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There is a strong biologic rationale that poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors may benefit a broader range of metastatic breast cancer (MBC) patients than covered by current approvals, which require a germline BRCA1/2 sequence variant affecting function. We report a patient with germline/somatic BRCA1/2 wild-type MBC, who had a dramatic response to the PARP inhibitor olaparib of at least 8 months’ duration. The patient is a 37-year-old woman with recurrent, hormone receptor-positive, HER2-negative MBC that had progressed despite hormonal therapy and palbociclib. Sensitivity to olaparib was likely conferred by a germline sequence variant affecting function in PALB2 (exon 1, c.18G>T, p.(=)). This case documenting activity of olaparib monotherapy in germline/somatic BRCA1/2 wild-type MBC illustrates that the clinical potential of PARP inhibition in MBC extends beyond currently approved indications to additional patients whose tumors have (epi)genetic changes affecting homologous recombination repair.

Background: Breast cancer (BC) patients with ≥ 4 positive lymph nodes have a particularly poor prognosis with shorter disease free survival (DFS) and overall survival (OS) than pts with pN1a. However this is a highly heterogeneous group. The implementation of genomic signatures and/or Ki-67 status for hormone receptor positive BC pts with node negative or positive (≤ pN1a) disease enables identification of a subgroup of pts with favourable outcome and no survival benefit from chemotherapy (CTX). However, here is lack of information regarding pts with ≥ 4 positive lymph nodes, and so far all patients receive a recommendation for CTX. In addition, there are no predictive factors for use of dd CTX in this group so far. Methods: Between 1996–2000, 231 BC pts ≥ pN2a (median positive lymph nodes n= 6) with no evidence of distant metastases, were randomized to either adjuvant dd treatment with dd 3 × epirubicin (E, 90 mg/m2) + paclitaxel (P, 175 mg/m2) every 2 weeks (q2w) followed by 3 × cyclophosphamide (C)/methotrexate/5-fluorouracil (CMF, 600/40/600 mg/m2, q2w), or standard (st) treatment : 4 × E + C (C, 600 mg/m2) q3w followed by 3 × CMF q3w. Pts in the dd arm had a significantly better DFS (adjusted p = 0.027) with a non-significant trend to better OS (adjusted p = 0.058). Due to the recruitment period, there is no information on the HER2 status of the included pts (Reinisch et al, 2018). The BC360 panel analysis was performed on 147 tumor specimens (dd arm n= 75; st arm n= 72). Samples were run on the 770 gene BC360 panel with additional 6 spike-in genes. Genes related to adhesion and migration, immune activation, ER signaling, DNA damage and repair, apoptosis, and proliferation were analyzed. The survival analysis was used to create the forest plot incorporating a Cox proportional hazards model with the survival outcome as a dependent variable, the observed normalized gene expression or signature score data as a continuous covariate, and any grouping variable included as a strata variable in the model. Results: After quality control, 144/147 tumor specimens were available for the analysis (dd arm: 72; st arm; 72). The intrinsic subtype was equivalently distributed between the arms. The expression of PD-L1 (p = 0.025), PD-L2 (p = 0.007) and the presence of macrophages (p = 0.019) were positively correlated with an improved DFS in pts receiving dd but not st CTX. An improved OS was also associated with the presence of macrophages (p = 0.018) and the expression of TGF-β (p = 0.035) only in pts receiving dd CTX. Pts with a HER2 enriched subtype benefited from the use of dd CTX. Dd CTX does not influence the outcome in BRCAness and HRD positive pts regardless the applied CTX. Further prognostic and predictive factors correlated to a median FU of 20 years will be presented at the meeting. Conclusions: To our best knowledge, this is the first time the BC360 panel was run on samples of a cohort of high risk pts with ≥ pN2a with a median long term FU of 20 years. Our data may indicate that markers associated with immune activation are predictive factors for the use of dd therapies. High risk pts with different benefit from CTX may be identified. In pts with a HER2 enriched subtype not having received anti-HER2 therapy, the application of dd therapy may correlate with a better outcome. This analysis highlights the prognostic and predictive value of gene signatures to provide treatment guidance. Citation Format: Mattea Reinisch, Oleg Gluz, Beyhan Ataseven, Peter Schmid, Jens-Uwe Blohmer, Christine Dittmer-Grabwoski, Anna Rueland, Simona Bruzas, Christine Seiberling, Hakima Harrach, Daniel Gebauer, Alexander Traut, Sherko Kuemmel. Prognostic and predictive impact of genes and signatures measured with the BC360 panel (Nanostring) in node positive (≥pN2a) high risk patients (pts) receiving dose dense (dd) versus standard dosed chemotherapy in an adjuvant randomized trial with a long term follow-up (FU) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD5-09.

Next-generation sequencing (NGS) followed by matched therapy has opened up new therapeutic options to patients with metastatic breast cancer (mBC). Here we report our experience with this approach in everyday clinical practice. This retrospective study included 95 patients with mBC who were genotyped with the FoundationOne® (CDx) assay in a commercial molecular pathology laboratory. Genetic alterations were identified in all tumor specimens, and 83 patients (87.4%) had a median of 2 (range, 1–6) potentially actionable alterations. A multidisciplinary tumor board recommended genomically guided therapy to 63 patients, 30 of whom received such treatment. Everolimus (n = 15) and anti-human epidermal growth factor receptor 2 (HER2) therapy (n = 6) were most frequently administered. The ratio of progression-free survival (PFS) under NGS-based therapy to PFS under the last line of standard therapy prior to NGS was &gt, 1.3 in 13 (43.3%) patients, indicative of a clinical benefit to NGS-directed therapy. One-year overall survival rates were 22.7% (95% CI, 6.5–44.4) in 65 patients allocated to the standard therapy versus 62.9% (95% CI, 41.6–78.2) in 30 patients receiving the matched therapy. In conclusion, NGS-matched treatment improved the clinical outcomes in a subgroup of mBC patients.

BackgroundThe genomic landscape of phyllodes tumors (PTs) of the breast is not well defined, especially in patients with advanced disease. To shed light on this topic, paired primary and progressed tumor samples from two patients with malignant PTs were subjected to next-generation sequencing (NGS) followed by functional analysis of genetic alterations using two prediction tools.MethodsThe DNA of both the primary tumor and distant metastases of Patient 1 and the primary and recurrent tumor of Patient 2 were subjected to molecular profiling. NGS with the FoundationOne® assay was performed in a commercial molecular pathology laboratory. Two in silico prediction tools were used to estimate the pathogenicity of indicated genetic alterations.ResultsIn total, 38 genomic alterations were detected, of which 11 were predicted to be probably benign. In Patient 1, 14 aberrations were identified in the primary tumor and 17 in pulmonary metastases, 12 of which were identical. In the primary and recurrent tumor of Patient 2, 17 and 15 sequence variants, respectively, were found, with 13 overlapping findings. Affected genes included seven (TP53,TERT,APC,ARID1A,EGFR,KMT2D, andRB1) of the top 10 most frequently altered genes in other advanced cancer entities, as well as four actionable therapeutic targets (EGFR,KIT,PDGFRA, andBRIP1). Of note, seven genes coding for receptor tyrosine kinases were affected: three in Patient 1 and four in Patient 2. Several genes (e.g.EPHA3,EPHA7, andEPHB1) were shown to be altered for the first time in PTs.ConclusionsThe two progressed malignant PTs investigated here share some of the major genetic events occurring in other advanced cancers.

Objective This study aimed to investigate the feasibility and accuracy of non-radioactive target lymph node (TLN) biopsy and targeted axillary dissection (TAD) in routine clinical practice. Background data TAD involves TLN biopsy (TLNB) and sentinel lymph node biopsy (SLNB) and was recently introduced as a new standard for less invasive axillary staging in breast cancer (BC) patients undergoing neoadjuvant systemic therapy (NST); however, clinical evidence is limited. Methods The SenTa study is a prospective registry study conducted at 50 centers. Patients with invasive BC who underwent clip insertion into the most suspicious axillary lymph node (LN) were eligible. Axillary surgery was performed with or without SLNB, TLNB, and/or axillary lymph node dissection (ALND). Main endpoints were the detection rate (DR) and false-negative rate (FNR) of TLNB and TAD after NST. Results Between 2017 and 2018, 548 consecutive BC patients underwent clip placement into biopsy-confirmed positive LNs. After NST (n = 473), the clipped TLN was intraoperatively resected in 329 of 423 patients (77.8%, 95% confidence interval [CI]: 74.0 to 82.0). TAD was successful in 199 of 229 patients (DR: 86.9%, 95% CI: 81.8 to 91.0), the SLN and TLN were identical in 129 patient (64.8%). FNRs were 7.2% (8 of 111, 95% CI: 3.1 to 13.6) for TLNB followed by ALND (n = 203) and 4.3% (2 of 46, 95% CI: 0.5 to 14.8) for TAD followed by ALND (n = 77). Conclusions The SenTa study demonstrates the feasibility of TAD in a real-world cohort of BC patients. Our findings are of great importance for de-escalation of surgical strategies.

Costimulatory molecules, such as the programmed death ligand (PD-L1), might exert differential effects on T-cell function, depending on the clinical setting and/or immunological environment. Given the impact of T cells on bronchiolitis obliterans (BO) in lung transplantation, we used an established tracheal transplant model inducing BO-like lesions to investigate the impact of PD-L1 on alloimmune responses and histopathological outcome in BO. In contrast to other transplant models in which PD-L1 generally shows protective functions, we demonstrated that PD-L1 has divergent effects depending on its location in donor versus recipient tissue. Although PD-L1 deficiency in donor tissue worsened histopathological outcome, and increased systemic inflammatory response, recipient PD-L1 deficiency induced opposite effects. Mechanistic studies revealed PD-L1–deficient recipients were hyporesponsive toward alloantigen, despite increased numbers of CD8 + effector T cells. The function of PD-L1 on T cells after unspecific stimulation was dependent on both cell type and strength of stimulation. This novel function of recipient PD-L1 may result from the high degree of T-cell activation within the highly immunogenic milieu of the transplanted tissue. In this model, both decreased T-cell alloimmune responses and the reduction of BO in PD-L1–deficient recipients suggest a potential therapeutic role of selectively blocking PD-L1 in the recipient. Further investigation is warranted to determine the impact of this finding embedded in the complex pathophysiological context of BO.

Obliterative bronchiolitis (OB) remains the most significant cause of death in long-term survival of lung transplantation. Using an established murine heterotopic tracheal allograft model, the effects of different routes of administration of bone marrow-derived multipotent stromal cells (MSCs) on the development of OB were evaluated. Tracheas from BALB/c mice were implanted into the subcutaneous tissue of major histocompatibility complex- (MHC-) disparate C57BL/6 mice. At the time of transplant, bone marrow-derived MSCs were administered either systemically or locally or via a combination of the two routes. The allografts were explanted at various time points after transplantation and were evaluated for epithelial integrity, inflammatory cell infiltration, fibrosis, and luminal obliteration. We found that the most effective route of bone marrow-derived MSC administration is the combination of systemic and local delivery. Treatment of recipient mice with MSCs suppressed neutrophil, macrophage, and T-cell infiltration and reduced fibrosis. These beneficial effects were observed despite lack of significant MSC epithelial engraftment or new epithelial cell generation. Our study suggests that optimal combination of systemic and local delivery of MSCs may ameliorate the development of obliterative airway disease through modulation of immune response.