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BACKGROUND: Studies have consistently demonstrated that breast cancers arise in the left breast more often than the right breast, but no factors have been able to account for this. Some studies have shown age younger than 45 years and late age at menarche to be associated with somewhat higher incidence of cancer in the right breast. However, most of these studies were conducted in the 1990s. We sought to determine if demographic factors, pathologic findings, or treatment impact laterality. METHODS: We performed a single-institution IRB-approved retrospective chart review of US female breast cancer patients diagnosed with DCIS (stage 0) or stages I-III breast cancer from 1997 to April 2020. Clinicopathologic characteristics, demographic, and treatment information were collected. Statistical analyses evaluated differences in laterality. Association between laterality and continuous variables was determined using Kruskal-Wallis test. Association of laterality and categorical variables was determined using Chi-square test or Fisher exact test if applicable. RESULTS: 5328 female patients with 5474 breast cancers were evaluated with a median age of 60 years old. Majority of tumors were stage T1(2542, 54.4%) and 75% were IDC. Overall left-sided cancer showed a predominance (2797, 51.1%). Breast cancer laterality was not significantly associated with grade, receptor status, tumor size, pathologic type, or recurrent tumors. Laterality was evaluated regarding age, based on age less than 61 years old versus greater than or equal to age 61. Laterality was significantly associated with age overall with an increase in left-sided breast cancers (2797 vs 2677, p=0.029). Left-sided breast cancer was significantly increased in women greater than or equal to age 61, 1456 (53%) vs right-sided 1290 (47%). Whereas, right-sided breast cancer was significantly associated with age less than 61, (1387, 50.8% vs left 1341, 49.2%, p=0.004). CONCLUSION: Our analysis confirms prior studies that overall left-sided breast cancer is more common in women. However, there are age differences with left-sided breast cancers more prevalent in older age women greater than or equal to age 61. On the other hand, right-sided breast cancer was seen more often in women under the age of 61. Further studies are needed to better ascertain why the overall laterality of breast cancer occurs more frequently in the left breast, but also to determine an explanation for the laterality age differences. Anatomical factors such as blood supply, breast size, inherited genetic mutations, tumor genomics, lactation history and others are possible factors that need to be further explored. Studies are ongoing. This information will be potentially helpful in allocating diagnostic and therapeutic resources for breast cancer patients. Citation Format: Kelly Elleson, Gerald H. Sokol, Weihong Sun, Junmin Whiting, Marie C. Lee, Brian J. Czerniecki, Loretta Loftus. Breast cancer laterality: Is age a factor? [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-05-29.

Background: HER2-positive versus HER2-negative ductal carcinoma in situ (DCIS) of the breast has been associated with an increased risk of local recurrence after breast-conserving surgery (BCS) and radiotherapy (RT). In recognition of this, the NASBP-B43 trial was designed to determine if two doses of trastuzumab would improve local control with BCS plus RT in HER2-positive DCIS. The trial demonstrated a non-statistically significant advantage with the addition of trastuzumab in reducing ipsilateral breast recurrence (IBR). The predictive 7-gene DCIS biosignature, DCISionRT with Residual Risk Subtype (PreludeDxTM, Laguna Hills, CA) has been shown to classify DCIS patients into two distinct groups of patients with substantially different rates of IBR following BCS plus RT. Based upon these differences in outcome, we assessed the IBR rate in patients with HER2(+) DCIS treated with BCS and RT who were or were not in the Residual Risk Subtype group defined using DCISionRT, while accounting for the varying clinicopathologic profile of the patients. Materials & Methods: DCISionRT was evaluated in a subset of 178 women with HER2(+) DCIS treated with BCS and RT as part of a multinational cohort of 926 patients from the United States, Sweden, and Australia, who were used in the validation studies for DCISionRT. Central pathology review and biosignature testing were performed at a CLIA-certified lab (Laguna Hills, CA). HER2(+) DCIS was defined as patients with a HER2(3+) immunohistochemistry >10% per ASCO/CAP guidelines. The IBR rate was calculated for the overall group of HER2(+) patients and those in the Residual Risk group. Individual patient outcome and biosignature results were analyzed using Kaplan Meier and Cox Proportional Hazard analyses. Results: The biosignature classified 113 of the 178 (63%) HER2(+) women into the Residual Risk group (DS>2.8 with RRt). Patients in the Residual Risk group had a significantly greater IBR (HR=8.3; 95%CI: 1.1,50, p=.012) over 10-years, with a corresponding 10-year total IBR rate of 16.2% (95%CI: 9.7%, 26.5%) versus 1.6% (95%CI: 0.2%, 10.9%) for all other HER2(+) patients. In univariate analysis, younger patients tended to have higher IBR rate after BCS plus RT, but only Residual Risk was significantly associated with IBR rate after BCS plus RT. Moreover, multivariable analysis demonstrated that the Residual Risk group was eight times more likely to recur after BCS and RT, while clinicopathologic factors (age, grade, tumor size) were not associated with higher IBR rates. Conclusion: The DCISionRT Residual Risk group was predictive for 10-year IBR risk after BCS plus RT in women with HER2(+) DCIS. Approximately 40% of patients with HER2(+) DCIS would be expected to achieve low rates of recurrence with BCS and RT, while about 60% of these women (classified in the Residual Risk group) would have higher recurrence rates and may benefit from further therapy, such as HER2-directed therapies. These findings suggest that if the results of the B43 trial were re-analyzed using the predictive 7-gene biosignature (DCISionRT with Residual Risk Subtype), better clarity could be gained on the true impact of trastuzumab on IBR rates in patients with HER2(+) DCIS and the patients most likely to benefit from this additional therapy. Table 1. Univariate and Multivariable Cox Proportional Hazards Analyses. Citation Format: Frank Vicini, Chirag Shah, Rachel Rabinovitch, Pat Whitworth, Julie A. Margenthaler, Brian J. Czerniecki, DAVID J. DABBS, Sheila Weinmann, Michael Leo, G Bruce Mann, Fredrik Wärnberg, jess Savala, Steven C. Shivers, Karuna Mittal, Troy Bremer. Characterization of recurrence risk after lumpectomy and radiotherapy in HER2-positive ductal carcinoma in situ of the breast, using 7-gene predictive biosignature: Implications for the NSABP-B43 trial results [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-04-06.

Background: As systemic therapy improves, there has been an increasing number of breast cancer patients who develop brain metastasis. Screening of asymptomatic stage IV breast cancer patients with brain MRIs is not currently recommended by the National Comprehensive Cancer Network (NCCN) Guidelines. Retrospective reports suggest breast cancer patients are more likely to present with more advanced central nervous system disease at the time of brain metastasis diagnosis compared to melanoma and non-small cell lung cancer (NSCLC) patients. This may be in part due to routine screening recommendations in melanoma and NSCLC. Early detection and treatment of brain metastases may improve outcomes for breast cancer patients. Trial Design: The study is designed as a single arm, nonrandomized phase II study, with the goal of investigating the role of screening brain MRIs in neurologically asymptomatic patients with metastatic breast cancer. Breast cancer patients will be allocated based on receptor subtypes into triple negative (TN), HER2+, and hormone receptor (HR)+/HER2- breast cancer. Following study enrollment, patients will undergo a screening brain MRI. Patients will undergo a second brain MRI at first systemic progression or at 6 months whichever event occurs sooner. Eligibility: Asymptomatic, stage IV breast cancer patients that have progressed past first line therapy in the metastatic setting with an ECOG/= 6 months are eligible. Specific Aims: The primary objective is to determine the incidence of asymptomatic brain metastasis in metastatic breast cancer by subtype. Secondary objectives include determining the incidence of asymptomatic leptomeningeal disease, the number and size of brain metastases at diagnosis, the number of patients requiring whole brain radiation therapy vs. stereotactic radiation following diagnosis and overall survival and brain metastasis specific survival following brain metastasis diagnosis in metastatic breast cancer by subtype. Statistical Methods: A total of 30, 30, and 40 TN, HER2+, and HR+/HER2-, breast cancer patients will be enrolled, respectively. Using an incidence rate of 17%, the 95% CI by subtype will be (0.06,0.351), (0.06,0.351), and (0.07,0.322). Patient Accrual: This study is open with 30 patients enrolled at the time of submission. A total of 100 patients will be enrolled. Contact Information: Kamran A. Ahmed MD, Moffitt Cancer Center, email: kamran.ahmed@moffitt.org, Clinical trial information: NCT05115474. Funding: Florida Breast Cancer Foundation. Citation Format: Kamran A. Ahmed, Youngchul Kim, Avan Armaghani, John Arrington, Ricardo Costa, Brian J. Czerniecki, Roberto Diaz, Peter A. Forsyth, Hung Khong, Kimberley Lee, Loretta Loftus, Marilin Rosa, Hatem H. Soliman, Iman Washington, Aixa Soyano, Hyo S. Han. Phase II Study of Screening Brain MRIs in Stage IV Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-19-01.

Background: Prognostic and predictive tools are needed to optimize treatment for women diagnosed with ductal carcinoma in situ (DCIS). While radiotherapy (RT) is standard of care for DCIS after breast conserving surgery (BCS), those at low-risk for ipsilateral breast recurrence (IBR) risk may be treated without RT. Low-risk has been defined as the absence of high risk clinicopathologic (CP) factors, including larger (>2 cm), palpable, or high nuclear grade (NG) tumors, and younger age (< 50 yrs). However, prospective trials have failed to identify low risk patients (pts) who do not clinically benefit from RT after BCS (RTOG 9804). DCISionRT® (PreludeDxTM, CA) is a 7-gene predictive biosignature providing a validated score (DS) to assess the 10-yr IBR risk and RT benefit, using individual tumor biology and CP factors. This study assessed total 10-yr IBR rates, RT benefit, and number needed to treat (NNT) for risk groups defined by biosignature and CP criteria. Methods: DCIS patients (n=926) from four international cohorts (median follow up 8.5 yrs, 1-3rd quartile 5.8 – 10.2 yrs) treated with BCS (negative margins), with (n=641) and without RT (n=335), had formalin-fixed paraffin-embedded tissues analyzed at a CLIA lab (PreludeDx, Laguna Hills, CA) for DCISionRT with a Residual Risk subtype (RRt). A biosignature Low Risk group (DS≤2.8 without RRt) was contrasted to a High Risk group comprising Elevated Risk (DS>2.8 without RRt) and Residual Risk (DS>2.8 with RRt) groups. Low-risk CP groups were RTOG 9804-like (NG1-2, non-palpable, negative margins, screening detected) or (age >50 and NG 1-2). Total 10-yr IBR rates were evaluated using Cox Proportional Hazards and Kaplan Meier analysis by treatment, biosignature and CP risk groups. NNT was determined with 10-yr IBR rate differences with RT. Results: The biosignature classified 37% (n=338) of women as Low Risk and 63% (n=588) as High Risk. Among women who did not receive RT, biosignature Low Risk pts had lower IBR than biosignature High Risk pts (5.6% vs. 25.7%, p Conclusion: In a large multicenter population, DCISionRT was a better predictor of 10-yr prognosis and RT benefit than CP criteria alone. Pts with biosignature Low Risk disease, comprising about 1/3 of CP high-risk pts, had no significant RT benefit. Whereas pts with biosignature High Risk disease, comprising about 1/2 of CP low-risk pts, significantly benefited from RT, highlighting the lack of accuracy of these CP factors in assessing RT benefit. Table 1. Ten-Year Risk of Ipsilateral Breast Recurrence (IBR) Citation Format: Rachel Rabinovitch, Frank Vicini, Chirag Shah, Julie A. Margenthaler, Brian J. Czerniecki, Pat Whitworth, DAVID J. DABBS, G Bruce Mann, Fredrik Wärnberg, Sheila Weinmann, Michael Leo, Jess Savala, Steven C. Shivers, Karuna Mittal, Troy Bremer. PD15-07 7-gene predictive biosignature improves risk stratification for breast ductal carcinoma in situ patients compared to clinicopathologic criteria, identifying a low risk group not clinically benefiting from adjuvant radiotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD15-07.

Background: Breast cancer patients with brain metastases have a high unmet clinical need and improved management strategies are needed. There has been interest in studying CDK 4/6 inhibitors in the management of breast cancer brain metastases. A phase II study has shown abemaciclib to have activity in the management of hormone receptor (HR)+/HER2- brain metastases. Pre-clinical data suggests a potential synergy with CDK inhibitors and radiation therapy. Stereotactic radiosurgery (SRS) is a cornerstone in the management of limited brain metastases. We hypothesize treatment with abemaciclib and SRS will be safe and improve intracranial progression free survival (PFS) compared to abemaciclib alone. Trial Design: The study is designed as a prospective, single-arm, nonrandomized, open-label, phase I/II trial of abemaciclib and endocrine therapy with SRS among patients with HR+/HER2- metastatic breast cancer brain metastases. Treatment will be initiated with one week of abemaciclib followed by stereotactic radiation to sites of brain metastases or post-operative cavities with continued abemaciclib. Safety will be monitored initially by a 3+3 design. If unexpected neurologic toxicities are noted, the dose of radiation therapy will be reduced. This will be followed by a phase II study to evaluate intracranial PFS. Eligibility: Eligible patients include those that are HR+/HER2-, ≥18, ECOG ≤2 with ≤15 breast cancer brain metastases with measurable disease per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Specific Aims: The primary objective of the phase I study is to evaluate the safety and feasibility of abemaciclib and SRS to sites of brain metastases in the management of HR+/HER2- metastatic breast cancer with brain metastases. The primary objective of the phase II portion is to determine PFS intracranially. Secondary objectives include evaluation of extracranial PFS, local and distant intracranial control, and overall survival. Statistical Methods: Safety and feasibility will be monitored in the phase I study using a 3 + 3 design followed by a phase II study to assess intracranial PFS. The phase II study is designed as a single-arm, two-stage trial using the Restricted-Kwak-and-Jung’s method. In the first stage, a total of 21 patients will be enrolled. If pre-specified endpoints are met, an additional 10 patients will be enrolled in the second stage. Patient Accrual: A total of up to 31 patients will be enrolled inclusive of patients in the phase I portion treated at the recommended phase II dose. Clinical trial information: NCT04923542. Citation Format: Kamran A. Ahmed, Youngchul Kim, Michelle DeJesus, Sasha J. Beyer, Nicole O. Williams, Joshua Palmer, Kristina D. Woodhouse, Rashmi K. Murthy, Jing Li, Avan J. Armaghani, John A. Arrington, Ricardo L. Costa, Brian J. Czerniecki, Arnold B. Etame, Peter A. Forsyth, Hung T. Khong, Daniel E. Oliver, Marilin Rosa, Solmaz Sahebjam, Hatem H. Soliman, Aixa E. Soyano, Michael A. Vogelbaum, Michael Yu, Hyo S. Han. Phase I/II study of stereotactic radiation and abemaciclib in the management of hormone receptor positive HER2 negative breast cancer brain metastases [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-09-01.

Immunotherapy (IT) and targeted therapy (TT) are both effective against melanoma, but their combination is frequently toxic. Here, we investigated whether the sequence of IT (anti–PD-1)→ TT (ceritinib–trametinib or dabrafenib–trametinib) was associated with improved antitumor responses in mouse models of BRAF- and NRAS-mutant melanoma. Mice with NRAS-mutant (SW1) or BRAF-mutant (SM1) mouse melanomas were treated with either IT, TT, or the sequence of IT→TT. Tumor volumes were measured, and samples from the NRAS-mutant melanomas were collected for immune-cell analysis, single-cell RNA sequencing (scRNA-seq), and reverse phase protein analysis (RPPA). scRNA-seq demonstrated that the IT→TT sequence modulated the immune environment, leading to increased infiltration of T cells, monocytes, dendritic cells and natural killer cells, and decreased numbers of tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells. Durable responses to the IT→TT sequence were dependent on T-cell activity, with depletion of CD8+, but not CD4+, T cells abrogating the therapeutic response. An analysis of transcriptional heterogeneity in the melanoma compartment showed the sequence of IT→TT enriched for a population of melanoma cells with increased expression of MHC class I and melanoma antigens. RPPA analysis demonstrated that the sustained immune response induced by IT→TT suppressed tumor-intrinsic signaling pathways required for therapeutic escape. These studies establish that upfront IT improves the responses to TT in BRAF- and NRAS-mutant melanoma models.

S1: IT monotherapy in SW1 model S2: IT->dabrafenib-trametinib therapy in BRAF mutant melanoma. S3: IT->TT sequence in NRAS#5 model S4: Expanded heatmap of all immune cells S5: IT->TT increases accumulation of activated CD8+ T cells S6: The TT->IT sequence on T cells, Tregs and MDSCS S7: Expanded heatmap of T and NK cells S8: IT->TT increases accumulation of activated CD8+ T cells, pathway analysis. S9: Expanded heatmap of myeloid cell data S10: IT->TT sequence increases expression of MHC I mRNAs S11: TT affects melanoma antigens S12: IC50 curves showing resistance to TT S13: Model showing mechanism of IT->TT sequence ST1: tumor weights at the end of the experiment

Vaccination strategies incorporating the immunodominant HLA-A2–restricted HER2/neu-derived peptide 369–377 (HER2369–377) are increasingly utilized in HER2/neu-expressing cancer patients. The failure of postvaccination HER2369–377-specific CD8+ T cells to recognize HLA-A2posHER2/neu-expressing cells in vitro, however, has been attributed to impaired MHC class I/HLA-A2 presentation observed in HER2/neu-overexpressing tumors. We reconcile this controversy by demonstrating that HER2369–377 is directly recognized by high functional-avidity HER2369–377-specific CD8+ T cells—either genetically modified to express a novel HER2369–377 TCR or sensitized using HER2369–377-pulsed type 1–polarized dendritic cells (DC1)—on class I–abundant HER2low, but not class I–deficient HER2high, cancer cells. Importantly, a critical cooperation between CD4+ T-helper type-1 (Th1) cytokines IFNγ/TNFα and HER2/neu-targeted antibody trastuzumab is necessary to restore class I expression in HER2high cancers, thereby facilitating recognition and lysis of these cells by HER2369–377-specific CD8+ T cells. Concomitant induction of PD-L1 on HER2/neu-expressing cells by IFNγ/TNF and trastuzumab, however, has minimal impact on DC1-sensitized HER2369–377-CD8+ T-cell–mediated cytotoxicity. Although activation of EGFR and HER3 signaling significantly abrogates IFNγ/TNFα and trastuzumab-induced class I restoration, EGFR/HER3 receptor blockade rescues class I expression and ensuing HER2369–377-CD8+ cytotoxicity of HER2/neu-expressing cells. Thus, combinations of CD4+ Th1 immune interventions and multivalent targeting of HER family members may be required for optimal anti-HER2/neu CD8+ T-cell–directed immunotherapy. Cancer Immunol Res; 3(5); 455–63. ©2015 AACR.

Figure S1: HER2high cells are susceptible to NK-mediated ADCC, but not HER2369-377-sensitized CD8+ T-cell-mediated cytotoxicity. Figure S2: Cell line-specific IFN-γ receptor expression and impact of IFN-γ dose titration on MHC class I expression. Figure S3: Comparative effects of trastuzumab or lapatinib in conjunction with Th1 cytokines on class I and HER2 expression. Table S1: Demographic, tumor, and HLA-A typing characteristics of HER2pos-DCIS patients utilized for in vitro sensitization, recognition, and cytotoxicity assays.

Supplemental Table 1: Overall immune response detected in the peripheral blood by route of vaccine administration and ER status

Purpose: Vaccination with HER2 peptide-pulsed DC1s stimulates a HER2-specific T-cell response. This randomized trial aimed to establish safety and evaluate immune and clinical responses to vaccination via intralesional (IL), intranodal (IN), or both intralesional and intranodal (ILN) injection.Experimental Design: Fifty-four HER2pos patients [42 pure ductal carcinoma in situ (DCIS), 12 early invasive breast cancer (IBC)] were enrolled in a neoadjuvant HER2 peptide-pulsed DC1 vaccine trial. Patients were randomized to IL (n = 19), IN (n = 19), or ILN (n = 16) injection. Immune responses were measured in peripheral blood and sentinel lymph nodes by ELISPOT or in vitro sensitization assay. Pathologic response was assessed in resected surgical specimens.Results: Vaccination by all injection routes was well tolerated. There was no significant difference in immune response rates by vaccination route (IL 84.2% vs. IN 89.5% vs. ILN 66.7%; P = 0.30). The pathologic complete response (pCR) rate was higher in DCIS patients compared with IBC patients (28.6% vs. 8.3%). DCIS patients who achieved pCR (n = 12) and who did not achieve pCR (n = 30) had similar peripheral blood anti-HER2 immune responses. All patients who achieved pCR had an anti-HER2 CD4 immune response in the sentinel lymph node, and the quantified response was higher by response repertoire (P = 0.03) and cumulative response (P = 0.04).Conclusions: Anti-HER2 DC1 vaccination is a safe and immunogenic treatment to induce tumor-specific T-cell responses in HER2pos patients; immune and clinical responses were similar independent of vaccination route. The immune response in the sentinel lymph nodes, rather than in the peripheral blood, may serve as an endpoint more reflective of antitumor activity. Clin Cancer Res; 23(12); 2961–71. ©2016 AACR.

Supplementary Materials, Methods, Figures and Table legends - PDF file 87K, Supplementary file giving details of supplementary materials and methods, figure legends and table legends

Supplementary Figure S2 - PDF file 84K, Phenotype of DCs following lysate-pulsing (i.e. HOCl-L, UVB-L or FTL), and activation with LPS and IFN-gamma. Unpulsed, mature (mDC) or immature DCs (iDC) served as controls. Data was presented as mean plus-minus SEM

Supplementary Table S1 - PDF file 191K, Cytokine and chemokine productions from DCs of ovarian cancer subjects that were loaded with HOCl-oxidized autologous whole tumor lysate and matured with LPS and IFN-gamma

Supplemental Table 2: Pathologic complete response rates by route of vaccine administration and ER status in 42 DCIS patients

Purpose: Whole tumor lysates are promising antigen sources for dendritic cell (DC) therapy as they contain many relevant immunogenic epitopes to help prevent tumor escape. Two common methods of tumor lysate preparations are freeze-thaw processing and UVB irradiation to induce necrosis and apoptosis, respectively. Hypochlorous acid (HOCl) oxidation is a new method for inducing primary necrosis and enhancing the immunogenicity of tumor cells.Experimental Design: We compared the ability of DCs to engulf three different tumor lysate preparations, produce T-helper 1 (TH1)-priming cytokines and chemokines, stimulate mixed leukocyte reactions (MLR), and finally elicit T-cell responses capable of controlling tumor growth in vivo.Results: We showed that DCs engulfed HOCl-oxidized lysate most efficiently stimulated robust MLRs, and elicited strong tumor-specific IFN-γ secretions in autologous T cells. These DCs produced the highest levels of TH1-priming cytokines and chemokines, including interleukin (IL)-12. Mice vaccinated with HOCl-oxidized ID8-ova lysate–pulsed DCs developed T-cell responses that effectively controlled tumor growth. Safety, immunogenicity of autologous DCs pulsed with HOCl-oxidized autologous tumor lysate (OCDC vaccine), clinical efficacy, and progression-free survival (PFS) were evaluated in a pilot study of five subjects with recurrent ovarian cancer. OCDC vaccination produced few grade 1 toxicities and elicited potent T-cell responses against known ovarian tumor antigens. Circulating regulatory T cells and serum IL-10 were also reduced. Two subjects experienced durable PFS of 24 months or more after OCDC.Conclusions: This is the first study showing the potential efficacy of a DC vaccine pulsed with HOCl-oxidized tumor lysate, a novel approach in preparing DC vaccine that is potentially applicable to many cancers. Clin Cancer Res; 19(17); 4801–15. ©2013 AACR.

Supplemental Figure 1: CONSORT diagram of the 58 patients enrolled in the vaccine trial. A total of 54 were randomized to one of the three vaccination routes. After the twenty second patient completed the vaccine, subsequent ER positive patients were treated with concurrent anti-estrogen therapy.

Supplemental Figure 4: The CD4pos Th1 immune response in the peripheral blood pre-vaccination and post-vaccination by clinical response (

Supplementary legend

Overexpression of HER-2/neu (c-erbB2) is associated with increased risk of recurrent disease in ductal carcinoma in situ (DCIS) and a poorer prognosis in node-positive breast cancer. We therefore examined the early immunotherapeutic targeting of HER-2/neu in DCIS. Before surgical resection, HER-2/neupos DCIS patients (n = 13) received 4 weekly vaccinations of dendritic cells pulsed with HER-2/neu HLA class I and II peptides. The vaccine dendritic cells were activated in vitro with IFN-γ and bacterial lipopolysaccharide to become highly polarized DC1-type dendritic cells that secrete high levels of interleukin-12p70 (IL-12p70). Intranodal delivery of dendritic cells supplied both antigenic stimulation and a synchronized preconditioned burst of IL-12p70 production directly to the anatomic site of T-cell sensitization. Before vaccination, many subjects possessed HER-2/neu–HLA-A2 tetramer-staining CD8pos T cells that expressed low levels of CD28 and high levels of the inhibitory B7 ligand CTLA-4, but this ratio inverted after vaccination. The vaccinated subjects also showed high rates of peptide-specific sensitization for both IFN-γ–secreting CD4pos (85%) and CD8pos (80%) T cells, with recognition of antigenically relevant breast cancer lines, accumulation of T and B lymphocytes in the breast, and induction of complement-dependent, tumor-lytic antibodies. Seven of 11 evaluable patients also showed markedly decreased HER-2/neu expression in surgical tumor specimens, often with measurable decreases in residual DCIS, suggesting an active process of “immunoediting” for HER-2/neu–expressing tumor cells following vaccination. DC1 vaccination strategies may therefore have potential for both the prevention and the treatment of early breast cancer. [Cancer Res 2007;67(4):1842–52]

Supplementary Figure 5 from Targeting HER-2/neu in Early Breast Cancer Development Using Dendritic Cells with Staged Interleukin-12 Burst Secretion

Supplementary Figure 4 from Targeting HER-2/neu in Early Breast Cancer Development Using Dendritic Cells with Staged Interleukin-12 Burst Secretion

Supplementary Table 1 from Targeting HER-2/neu in Early Breast Cancer Development Using Dendritic Cells with Staged Interleukin-12 Burst Secretion

Supplementary Figure 2 from Targeting HER-2/neu in Early Breast Cancer Development Using Dendritic Cells with Staged Interleukin-12 Burst Secretion

The HER3/ERBB3 receptor is an oncogenic receptor tyrosine kinase that forms heterodimers with EGFR family members and is overexpressed in numerous cancers. HER3 overexpression associates with reduced survival and acquired resistance to targeted therapies, making it a potential therapeutic target in multiple cancer types. Here, we report on immunogenic, promiscuous MHC class II–binding HER3 peptides, which can generate HER3-specific CD4+ Th1 antitumor immune responses. Using an overlapping peptide screening methodology, we identified nine MHC class II–binding HER3 epitopes that elicited specific Th1 immune response in both healthy donors and breast cancer patients. Most of these peptides were not identified by current binding algorithms. Homology assessment of amino acid sequence BLAST showed >90% sequence similarity between human and murine HER3/ERBB3 peptide sequences. HER3 peptide–pulsed dendritic cell vaccination resulted in anti-HER3 CD4+ Th1 responses that prevented tumor development, significantly delayed tumor growth in prevention models, and caused regression in multiple therapeutic models of HER3-expressing murine tumors, including mammary carcinoma and melanoma. Tumors were robustly infiltrated with CD4+ T cells, suggesting their key role in tumor rejection. Our data demonstrate that class II HER3 promiscuous peptides are effective at inducing HER3-specific CD4+ Th1 responses and suggest their applicability in immunotherapies for human HER3-overexpressing tumors.

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. 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. 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

Background Combination CDK4/6 inhibitor and endocrine therapy has been shown to significantly improve progression‐free survival (PFS) in patients with hormone receptor (HR)‐positive, HER2‐negative metastatic breast cancer (mBC). The aim of this retrospective study was to evaluate the real‐world benefit of first‐line combination therapy in this cohort and to correlate treatment efficacy with neutropenia, a common toxicity of CDK4/6 inhibitors. Methods This study included HR‐positive, HER2‐negative advanced or mBC patients who were treated with palbociclib plus endocrine therapy, mainly letrozole, between 1 January 2015 and 1 March 2018. Progression‐free survival (PFS) was determined using Kaplan–Meier analysis. The predictive value of absolute neutrophil count (ANC) and neutrophil‐to‐lymphocyte ratio (NLR) for PFS were explored using Cox regression models. Both ANC and NLR were used as a time‐dependent variable. Results In total, 165 patients were included with median PFS of 24.19 months (95% CI 18.93–NR). Median PFS for patients with bone‐only metastases (n = 54) was not reached (95% CI 18.21–NR). Among patients with all other metastases (n = 111), median PFS was 24.19 months (95% CI 16.33–33.82). Lower ANC was correlated with decreased risk of progression (HR 0.84, 95% CI 0.71–0.97, p = 0.008). There was no significant association between NLR and the risk of disease progression (HR 1.07, 95% CI 0.97–1.18, p = 0.203). Conclusion The effectiveness of palbociclib and endocrine therapy in the treatment of HR‐positive, HER2‐negative mBC in the real‐world setting is similar to the efficacy reported in the PALOMA‐2 trial. Patients with lower neutrophil count may have a lower risk of early disease progression., The real‐world benefit of combination CDK4/6 inhibitor and endocrine therapy is similar to that reported in clinical trials. Treatment‐related neutropenia, assessed by absolute neutrophil count (ANC), may be correlated with lower risk of disease progression and a lower ANC threshold for dose reduction may be warranted.