosurgeons specializing in the treatment of breast cancer reviewed the available published literature and compiled a comprehensive review on the current state of BCBM. RESULTS: We discuss the pathogenesis, epidemiology, diagnosis, treatment options (including systemic, surgical, and radiotherapy treatment modalities), and treatment response evaluation for BCBM. Furthermore, we discuss the ongoing prospective trials enrolling BCBM patients and their biologic rationale. CONCLUSIONS: BCBM management is an increasing clinical concern. Multidisciplinary management combining the strengths of surgical, systemic, and radiation treatment modalities with prospective trials incorporating knowledge from the basic and translational sciences will ultimately lead to improved clinical outcomes for BCBM patients.

Breast leptomeningeal disease: a review of current practices and updates on management.

PURPOSE: Leptomeningeal disease (LMD) is an advanced metastatic disease presentation portending a poor prognosis with minimal treatment options. The advent and widespread use of new systemic therapies for metastatic breast cancer has improved systemic disease control and extended survival; however, as patients live longer, the rates of breast cancer LMD are increasing. METHODS: In this review, a group of medical oncologists, radiation oncologists, radiologists, breast surgeons, and neurosurgeons specializing in treatment of breast cancer reviewed the available published literature and compiled a comprehensive review on the current state of breast cancer LMD. RESULTS: We discuss the pathogenesis, epidemiology, diagnosis, treatment options (including systemic, intrathecal, surgical, and radiotherapy treatment modalities), and treatment response evaluation specific to breast cancer patients. Furthermore, we discuss the controversies within this unique clinical setting and identify potential clinical opportunities to improve upon the diagnosis, treatment, and treatment response evaluation in the management of breast LMD. CONCLUSIONS: We recognize the shortcomings in our current understanding of the disease and explore the future role of genomic/molecular disease characterization, technological innovations, and ongoing clinical trials attempting to improve the prognosis for this advanced disease state.

Clinical outcomes of breast leptomeningeal disease treated with intrathecal trastuzumab, intrathecal chemotherapy, or whole brain radiation therapy.

PURPOSE: Leptomeningeal disease is a rare presentation of advanced metastatic breast cancer. The purpose of this study was to evaluate craniospinal progression between intrathecal (IT) trastuzumab, IT chemotherapy, and whole brain radiation therapy (WBRT) in leptomeningeal disease. METHODS: A total of 56 patients were identified with breast cancer leptomeningeal disease at our institution treated with IT trastuzumab (n = 18; 32%), single-agent IT chemotherapy (methotrexate n = 14 or thiotepa n = 1; 27%), or WBRT alone (n = 23; 41%). Patients were treated beginning November 2012 and followed until November 2018. RESULTS: Median time from breast cancer diagnosis to development of leptomeningeal disease was 4.3 years. There were no significant differences noted between IT trastuzumab, IT chemotherapy, or WBRT groups in age (p = 0.4), Karnofsky Performance Status (KPS) (p = 0.07), or receipt of systemic therapy at time of leptomeningeal disease treatment (p = 0.47). Median follow-up of patients from leptomeningeal diagnosis was 5 months (range 0.2-81.1 months). Significant differences were noted in Kaplan-Meier (KM) craniospinal progression-free survival (CS-PFS) with 6-month rates of 44%, 18%, and 26% (p = 0.04) between IT trastuzumab, IT chemotherapy, and WBRT, respectively. Craniospinal control > 10 months was achieved in four patients treated with IT trastuzumab. Twelve-month KM OS rates were 54%, 10%, and 19% (p = 0.01) between IT trastuzumab, IT chemotherapy, and WBRT groups, respectively. IT therapy was adequately tolerated with three patients undergoing treatment-related hospitalizations. CONCLUSIONS: In our institutional series, significant differences were noted in CS-PFS and OS by treatment modality. IT trastuzumab should be considered in the management HER2+ breast leptomeningeal disease.

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.

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.

Transected thin melanoma: Implications for sentinel lymph node staging.

BACKGROUND AND OBJECTIVES: Indications for sentinel lymph node (SLN) biopsy in patients with thin melanoma (≤1 mm thick) are controversial. We asked whether deep margin (DM) positivity at initial biopsy of thin melanoma is associated with SLN positivity. METHODS: Cases were identified using prospectively maintained databases at two melanoma centers. Patients who had undergone SLN biopsy for melanoma ≤1 mm were included. DM status was assessed for association with SLN metastasis in univariate and multivariate analyses. RESULTS: 1413 cases were identified, but only 1129 with known DM status were included. 39% of patients had a positive DM on original biopsy. DM-positive and DM-negative patients did not differ significantly in primary thickness, ulceration, or mitotic activity. DM-positive and DM-negative patients had similar incidence of SLN metastasis (5.7% vs 3.5%; P = 0.07). Positive DM was not associated with SLN metastasis on univariate analysis (OR 1.69, 95% CI: 0.95-3.00, P = 0.07) or on multivariate analysis adjusted for Breslow depth, Clark level, mitotic rate, and ulceration (OR = 1.59, 95% CI: 0.89-2.85; P = 0.12). CONCLUSIONS: For patients with thin melanoma, a positive DM on initial biopsy is not associated with risk of SLN metastasis, so DM positivity should not be considered an indication for SLN staging in an otherwise low-risk patient.

Histological immune response patterns in sentinel lymph nodes involved by metastatic melanoma and prognostic significance.

BACKGROUND: To further characterize the micromorphometric immunological pattern to metastatic melanoma in sentinel lymph node (SLN) biopsies and completion lymph node (CLN) dissections and their relation to 5-year overall survival (OS). METHODS: Retrospective cohort of 49 patients from 1996 to 2005 with a positive SLN who underwent CLN dissection (CLD) was studied. Micromorphometric characteristics included follicular center count (FCC)/profile, sinus histiocytosis, metastatic size, tumor infiltrating lymphocytes (intranodal), paracortical dendritic cells, germinal center reaction and morphology. Comparison of Kaplan-Meier survival curves used the exact log-rank statistic. RESULTS: In the high-FCC (n = 5-51) vs the low-FCC (n < 5) lymph nodes, a delayed separation occurred at 3 years, with 5-year OS rates being 73% vs 54% in the high- and low-FCC groups, respectively. Improved survival up to 3 years was also noted in CLDs that showed a higher FCC when compared to the prior SLN. Patients with metastatic deposits >2 mm had significantly lower 5-year survival (both <.001). CONCLUSIONS: Nodal micromorphometric features (ie, FCC) are probably related to host immune response to metastasis. Quantitative evaluation of lymphoid follicular centers could provide valuable prognostic information to help to stratify patients.

Neoadjuvant radiotherapy of early-stage breast cancer and long-term disease-free survival.

BACKGROUND: Compared with surgery alone, postoperative adjuvant radiotherapy (RT) improves relapse-free survival of patients with early-stage breast cancer. We evaluated the long-term overall and disease-free survival rates of neoadjuvant (presurgical) versus adjuvant RT in early-stage breast cancer patients. METHODS: We used the Surveillance, Epidemiology, and End Results (SEER) database provided by the National Institutes of Health to derive an analytic dataset of 250,195 female patients with early-stage breast cancer who received RT before (n = 2554; 1.02%) or after (n = 247,641; 98.98%) surgery. Disease-free survival, defined as time to diagnosis of a second primary tumor at any location, was calculated from automated patient identification matching of all SEER records. RESULTS: Partial and complete mastectomies were performed in 94.4% and 5.6% of patients, respectively. In the largest cohort of estrogen receptor-positive women who underwent partial mastectomy, the HR of developing a second primary tumor after neoadjuvant compared with adjuvant RT was 0.64 (95% CI 0.55-0.75; P < 0.0001). Overall survival was independent of radiation sequence (HR 1; P = 0.95). Neoadjuvant RT also resulted in a lower HR for second primary cancer among estrogen receptor-positive patients who underwent mastectomy compared with those who received adjuvant RT (HR 0.48, 95% CI 0.26-0.87; P = 0.0162). CONCLUSIONS: Neoadjuvant RT may significantly improve disease-free survival without reducing overall survival, especially for estrogen receptor-positive patients with early-stage breast cancer. This finding warrants further exploration of potential long-term benefits of neoadjuvant radiotherapy for early-stage breast cancer in a controlled, prospective clinical trial setting, with correlative studies done to identify potential mechanisms of superiority.

Loss of Anti-HER-3 CD4+ T-Helper Type 1 Immunity Occurs in Breast Tumorigenesis and is Negatively Associated with Outcomes.

BACKGROUND: We previously demonstrated a progressive loss of the anti-human epidermal growth factor receptor 2 (HER2) CD4+ T-helper type 1 (Th1) response during HER2pos breast tumorigenesis. This loss is associated with residual disease following neoadjuvant therapy and increased risk of recurrence. In this study, we assessed the fate of anti-HER3 Th1 immunity during breast tumorigenesis. METHODS: Peripheral blood from 131 subjects, including healthy donors (HDs), patients with benign breast disease (BD), ductal carcinoma in situ (DCIS) and invasive breast cancer (IBC), was collected. Interferon (IFN)-γpos immune responses to four HER3-derived major histocompatibility complex (MHC) class II promiscuous peptides were tested via enzyme-linked immunosorbent (ELISPOT) assays, and three immune response parameters were compared: anti-HER3 (i) responsivity, or proportion of subjects responding to at least one peptide; (ii) repertoire, or number of responding peptides; and (iii) cumulative response, or summed peptide response. RESULTS: A significant decline in anti-HER3 Th1 response was observed going from HDs to IBC patients; patients with triple-negative breast cancer (TNBC) demonstrated the lowest responses. HDs had significantly higher Th1 responses versus estrogen receptor (ER)pos IBC and TNBC patients across all three immune parameters; HER2pos IBC patients displayed responses similar to HDs and BDs. Patients with recurrent breast cancer and residual disease following neoadjuvant therapy demonstrated significantly lower anti-HER3 Th1 immunity compared with patients without recurrence or with a pathologic complete response to neoadjuvant therapy. CONCLUSIONS: Anti-HER3 CD4+ Th1 responses decline during breast tumorigenesis, particularly in TNBC. Attempts to immunologically restore depressed responses in vulnerable subgroups may help mitigate recurrence.

Thin Melanoma with Nodal Involvement: Analysis of Demographic, Pathologic, and Treatment Factors with Regard to Prognosis.

BACKGROUND: Although only a small proportion of thin melanomas result in lymph node metastasis, the abundance of these lesions results in a relatively large absolute number of patients with a diagnosis of nodal metastases, determined by either sentinel lymph node (SLN) biopsy or clinical nodal recurrence (CNR). METHODS: Independent cohorts with thin melanoma and either SLN metastasis or CNR were identified at two melanoma referral centers. At both centers, SLN metastasis patients were included. At center 1, the CNR cohort included patients with initial negative clinical nodal evaluation followed by CNR. At center 2, the CNR cohort was restricted to those presenting in the era before the use of SLN biopsy. Uni- and multivariable analyses of melanoma-specific survival (MSS) were performed. RESULTS: At center 1, 427 CNR patients were compared with 91 SLN+ patients. The 5- and 10-year survival rates in the SLN group were respectively 88 and 84 % compared with 72 and 49 % in the CNR group (p < 0.0001). The multivariate analysis showed age older than 50 years (hazard ratio [HR] 1.5; 95 % confidence interval [CI] 1.2-1.9), present ulceration (HR 1.9; 95 % CI 1.2-2.9), unknown ulceration (HR 1.6; 95 % CI 1.3-2.1), truncal site (HR 1.6; 95 % CI 1.2-2.2), and CNR (HR 3.3; 95 % CI 1.8-6.0) to be associated significantly with decreased MSS (p < 0.01 for each). The center 2 cohort demonstrated remarkably similar findings, with a 5-year MSS of 88 % in the SLN (n = 29) group and 76 % in the CNR group (n = 39, p = 0.09). CONCLUSION: Patients with nodal metastases from thin melanomas have a substantial risk of melanoma death. This risk is lower among patients whose disease is discovered by SLN biopsy rather than CNR.

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

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.