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Background: In contrast to the IMpassion130 trial evaluating atezo + nab-pac [Schmid, NEJM 2018], the randomized phase 3 IMpassion131 trial (NCT03125902) did not demonstrate significantly improved progression-free survival (PFS; primary endpoint) and showed no improvement in overall survival (OS; secondary endpoint) with the addition of atezo to pac as first-line therapy for mTNBC in either the PD-L1+ or the intention-to-treat (ITT) population [Miles, Ann Oncol 2021]. In IMpassion130, enhanced PFS and OS improvement with atezo + nab-pac were seen in the basal-like immune-activated (BLIA) subtype, whereas potential resistance to atezo + nab-pac was observed in the luminal androgen receptor (LAR) subtype [Emens, ASCO 2021]. LAR may be more prevalent in Asian populations [Ding, Oncotarget 2019], which represented one-third of patients enrolled in IMpassion131 and could have influenced the overall result. PFS outcomes were numerically worse in Asian vs non-Asian subgroups in IMpassion131 [Miles, Ann Oncol 2021]. To investigate potential reasons for observing different effects in IMpassion130 and IMpassion131, we explored the prevalence and impact on clinical outcomes of TNBC molecular subtypes and race in IMpassion131. Patients and Methods: Patients with mTNBC (no prior systemic therapy or ≥12 months since [neo]adjuvant chemotherapy) were randomized 2:1 to atezolizumab 840 mg or placebo (days 1, 15), both with paclitaxel 90 mg/m2 (days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity, stratified by tumor PD-L1 status, prior taxane, liver metastases, and geographic region. Molecular subtypes according to Burstein classification were determined by RNA sequencing (Illumina TruSeq RNA Access) of baseline tumor samples. Prevalence of Burstein molecular subtypes [Burstein, Clin Cancer Res 2015] was assessed in Asian (of whom 69% were enrolled in China) and non-Asian populations; clinical outcomes were assessed according to molecular subtype and race using Cox proportional hazards analysis. All analyses were performed using the final data cut-off (Sep 4, 2020; median follow-up duration: 14.4 months). Results: The biomarker-evaluable population (BEP; n=471) was representative of the ITT population (n=651) with respect to baseline characteristics and PFS hazard ratio (HR; 0.75 [95% CI 0.61-0.92] vs 0.81 [95% CI 0.68-0.96], respectively). Distribution of molecular subtypes in the BEP was: 30% BLIA, 41% basal-like immune suppressed (BLIS), 24% LAR, 5% mesenchymal (MES), similar to IMpassion130. Among the BLIA samples, 82% were PD-L1+ and 18% PD-L1-; corresponding percentages were 41% vs 59% for BLIS, 31% vs 69% for LAR, and 32% vs 68% for MES. Compared with non-Asian patients, the Asian subgroup (n=117) included more LAR (31% vs 22%) and fewer MES (1% vs 6%) samples; this was particularly pronounced in the cohort enrolled in China (n=79; 37% LAR, 0% MES). PFS was improved with atezo + pac in the BLIA subtype (HR 0.66, 95% CI 0.45-0.97). None of the Burstein subgroups derived OS benefit from atezo + pac. Findings were similar irrespective of PD-L1 status. Direction of effect for PFS and OS favored the placebo + pac arm in the LAR Asian subgroup (n=30). Conclusion: In these exploratory analyses, the distribution of molecular subtypes and enhanced effect of atezo + pac in the BLIA subtype are consistent with findings from IMpassion130. The lack of improved efficacy with the combination of atezo + pac in the IMpassion131 trial cannot be explained by overrepresentation of a Burstein subtype less sensitive to atezo in the trial population. Citation Format: Fabrice André, Regula Deurloo, Aditi Qamra, David Cameron, Joseph Gligorov, Andreas Schneeweiss, Carlos Barrios, Binghe Xu, Ching-Wei Chang, Luciana Molinero, Shilpen Patel, Andrea Liptrot, Leilani Morales, David Miles, Joyce O’Shaughnessy. Activity of atezolizumab (atezo) plus paclitaxel (pac) in metastatic triple-negative breast cancer (mTNBC) according to Burstein molecular subtype: Analysis of the IMpassion131 trial [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 PD10-05.

Triple-negative breast cancer (TNBC) accounts for approximately 12% to 17% of all breast cancers and has an aggressive clinical behavior. Increased tumor-infiltrating lymphocyte counts are prognostic for survival in TNBC, making this disease a potential target for cancer immunotherapy. Research on immunophenotyping of tumor-infiltrating lymphocytes is revealing molecular and structural organization in the tumor microenvironment that may predict patient prognosis. The anti–programmed death-ligand 1 (PD-L1) antibody atezolizumab plus nab-paclitaxel was the first cancer immunotherapy combination to demonstrate progression-free survival benefit and clinically meaningful overall survival benefit in the first-line treatment of metastatic TNBC (mTNBC) in patients with PD-L1–expressing tumor-infiltrating immune cells in 1% or more of the tumor area. This led to its United States and European Union approval for mTNBC and US approval of the VENTANA PD-L1 (SP142) assay as a companion diagnostic immunohistochemistry assay. Subsequently, the anti–programmed death-1 (PD-1 ) antibody pembrolizumab plus chemotherapy was approved by the US Food and Drug Administration for mTNBC based on progression-free survival benefit in patients with a combined positive score of at least 10 by its concurrently approved 22C3 companion diagnostic assay. Treatment guidelines now recommend PD-L1 testing for patients with mTNBC, and the testing landscape will likely become increasingly complex as new anti–PD-L1 and anti–PD-1 agents and diagnostics are approved for TNBC. Integrating PD-L1 testing into current diagnostic workflows for mTNBC may provide more treatment options for these patients. Therefore, it is critical for medical oncologists and pathologists to understand the available assays and their relevance to therapeutic options to develop an appropriate workflow for immunohistochemistry testing.

The PD-L1 inhibitor atezolizumab received US FDA accelerated approval as treatment for PD-L1-positive metastatic triple-negative breast cancer (TNBC). In IMpassion130, combining atezolizumab with first-line nab-paclitaxel for metastatic TNBC significantly improved progression-free survival and showed a clinically meaningful effect on overall survival in patients with PD-L1-positive tumors. The placebo-controlled randomized Phase III IMpassion132 (NCT03371017) trial is evaluating atezolizumab with first-line chemotherapy (capecitabine [mandatory in platinum-pretreated patients] or gemcitabine/carboplatin) for inoperable locally advanced/metastatic TNBC recurring ≤12 months after completing standard (neo)adjuvant anthracycline and taxane chemotherapy. Stratification factors are: visceral metastases, tumor immune cell PD-L1 status and selected chemotherapy. Patients are randomized to atezolizumab 1200 mg or placebo every 3 weeks with the chosen chemotherapy, continued until progression, unacceptable toxicity or withdrawal. The primary end point is overall survival.

1083 Background: The immune checkpoint inhibitor (ICI) atezo showed disparate outcomes as first-line therapy for metastatic TNBC when combined with nab-paclitaxel (nPac) in IMpassion130 [Schmid 2018] vs solvent-based paclitaxel (Pac) in IMpassion131 [Miles 2021]. A key difference between the trials was use of steroid premedication for Pac in IMpassion131 but not for nPac in IMpassion130. In patients (pts) receiving ICIs, prior steroid exposure has been linked to worse outcome [Drakaki 2020]. Further, IMpassion130 and IMpassion131 subgroup analyses suggested reduced atezo treatment effect in taxane-pretreated pts. This post hoc biomarker study explored the impact of: 1) steroids on systemic immune cell activation with atezo+taxane; 2) prior taxane exposure on atezo-induced immune cell activation. Methods: PBMCs collected at baseline and at day 1, cycle 2 (wk 4) were selected from matched pts (RECIST responders, PD-L1+, no liver metastases) from IMpassion130 and IMpassion131. Single-cell RNAseq was performed and the transcriptomic profile of immune cells was analyzed using GSEA pathway analyses, cell proportion and TCR clonality. Results: CITEseq from 695,851 single cells was generated from 39 IMpassion130 PBMC pairs (29 atezo+nPac; 10 placebo [Pla]+nPac) and 35 IMpassion131 pairs (26 atezo+Pac; 9 Pla+Pac). At wk 4, atezo+nPac resulted in increased IFNα and IFNγ responses across multiple cell types (CD4+ and CD8+ T cells, B cells, NK cells and monocytes) and proliferation in NK cells, but reduced TNF signaling across multiple cell types. In contrast, 4 wks of Pla+nPac increased TNF signaling but decreased IFNα and IFNγ responses. In the presence of steroids, 4 wks of atezo+Pac also increased IFNα and IFNγ responses mainly in NK cells and monocytes, but not T cells, and reduced proliferative pathways across B and T cells and TNF signaling. Pla+Pac increased TNF signaling only in NK cells, but reduced proliferative signatures across cell types. The only on-treatment change differing significantly between atezo+nPac vs atezo+Pac was the increase in proliferation pathways in NK, T and B cells with atezo+nPac. There were no significant changes in proportions of cell subsets or TCR clonality. PBMCs from taxane-pretreated pts had higher RNA-based metabolic profile (OxPhos, DNA repair and IFNα). Taxane-naive but not taxane-pretreated immune cells had increased IFNγ and IFNα response after atezo+taxane. Conclusions: Our results suggest that atezo+taxane promotes IFNα and IFNγ responses and that steroid co-administration reduces proliferation pathways across immune cells. Prior taxane exposure was associated with an increased metabolic status, possibly rendering immune cells less sensitive to atezo-induced activation. The immune context of taxane-naive TNBC may result in more potent immune activation with atezo. Clinical trial information: NCT02425891 and NCT03125902.

Simple Summary Patients with “HER2-positive” early breast cancer are treated with antibodies to the HER2 protein along with chemotherapy, regardless of whether their cancer also has hormone receptors, or of its molecular features. Because patients with HER2-positive/hormone receptor-positive disease tend to live longer than those with HER2-positive/hormone receptor-negative disease, there may be some patients who are being overtreated under current guidelines. The aim of our exploratory translational analysis of the ADAPT HER2-positive/hormone receptor-positive trial was to investigate the potential of several prognostic (outcome regardless of therapy) and predictive (effect of therapy) biomarkers as early predictors of response to treatment before surgery. Comparison of these biomarkers before and after one treatment cycle, and their effects on whether patients’ cancers were completely removed at surgery, suggest that certain patients (those with treatment-induced CD8 protein-expressing cells infiltrating the cancer; without PIK3CA mutation; those with HER2-enriched tumors) may be candidates for less intensive treatment following pre-surgical therapy. Abstract Prognostic or predictive biomarkers in HER2-positive early breast cancer (EBC) may inform treatment optimization. The ADAPT HER2-positive/hormone receptor-positive phase II trial (NCT01779206) demonstrated pathological complete response (pCR) rates of ~40% following de-escalated treatment with 12 weeks neoadjuvant ado-trastuzumab emtansine (T-DM1) ± endocrine therapy. In this exploratory analysis, we evaluated potential early predictors of response to neoadjuvant therapy. The effects of PIK3CA mutations and immune (CD8 and PD-L1) and apoptotic markers (BCL2 and MCL1) on pCR rates were assessed, along with intrinsic BC subtypes. Immune response and pCR were lower in PIK3CA-mutated tumors compared with wildtype. Increased BCL2 at baseline in all patients and at Cycle 2 in the T-DM1 arms was associated with lower pCR. In the T-DM1 arms only, the HER2-enriched subtype was associated with increased pCR rate (54% vs. 28%). These findings support further prospective pCR-driven de-escalation studies in patients with HER2-positive EBC.

International audience; When the VEGF-A-targeting monoclonal antibody bevacizumab (Avastin®) entered clinical practice more than 15 years ago, it was one of the first targeted therapies and the first approved angiogenesis inhibitor. Marking the beginning for a new line of anti-cancer treatments, bevacizumab remains the most extensively characterized anti-angiogenetic treatment. Initially approved for treatment of metastatic colorectal cancer in combination with chemotherapy, its indications now include metastatic breast cancer, non-small-cell lung cancer, glioblastoma, renal cell carcinoma, ovarian cancer and cervical cancer. This review provides an overview of the clinical experience and lessons learned since bevacizumab's initial approval, and highlights how this knowledge has led to the investigation of novel combination therapies. In the past 15 years, our understanding of VEGF's role in the tumor microenvironment has evolved. We now know that VEGF not only plays a major role in controlling blood vessel formation, but also modulates tumor-induced immunosuppression. These immunomodulatory properties of bevacizumab have opened up new perspectives for combination therapy approaches, which are being investigated in clinical trials. Specifically, the combination of bevacizumab with cancer immunotherapy has recently been approved in non-small-cell lung cancer and clinical benefit was also demonstrated for treatment of hepatocellular carcinoma. However, despite intense investigation, reliable and validated biomarkers that would enable a more personalized use of bevacizumab remain elusive. Overall, bevacizumab is expected to remain a key agent in cancer therapy, both due to its established efficacy in approved indications and its promise as a partner in novel targeted combination treatments.

Background: Immune and apoptosis biomarkers are potential prognostic/predictive markers in HER2+ EBC. High PD-L1 expression was shown to be predictive for lower pCR after chemotherapy+trastuzumab+/-pertuzumab, particularly in HER2+, ER- disease. Yet, HER2+ EBC co-expressing hormone receptors is a distinct entity. The ADAPT HER2+/HR+ phase II trial (n=376) compared 12 weeks of neoadjuvant T-DM1 + ET vs. trastuzumab (T)+ET and demonstrated pCR rates of about 41% in both (well tolerated) T-DM1 arms. Methods: In order to identify potential early predictors for pCR (i.e. no invasive tumor in breast and lymph nodes), immune markers (PDL1 on infiltrating immune cells (IIC) and on tumor cells (TC); CD8 in invasive margin and in tumor center) and apoptosis markers (bcl-2; mcl-2) were determined by immunohistochemistry (IHC; H-scores) in core biopsy sections obtained at primary diagnosis and at cycle 2. For multivariate logistic regression, each biomarker (separately), clinical factors (Ki-67, cT, cN) and therapy were entered. All analyses were exploratory. Results:Biomarkers were available in up to 326 patients (pts) at baseline and up to 170 pts at 3 weeks (due to low tumor content in 2nd core biopsy). Baseline IIC-PDL1 was associated with pCR in the T-DM1 arm (OR 2.89; 95%CI: 1.11-7.51); IIC-PDL1 at cycle 2 was not associated with pCR. PD-L1 expression in TC was rare (2%); cycle-2 TC-PD-L1 was associated with pCR in all pts and in the pooled TDM-1 arms. High baseline CD8 in tumor center was associated with pCR in the whole cohort (OR 2.4; CI: 1.04 – 5.5) and in the T+ET arm (OR=10.1; CI: 1.12 - 91.6) and at cycle 2 in all pts (OR=9.52; CI: 2.17 – 41), in pooled TDM-1 arms (OR=15.7; CI: 2.49 – 99), and in TDM-1+ET (OR=25.05; CI: 2.12 – 295). Increases in this marker also predicted pCR in all pts, pooled TDM-1, and in TDM-1+ET. Association of cycle-2 CD8 in tumor center with pCR persisted in multivariate models. Lower baseline CD8 in invasive margin was associated with pCR in the T-DM1 arm (OR=0.09; CI: 0.01-0.69), but at cycle 2 in all pts (OR=18.1; CI: 1.60 – 204) and in pooled TDM-1 arms (OR=23.5; CI: 1.1 - 500). This positive impact persisted in multivariate models. Bcl-2 expression at baseline was associated with non-pCR in all pts (OR=0.28, CI: 0.12 - 0.66), in the pooled T-DM1 arms (OR=0.216, CI: 0.08 - 0.61), and particularly in the T-DM1+ET arm (OR=0.14; CI: 0.03 - 0.71). This association persisted in multivariate analysis. At cycle 2, lower bcl-2 had OR=0.16 (CI: 0.03 - 0.96) in the pooled T-DM1 arms. No association with efficacy was seen for mcl-1. Conclusions: The WSG-ADAPT HER2+/HR+ phase II trial is the first international trial to focus on HER2+/HR+ EBC alone and the first to show substantial pCR rates of > 40% after only 12 weeks of T-DM1 -- without standard chemotherapy. Expression of bcl-2 may affect resistance to T-DM1. High immune activity at baseline and/or cycle 2 seems to be associated with pCR. The association of CD8 expression and its changes with therapy efficacy is complex and could depend on ET. Further biomarker analyses are ongoing and will be presented at the meeting. Citation Format: Harbeck N, Nitz UA, Matthias C, Kates R, Braun M, Kümmel S, Schumacher C, Potenberg J, Kraemer S, Kleine-Tebbe A, Augustin D, Aktas B, Forstbauer H, Tio J, Liedtke C, Grischke E-M, de Haas SL, Deurloo R, Schumacher J, Wuerstlein R, Kreipe HH, Gluz O. The role of immune and apoptosis markers for prediction of pCR in the WSG-ADAPT HER2+/HR+ phase II trial evaluating 12-weeks of neoadjuvant TDM1 ± endocrine therapy (ET) versus T + ET in HER2-positive hormone-receptor-positive early breast cancer (EBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-09-05.

Background: Several candidate BMs have been explored in randomized trials of BEV across tumor types with the aim of identifying patients (pts) deriving the most substantial benefit from BEV therapy. In phase III trials, baseline pVEGF-A and pVEGFR-2 showed potential predictive value in metastatic BC (AVADO, AVEREL), pancreatic cancer (AViTA), and gastric cancer (AVAGAST; VEGF-A only). The randomized phase III BEATRICE trial, evaluating the addition of BEV to adjuvant chemotherapy in pts with triple-negative early BC, includes a comprehensive program to identify potential BMs predicting efficacy and toxicity of BEV therapy. We report results for baseline pVEGF-A and pVEGFR-2. Methods: After selection of chemotherapy (anthracycline and/or taxane), pts with T1a-T3 operable BC were randomized 1:1 to receive ≥4 cycles of chemotherapy either alone or with 1 year of BEV 5 mg/kg/wk equivalent. The primary endpoint is invasive disease-free survival (IDFS). pEDTA samples were collected from consenting pts at baseline (before treatment, after surgery), during study treatment, and at relapse. Pts were dichotomized using the median baseline concentration of each marker as the cut-off between high and low cohorts; further exploratory analyses were also performed by quartile. Results: Between Dec 2007 and Mar 2010, 2591 pts were enrolled. Of these, 1273 (49%) consented to the BM study and 1178 (45%) were included in the BM-evaluable population (BEP). Overall, the BEP was representative of the ITT population except for lower proportions of Asian pts (12% vs 24%). IDFS was similar in the BEP and ITT populations. Baseline characteristics were balanced between arms in the BEP. Baseline pVEGF-A showed neither prognostic nor predictive value using the median as the cut-off, although with a third quartile (Q3) cut-off there was a more pronounced but non-significant differentiation between treatments (HR 0.92 [low] vs 0.64 [high]). High baseline pVEGFR-2 showed potential predictive value for BEV efficacy (HR 1.24 [low] vs 0.61 [high]; p=0.029). Conclusions: Unlike trials in metastatic BC (AVADO, AVEREL), in the adjuvant setting, baseline pVEGF-A concentration did not show predictive value for BEV efficacy with a median cut-off. However, analyses using the Q3 cut-off suggest a trend toward predictive value. High baseline pVEGFR-2 was associated with greater BEV treatment effect, consistent with previous results in AVADO and AVEREL. The impact of differing biology in the adjuvant setting, lower median VEGF-A concentration than in the metastatic setting (77.0 vs 125.0–129.1 pg/mL), and the possible influence of surgery immediately before treatment require further investigation. Additional exploratory analyses are ongoing to provide better understanding of the BEATRICE dataset and the complex biology of angiogenesis, including additional markers, changes over time, and combination signatures. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-34.

572Background: The ADAPT HER2+/HR+ phase II trial (NCT01745965) compared for the first time 12 wks. neoadjuvant T-DM1 (+/- endocrine therapy (ET)) with trastuzumab (T)+ET; pCR (ypT0/is ypN0) was > ...

5556Background: We explored potential prognostic effects of biomarkers (BMs) and clinical risk factors in OC pts receiving 1st-line BEV in the single-arm ROSiA study [Oza, ECC 2015]. Methods: Pts w...

Background: TNBC is a mutationally complex heterogeneous breast cancer subtype. In BEATRICE, adding bevacizumab to standard adjuvant chemotherapy for eTNBC improved neither invasive disease-free survival (IDFS; primary endpoint) nor overall survival (OS) [Cameron 2013; Bell SABCS 2014]. We explored prognostic effects of tumor-associated immune and stromal gene signatures. Methods: Gene expression (RNA) was assessed in pretreatment archival tumor tissue using an 800-gene nanostring platform. Given the low event rates and lack of bevacizumab effect in BEATRICE, treatment arms were pooled. The biomarker-evaluable population (BEP; all patients with an evaluable biomarker sample and ≥1 postbaseline efficacy assessment) was dichotomized using median gene expression level as the cutoff. Prognostic associations between IDFS/OS and prespecified candidate gene sets/de novo identified clusters were assessed using univariate Cox proportional hazards models. Results: Baseline characteristics and efficacy were similar in the BEP (988/2591 randomized pts; 38%) and the overall study population. In hierarchical cluster analysis based exclusively on immune gene expression, immune genes were enriched in 33% of samples, intermediate in 38%, and weak in 28%. Further characterization suggested differential prognostic value of distinct immune and stromal cell gene sets (Table). A significant prognostic effect for IDFS and OS was seen for CD8 effector T cell (Teff) and regulatory T cell (Treg) gene signatures, but not for the Teff:Treg ratio. A less pronounced positive prognostic effect was seen for other gene sets representing immune cells, including macrophages, CD4 T cells, and B cells (data not shown). Activated T helper (Th)-1 cell-derived chemokines and negative immune modulators of T cell activity (eg PD-L1) were highly prognostic for IDFS and OS. Both the cytokine IL-8 and ESM1 (target of VEGF-A pathway activation) were associated with worse IDFS and OS. No association was seen between outcome and markers for classic microvasculature (CD31, CD34), cancer-associated fibroblasts (FAP, BGN, DCN), VEGF-A, or VEGF-C. IDFSOSGene signatureHR (95% CI)Interaction p-valueHR (95% CI)Interaction p-valueTeff0.40 (0.28-0.57)7.2x10-70.29 (0.17-0.49)4.2x10-6Treg0.38 (0.26-0.54)1.6x10-70.23 (0.13-0.40)2.9x10-7Teff:Treg ratio0.80 (0.58-1.12)0.20.89 (0.57-1.39)0.6Th10.45 (0.31-0.64)8.1x10-60.43 (0.27-0.70)5.8x10-4PD-L10.42 (0.29-0.60)1.8x10-60.24 (0.14-0.41)3.4x10-7IL-81.48 (1.06-2.08)0.0221.89 (1.18-3.01)0.0076ESM11.73 (1.23-2.43)0.00172.22 (1.38-3.58)0.001 Conclusions: These molecular gene signature analyses in eTNBC confirm that markers of cytotoxic CD8 T cells are associated with good prognosis. This is the first report of a positive prognostic effect of regulatory T cell markers, immune checkpoint modulators, and macrophage-associated markers in the adjuvant TNBC setting. High VEGF-A activity, but not its expression, was associated with worse prognosis. The strong prognostic effect of immune checkpoint modulators suggests equilibrium between cytotoxic T cells and their inhibitors in eTNBC, supporting further exploration of immune checkpoint inhibitors in this therapeutic context. Citation Format: Molinero L, Yu J, Li C, Deurloo R, Dent RA, Bell R, Brown J, Parmar M, Toi M, Suter T, Steger G, Pivot X, Mackey J, Jackisch C, Hall P, Hegde P, Bais C, Cameron D. Analysis of molecular prognostic factors associated with tumor immune and stromal microenvironment in BEATRICE, an open-label phase 3 trial in early triple-negative breast cancer (eTNBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S1-01.