A phase 1 study of veliparib (ABT-888) plus weekly carboplatin and paclitaxel in advanced solid malignancies, with an expansion cohort in triple negative breast cancer (TNBC) (ETCTN 8620).

BACKGROUND: Veliparib is a poly-ADP-ribose polymerase (PARP) inhibitor, and it has clinical activity with every 3 weeks carboplatin and paclitaxel. In breast cancer, weekly paclitaxel is associated with improved overall survival. We aimed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib with weekly carboplatin and paclitaxel as well as safety, pharmacokinetics, and preliminary clinical activity in triple negative breast cancer (TNBC). METHODS: Patients with locally advanced/metastatic solid tumors and adequate organ function were eligible. A standard 3 + 3 dose-escalation design was followed by a TNBC expansion cohort. Veliparib doses ranging from 50 to 200 mg orally bid were tested with carboplatin (AUC 2) and paclitaxel (80 mg/m2) given weekly in a 21-day cycle. Adverse events (AE) were evaluated by CTCAE v4.0, and objective response rate (ORR) was determined by RECIST 1.1. RESULTS: Thirty patients were enrolled, of whom 22 had TNBC. Two dose-limiting toxicities were observed. The RP2D was determined to be 150 mg PO bid veliparib with weekly carboplatin and paclitaxel 2 weeks on, 1 week off, based on hematologic toxicity requiring dose reduction in the first 5 cycles of treatment. The most common grade 3/4 AEs included neutropenia, anemia, and thrombocytopenia. PK parameters of veliparib were comparable to single-agent veliparib. In 23 patients with evaluable disease, the ORR was 65%. In 19 patients with TNBC with evaluable disease, the ORR was 63%. CONCLUSION: Veliparib can be safely combined with weekly paclitaxel and carboplatin, and this triplet combination has promising clinical activity.

Perspectives in Immunotherapy: meeting report from Immunotherapy Bridge (Naples, November 30th-December 1st, 2022).

The discovery and development of novel treatments that harness the patient's immune system and prevent immune escape has dramatically improved outcomes for patients across cancer types. However, not all patients respond to immunotherapy, acquired resistance remains a challenge, and responses are poor in certain tumors which are considered to be immunologically cold. This has led to the need for new immunotherapy-based approaches, including adoptive cell transfer (ACT), therapeutic vaccines, and novel immune checkpoint inhibitors. These new approaches are focused on patients with an inadequate response to current treatments, with emerging evidence of improved responses in various cancers with new immunotherapy agents, often in combinations with existing agents. The use of cell therapies, drivers of immune response, and trends in immunotherapy were the focus of the Immunotherapy Bridge (November 30th-December 1st, 2022), organized by the Fondazione Melanoma Onlus, Naples, Italy, in collaboration with the Society for Immunotherapy of Cancer.

Emerging combination immunotherapy strategies for breast cancer: dual immune checkpoint modulation, antibody-drug conjugates and bispecific antibodies.

Breast cancer has historically been considered a non-immunogenic tumor. Multiple studies over the last 10-15 years have demonstrated that a small subset of breast cancers is immune-activated, with PD-L1 expression and/or TILs in the tumor microenvironment. The PD-1 inhibitor pembrolizumab in combination with chemotherapy is now approved by the US FDA for the first-line treatment of metastatic PD-L1 + triple negative breast cancer, and the PD-L1 inhibitor atezolizumab has also demonstrated clinical activity. The median progression-free survival for pembrolizumab or atezolizumab combined with chemotherapy increased with the addition of immunotherapy by 4.1 months and 2.5 months, respectively. Despite this success, there is major room for improvement. Clinical benefit is modest. Only about 40% of triple negative breast cancers are PD-L1 + , not all PD-L1 + patients with advanced triple negative breast cancer respond, and immunotherapy is not yet approved for advanced PD-L1-negative triple negative breast cancer, HER2 + breast cancer, or ER + breast cancer. It is likely that redundant pathways of immune suppression are active in breast cancer, or that important pathways of immune activation are silent. In this review, we discuss emerging strategies for targeting multiple pathways of immunoregulation in advanced breast cancer with dual immune checkpoint inhibition, bispecific antibodies, and novel antibody drug conjugates. We also discuss the potential of nanotechnology to improve the delivery of immunotherapeutics to the breast tumor microenvironment to enhance their antitumor activity.

Perspectives in Immunotherapy: meeting report from the Immunotherapy Bridge, December 1st-2nd, 2021.

Over the past decade, immunotherapy has become an increasingly fundamental modality in the treatment of cancer. The positive impact of immune checkpoint inhibition, especially anti-programmed death (PD)-1/PD-ligand (L)1 blockade, in patients with different cancers has focused attention on the potential for other immunotherapeutic approaches. These include inhibitors of additional immune checkpoints, adoptive cell transfer (ACT), and therapeutic vaccines. Patients with advanced cancers who previously had limited treatment options available may now benefit from immunotherapies that can offer durable responses and improved survival outcomes. However, despite this, a significant proportion of patients fail to respond to immunotherapy, especially those with less immunoresponsive cancer types, and there remains a need for new treatment strategies.The virtual Immunotherapy Bridge (December 1st-2nd, 2021), organized by the Fondazione Melanoma Onlus, Naples, Italy in collaboration with the Society for Immunotherapy of Cancer addressed several areas of current research in immunotherapy, including lessons learned from cell therapies, drivers of immune response, and trends in immunotherapy across different cancers, and these are summarised here.

Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer.

BACKGROUND: Unresectable locally advanced or metastatic triple-negative (hormone-receptor-negative and human epidermal growth factor receptor 2 [HER2]-negative) breast cancer is an aggressive disease with poor outcomes. Nanoparticle albumin-bound (nab)-paclitaxel may enhance the anticancer activity of atezolizumab. METHODS: In this phase 3 trial, we randomly assigned (in a 1:1 ratio) patients with untreated metastatic triple-negative breast cancer to receive atezolizumab plus nab-paclitaxel or placebo plus nab-paclitaxel; patients continued the intervention until disease progression or an unacceptable level of toxic effects occurred. Stratification factors were the receipt or nonreceipt of neoadjuvant or adjuvant taxane therapy, the presence or absence of liver metastases at baseline, and programmed death ligand 1 (PD-L1) expression at baseline (positive vs. negative). The two primary end points were progression-free survival (in the intention-to-treat population and PD-L1-positive subgroup) and overall survival (tested in the intention-to-treat population; if the finding was significant, then it would be tested in the PD-L1-positive subgroup). RESULTS: Each group included 451 patients (median follow-up, 12.9 months). In the intention-to-treat analysis, the median progression-free survival was 7.2 months with atezolizumab plus nab-paclitaxel, as compared with 5.5 months with placebo plus nab-paclitaxel (hazard ratio for progression or death, 0.80; 95% confidence interval [CI], 0.69 to 0.92; P=0.002); among patients with PD-L1-positive tumors, the median progression-free survival was 7.5 months and 5.0 months, respectively (hazard ratio, 0.62; 95% CI, 0.49 to 0.78; P<0.001). In the intention-to-treat analysis, the median overall survival was 21.3 months with atezolizumab plus nab-paclitaxel and 17.6 months with placebo plus nab-paclitaxel (hazard ratio for death, 0.84; 95% CI, 0.69 to 1.02; P=0.08); among patients with PD-L1-positive tumors, the median overall survival was 25.0 months and 15.5 months, respectively (hazard ratio, 0.62; 95% CI, 0.45 to 0.86). No new adverse effects were identified. Adverse events that led to the discontinuation of any agent occurred in 15.9% of the patients who received atezolizumab plus nab-paclitaxel and in 8.2% of those who received placebo plus nab-paclitaxel. CONCLUSIONS: Atezolizumab plus nab-paclitaxel prolonged progression-free survival among patients with metastatic triple-negative breast cancer in both the intention-to-treat population and the PD-L1-positive subgroup. Adverse events were consistent with the known safety profiles of each agent. (Funded by F. Hoffmann-La Roche/Genentech; IMpassion130 ClinicalTrials.gov number, NCT02425891 .).

Perspectives in immunotherapy: meeting report from the "Immunotherapy Bridge" (December 4th-5th, 2019, Naples, Italy).

Over the last few years, numerous clinical trials and real-world experience have provided a large amount of evidence demonstrating the potential for long-term survival with immunotherapy agents across various malignancies, beginning with melanoma and extending to other tumours. The clinical success of immune checkpoint blockade has encouraged increasing development of other immunotherapies. It has been estimated that there are over 3000 immuno-oncology trials ongoing, targeting hundreds of disease and immune pathways. Evolving topics on cancer immunotherapy, including the state of the art of immunotherapy across various malignancies, were the focus of discussions at the Immunotherapy Bridge meeting (4-5 December, 2019, Naples, Italy), and are summarised in this report.

Perspectives in immunotherapy: meeting report from the immunotherapy bridge (December 2nd-3rd, 2020, Italy).

Improved understanding of tumor immunology has enabled the development of therapies that harness the immune system and prevent immune escape. Numerous clinical trials and real-world experience has provided evidence of the potential for long-term survival with immunotherapy in various types of malignancy. Recurring observations with immuno-oncology agents include their potential for clinical application across a broad patient population with different tumor types, conventional and unconventional response patterns, durable responses, and immune-related adverse events. Despite the substantial achievements to date, a significant proportion of patients still fail to benefit from current immunotherapy options, and ongoing research is focused on transforming non-responders to responders through the development of novel treatments, new strategies to combination therapy, adjuvant and neoadjuvant approaches, and the identification of biomarkers of response. These topics were the focus of the virtual Immunotherapy Bridge (December 2nd-3rd, 2020), organized by the Fondazione Melanoma Onlus, Naples, Italy, in collaboration with the Society for Immunotherapy of Cancer and are summarised in this report.

Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomised, double-blind trial.

BACKGROUND: HER2-positive metastatic breast cancer is incurable and new treatments are needed. Addition of atezolizumab to trastuzumab emtansine might potentiate anticancer immunity and enhance the HER2-targeted cytotoxic activity of trastuzumab emtansine. We aimed to test this combination in HER2-positive advanced breast cancer that had progressed after previous treatment with trastuzumab and a taxane. METHODS: The KATE2 study is a randomised, double-blind, placebo-controlled, phase 2 study at 68 centres from nine countries across Asia, Australia, North America, and western Europe. Eligible patients were adults (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and centrally confirmed, measurable, HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. Patients were randomly assigned (2:1) either trastuzumab emtansine (3·6 mg/kg of bodyweight) plus atezolizumab (1200 mg) or trastuzumab emtansine plus placebo; all study drugs were administered by intravenous infusion every 3 weeks. Randomisation was done via an interactive voice and web response system using a permuted block scheme (block size of six) and was stratified by PD-L1 status, world region, and liver metastases. Patients, investigators, and study team members were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02924883, and the study has been completed. FINDINGS: Between Sept 26, 2016, and Aug 7, 2017, 330 patients were screened for the study, of whom 202 were randomly allocated either atezolizumab (n=133) or placebo (n=69). At the recommendation of the independent data monitoring committee, treatment assignment was unmasked on Dec 11, 2017, due to futility and the numerically higher frequency of adverse events among patients assigned atezolizumab. This date was set as the clinical cutoff for the primary analysis. Median follow-up was 8·5 months (IQR 6·1-11·5) for patients assigned atezolizumab and 8·4 months (5·3-11·1) for those assigned placebo. Median progression-free survival was 8·2 months (95% CI 5·8-10·7) for patients assigned atezolizumab versus 6·8 months (4·0-11·1) for those assigned placebo (stratified hazard ratio 0·82, 95% CI 0·55-1·23; p=0·33). The most common grade 3 or worse adverse events were thrombocytopenia (17 [13%] among 132 patients who received atezolizumab vs three [4%] among 68 who received placebo), increased aspartate aminotransferase (11 [8%] vs two [3%]), anaemia (seven [5%] vs 0), neutropenia (six [5%] vs three [4%]), and increased alanine aminotransferase (six [5%] vs two [3%]). Serious adverse events occurred in 43 (33%) of 132 patients who received atezolizumab and 13 (19%) of 68 patients who received placebo. One patient who received atezolizumab died due to a treatment-related adverse event (haemophagocytic syndrome). INTERPRETATION: Addition of atezolizumab to trastuzumab emtansine did not show a clinically meaningful improvement in progression-free survival and was associated with more adverse events. Further study of trastuzumab emtansine plus atezolizumab is warranted in a subpopulation of patients with PD-L1-positive, HER2-positive advanced breast cancer. FUNDING: F Hoffman-La Roche.

Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Immunotherapy in combination with chemotherapy has shown promising efficacy across many different tumour types. We report the prespecified second interim overall survival analysis of the phase 3 IMpassion130 study assessing the efficacy and safety of atezolizumab plus nab-paclitaxel in patients with unresectable, locally advanced or metastatic triple-negative breast cancer. METHODS: In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 246 academic centres and community oncology practices in 41 countries, patients aged 18 years or older, with previously untreated, histologically documented, locally advanced or metastatic triple-negative breast cancer, and Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) using a permuted block method (block size of four) and an interactive voice-web response system. Randomisation was stratified by previous taxane use, liver metastases, and PD-L1 expression on tumour-infiltrating immune cells. Patients received atezolizumab 840 mg or matching placebo intravenously on day 1 and day 15 of every 28-day cycle and nab-paclitaxel 100 mg/m2 of body surface area intravenously on days 1, 8, and 15 until progression or unacceptable toxicity. Investigators, patients, and the funder were masked to treatment assignment. Coprimary endpoints were investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1 and overall survival, assessed in the intention-to-treat population and in patients with PD-L1 immune cell-positive tumours (tumours with ≥1% PD-L1 expression). The final progression-free survival results were previously reported at the first interim overall survival analysis. The prespecified statistical testing hierarchy meant that overall survival in the subgroup of PD-L1 immune cell-positive patients could only be formally tested if overall survival was significantly different between the treatment groups in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02425891. FINDINGS: Between June 23, 2015, and May 24, 2017, 902 patients were enrolled, of whom 451 were randomly assigned to receive atezolizumab plus nab-paclitaxel and 451 were assigned to receive placebo plus nab-paclitaxel (the intention-to-treat population). Six patients from each group did not receive treatment. At the second interim analysis (data cutoff Jan 2, 2019), median follow-up was 18·5 months (IQR 9·6-22·8) in the atezolizumab group and 17·5 months (8·4-22·4) in the placebo group. Median overall survival in the intention-to-treat patients was 21·0 months (95% CI 19·0-22·6) with atezolizumab and 18·7 months (16·9-20·3) with placebo (stratified hazard ratio [HR] 0·86, 95% CI 0·72-1·02, p=0·078). In the exploratory overall survival analysis in patients with PD-L1 immune cell-positive tumours, median overall survival was 25·0 months (95% CI 19·6-30·7) with atezolizumab versus 18·0 months (13·6-20·1) with placebo (stratified HR 0·71, 0·54-0·94]). As of Sept 3, 2018 (the date up to which updated safety data were available), the most common grade 3-4 adverse events were neutropenia (38 [8%] of 453 patients in the atezolizumab group vs 36 [8%] of 437 patients in the placebo group), peripheral neuropathy (25 [6%] vs 12 [3%]), decreased neutrophil count (22 [5%] vs 16 [4%]), and fatigue (17 [4%] vs 15 [3%]). Treatment-related deaths occurred in two (<1%) patients in the atezolizumab group (autoimmune hepatitis related to atezolizumab [n=1] and septic shock related to nab-paclitaxel [n=1]) and one (<1%) patient in the placebo group (hepatic failure). No new treatment-related deaths have been reported since the primary clinical data cutoff date (April 17, 2018). INTERPRETATION: Consistent with the first interim analysis, this second interim overall survival analysis of IMpassion130 indicates no significant difference in overall survival between the treatment groups in the intention-to-treat population but suggests a clinically meaningful overall survival benefit with atezolizumab plus nab-paclitaxel in patients with PD-L1 immune cell-positive disease. However, this positive result could not be formally tested due to the prespecified statistical testing hierarchy. For patients with PD-L1 immune cell-positive metastatic triple-negative breast cancer, atezolizumab plus nab-paclitaxel is an important therapeutic option in a disease with high unmet need. FUNDING: F Hoffmann-La Roche and Genentech.

Development of [18F]FPy-WL12 as a PD-L1 Specific PET Imaging Peptide.

Expression of programmed cell death ligand 1 (PD-L1) within tumors is an important biomarker for guiding immune checkpoint therapies; however, immunohistochemistry-based methods of detection fail to provide a comprehensive picture of PD-L1 levels in an entire patient. To facilitate quantification of PD-L1 in the whole body, we developed a peptide-based, high-affinity PD-L1 imaging agent labeled with [18F]fluoride for positron emission tomography (PET) imaging. The parent peptide, WL12, and the nonradioactive analog of the radiotracer, 19FPy-WL12, inhibit PD-1/PD-L1 interaction at low nanomolar concentrations (half maximal inhibitory concentration [IC50], 26-32 nM). The radiotracer, [18F]FPy-WL12, was prepared by conjugating 2,3,5,6-tetrafluorophenyl 6-[18F]fluoronicotinate ([18F]FPy-TFP) to WL12 and assessed for specificity in vitro in 6 cancer cell lines with varying PD-L1 expression. The uptake of the radiotracer reflected the PD-L1 expression assessed by flow cytometry. Next, we performed the in vivo evaluation of [18F]FPy-WL12 in mice bearing cancer xenografts by PET imaging, ex vivo biodistribution, and blocking studies. In vivo data demonstrated a PD-L1-specific uptake of [18F]FPy-WL12 in tumors that is reduced in mice receiving a blocking dose. The majority of [18F]FPy-WL12 radioactivity was localized in the tumors, liver, and kidneys indicating the need for optimization of the labeling strategy to improve the in vivo pharmacokinetics of the radiotracer.

Safety, clinical activity and biomarker assessments of atezolizumab from a Phase I study in advanced/recurrent ovarian and uterine cancers.

OBJECTIVE: Patients with advanced/recurrent epithelial ovarian and uterine cancers have limited treatment options beyond platinum chemotherapy. Both tumor types can express programmed death-ligand 1 (PD-L1), providing a potential therapeutic target for these patients. Here we present data from the ovarian and uterine cancer cohorts of the Phase I atezolizumab monotherapy study (PCD4989g). METHODS: This Phase I, multi-center, first-in-human, open-label, dose-escalation/expansion clinical trial investigated single-agent atezolizumab in cohorts of patients with recurrent epithelial ovarian or uterine cancer. The primary objective was to evaluate the safety and tolerability of single-agent atezolizumab. Anti-tumor activity and preliminary assessment of potential biomarkers were evaluated as secondary and exploratory objectives, respectively. RESULTS: The ovarian and uterine cancer cohorts enrolled 12 and 15 patients, respectively (10 [83%] and 5 [33%], respectively, had PD-L1 ≥ 5% on tumor-infiltrating immune cells). Atezolizumab was generally well tolerated with no new safety signals identified. The safety profiles in both cohorts were consistent with the known profile of atezolizumab monotherapy. Treatment-related adverse events (AEs) were mostly Grade ≤ 2, with no treatment-related Grade ≥ 4 AEs reported. Preliminary anti-tumor activity, with long durations of response, was observed in 2 patients from each cohort (ovarian cancer, 8.1 and 30.6+ months; uterine cancer, 7.3 and 16.6+ months). High microsatellite instability and tumor mutational burden were noted in the responders from the uterine cancer cohort. CONCLUSIONS: Atezolizumab monotherapy was well tolerated in patients with epithelial ovarian or uterine cancer and may have clinical activity warranting further investigation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01375842.

Racial disparities in the rate of cardiotoxicity of HER2-targeted therapies among women with early breast cancer.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-targeted therapies are highly effective at preventing breast cancer recurrence but are associated with cardiotoxicity in some patients, and minimal data are available regarding racial disparities in the incidence of this toxicity. The authors conducted a retrospective study to analyze the association of black or white race with treatment-induced cardiotoxicity and incomplete therapy among patients with HER2-positive early breast cancer. METHODS: Women with HER2-positive, stage I through III breast cancer who initiated (neo)adjuvant HER2-targeted therapy (trastuzumab with or without pertuzumab) from January 2005 to March 2015 at the authors' institution were eligible. We analyzed differences in the incidence of cardiotoxicity (a decline in the left ventricular ejection fraction to <50% AND an absolute drop in the left ventricular ejection fraction of ≥10% from baseline) and incomplete therapy (<52 weeks of HER2-targeted therapy) between black and white women in univariate and multivariable analyses. RESULTS: The authors identified 59 black patients and 157 white patients who had a median follow-up 5.2 years. The median patient age was 53 years and was similar for black and white patients. The 1-year cardiotoxicity incidence was 12% overall (95% confidence interval [CI], 7%-16%), 24% in black women (95% CI, 12%-34%), and 7% in white women (95% CI, 3%-11%). Black patients had a significantly greater probability of incomplete therapy compared with white patients (odds ratio, 4.61; 95% CI, 1.70-13.07; P = .002). High correlation was observed between a cardiotoxicity event and incomplete therapy (96% concordance). CONCLUSIONS: Black patients have a higher rate of cardiotoxicity and resultant incomplete adjuvant HER2-targeted therapy than white patients. This patient population may benefit from enhanced cardiac surveillance, cardioprotective strategies, and early referral to cardiology when appropriate. Cancer 2018;124:1904-11. © 2018 American Cancer Society.

Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study.

PURPOSE: Agents targeting programmed death receptor 1 (PD-1) or its ligand (PD-L1) have shown antitumor activity in the treatment of metastatic breast cancer (MBC). The aim of this study was to assess the activity of avelumab, a PD-L1 inhibitor, in patients with MBC. METHODS: In a phase 1 trial (JAVELIN Solid Tumor; NCT01772004), patients with MBC refractory to or progressing after standard-of-care therapy received avelumab intravenously 10 mg/kg every 2 weeks. Tumors were assessed every 6 weeks by RECIST v1.1. Adverse events (AEs) were graded by NCI-CTCAE v4.0. Membrane PD-L1 expression was assessed by immunohistochemistry (Dako PD-L1 IHC 73-10 pharmDx). RESULTS: A total of 168 patients with MBC, including 58 patients with triple-negative breast cancer (TNBC), were treated with avelumab for 2-50 weeks and followed for 6-15 months. Patients were heavily pretreated with a median of three prior therapies for metastatic or locally advanced disease. Grade ≥ 3 treatment-related AEs occurred in 13.7% of patients, including two treatment-related deaths. The confirmed objective response rate (ORR) was 3.0% overall (one complete response and four partial responses) and 5.2% in patients with TNBC. A trend toward a higher ORR was seen in patients with PD-L1+ versus PD-L1- tumor-associated immune cells in the overall population (16.7% vs. 1.6%) and in the TNBC subgroup (22.2% vs. 2.6%). CONCLUSION: Avelumab showed an acceptable safety profile and clinical activity in a subset of patients with MBC. PD-L1 expression in tumor-associated immune cells may be associated with a higher probability of clinical response to avelumab in MBC.

PD-L1 expression and the immune microenvironment in primary invasive lobular carcinomas of the breast.

Tumor-infiltrating lymphocytes and immune checkpoint proteins such as PD-L1 are potential prognostic factors and therapeutic targets in breast cancer. Most studies characterizing the breast tumor immune microenvironment have focused on ductal carcinomas. Here we investigate the tumor microenvironment of primary invasive lobular carcinomas. Previously constructed tissue microarrays of 47 lobular carcinomas were labeled by immunohistochemistry for PD-L1, CD8, CD20, and FoxP3. The stromal immune infiltrate density was qualitatively scored as a percentage of tumor area: 1+ (<5%); 2+ (5-10%); 3+ (10-15%); or 4+ (>50%). The average immune cell subtype per high-power field was quantitatively scored. The percentage PD-L1 labeling on tumor-infiltrating lymphocytes was scored as none, focal (<5%), moderate (10-24%), or diffuse (50-100%). The percentage of membranous carcinoma cell PD-L1 labeling was also recorded, with <5% considered negative. All lobular carcinomas contained PD-L1+ tumor-infiltrating lymphocytes with the majority showing 1+ immune infiltrates with focal-moderate PD-L1 labeling. PD-L1 was expressed by tumor cells in 17% of lobular carcinomas. In contrast to ductal carcinomas, there was no correlation between the immune infiltrate density, the PD-L1 expression by lobular carcinoma cells, tumor grade, or the expression of estrogen receptor or human epidermal growth factor receptor-2. However, both the tumor-infiltrating lymphocyte density and the average CD8+ T-cell counts correlated with immune cell PD-L1 status (P=0.004 and 0.03, respectively). Similar to breast ductal carcinomas, PD-L1+ lobular breast carcinomas had higher numbers of PD-L1+ tumor-infiltrating lymphocytes (63%) than PD-L1- lobular carcinomas (23%; P=0.04). These data show that a subset of primary breast lobular carcinomas both express PD-L1 on tumor cells and contain PD-L1+ tumor-infiltrating lymphocytes, suggesting the possibility of both constitutive and adaptive PD-L1 expression. Together, these results support immunotherapy as a potential treatment for a subset of patients with primary invasive lobular breast carcinomas.

The immune microenvironment of breast ductal carcinoma in situ.

The host immune response has a key role in breast cancer progression and response to therapy. However, relative to primary invasive breast cancers, the immune milieu of breast ductal carcinoma in situ (DCIS) is less understood. Here, we profile tumor infiltrating lymphocytes and expression of the immune checkpoint ligand programmed death ligand 1 (PD-L1) in 27 cases of DCIS with known estrogen receptor (ER), progesterone receptor, and human epidermal growth factor 2 (HER-2) expression using tissue microarrays. Twenty-four cases were pure DCIS and three had associated invasive ductal carcinoma. Tumors were stained by immunohistochemistry for PD-L1, as well as the lymphocyte markers CD3, CD4, CD8, FoxP3, and CD20. The expression of PD-L1 by DCIS carcinoma cells and tumor infiltrating lymphocytes was determined, and the average tumor infiltrating lymphocytes per high power field were manually scored. None of the DCIS cells expressed PD-L1, but 81% of DCIS lesions contained PD-L1+ tumor infiltrating lymphocytes. DCIS with moderate-diffuse tumor infiltrating lymphocytes was more likely to have PD-L1+ tumor infiltrating lymphocytes (P=0.004). Tumor infiltrating lymphocytes with high levels of PD-L1 expression (>50% cells) were seen only in triple-negative DCIS (P=0.0008), and PD-L1-tumor infiltrating lymphocytes were seen only in ER+/HER-2-DCIS (P=0.12). The presence of PD-L1+ tumor infiltrating lymphocytes was associated with a younger mean patient age (P=0.01). Further characterization of the DCIS immune microenvironment may identify useful targets for immune-based therapy and breast cancer prevention.

Targeting the programmed cell death-1 pathway in breast and ovarian cancer.

PURPOSE OF REVIEW: Immune checkpoint blockade is changing cancer therapy. Targeting the programmed cell death-1 (PD-1) pathway releases T cells from inhibitory signals within the tumor microenvironment, thereby activating a latent antitumor immune response. Here, we review the biology underlying the activity of PD-1/programmed cell death-ligand 1 (PD-L1) antagonists, and data describing their clinical activity in breast and ovarian cancer. RECENT FINDINGS: Several antagonists of PD-1 and PD-L1 have been tested in breast and ovarian cancer. These drugs are generally well tolerated, with some immune-related adverse events that are typically easily managed. Objective response rates generally range from about 10 to 20% in both breast cancer and ovarian cancer, with durable responses noted in multiple trials. Selecting patients with PD-L1 expression by cells within the tumor microenvironment appears to enrich for responses. These agents are under accelerated development based on these promising early data. SUMMARY: Monoclonal antibody-based blockade of the PD-1 pathway results in objective and durable clinical responses in a subset of patients with breast or ovarian cancers, particularly those with PD-L1-positive cells within the tumor microenvironment. Current priorities are to refine biomarkers of therapeutic response, and to develop combination immunotherapy strategies that integrate PD-1/PD-L1 antagonists with both standard and immune-based cancer therapies to increase efficacy.

Immune targeting in breast cancer.

The immune system is active in breast cancer, playing a dual role in tumor progression and in immune surveillance. Infiltrating immune cells are both prognostic and predictive of response to standard breast cancer therapies. Breast cancer vaccines can activate and expand tumor-specific T cells, but have enjoyed minimal clinical success to date. Immune checkpoint blockade is a new approach to cancer immunotherapy, with documented clinical responses in diverse tumor types. Interest in breast cancer immunotherapy has been reignited by recent reports of objective responses in metastatic triple-negative breast cancer with both pembrolizumab (a programmed cell death protein 1 [PD-1] antagonist) and MPDL3280A (a programmed cell death ligand 1 [PD-L1] antagonist). Rational strategies for combination immunotherapy that expand and promote the trafficking of tumor-specific T cells, support their activity at the tumor site, and abrogate pathways of immune suppression within breast tumors are most likely to result in objective responses that translate into long-term disease control and cure.

Advances and challenges in cancer immunoprevention and immune interception.

Invasive cancers typically evade immune surveillance through profound local and systemic immunosuppression, preventing their elimination or control. Targeting immune interventions to prevent or intercept premalignant lesions, before significant immune dysregulation has occurred, may be a more successful strategy. The field of cancer immune interception and prevention is nascent, and the scientific community has been slow to embrace this potentially most rational approach to reducing the global burden of cancer. This may change due to recent promising advances in cancer immunoprevention including the use of vaccines for the prevention of viral cancers, the use of cancer-associated antigen vaccines in the setting of precancers, and the development of cancer-preventative vaccines for high-risk individuals who are healthy but carry cancer-associated heritable genetic mutations. Furthermore, there is increasing recognition of the importance of cancer prevention and interception by national cancer organizations. The National Cancer Institute (NCI) recently released the National Cancer Plan, which includes cancer prevention among the top priorities of the institute. The NCI's Division of Cancer Prevention has been introducing new funding opportunities for scientists with an interest in the field of cancer prevention: The Cancer Prevention-Interception Targeted Agent Discovery Program and The Cancer Immunoprevention Network. Moreover, the Human Tumor Atlas Network is spearheading the development of a precancer atlas to better understand the biology of pre-invasive changes, including the tissue microenvironment and the underlying genetics that drive carcinogenesis. These data will inform the development of novel immunoprevention/immuno-interception strategies. International cancer foundations have also started recognizing immunoprevention and immune interception with the American Association for Cancer Research, Cancer Research UK and the Society for Immunotherapy of Cancer each implementing programming focused on this area. This review will present recent advances, opportunities, and challenges in the emerging field of cancer immune prevention and immune interception.