Palbociclib Rechallenge for Hormone Receptor-Positive/HER-Negative Advanced Breast Cancer: Findings from the Phase II BioPER Trial

Hormone receptor; Advanced breast cancerCàncer de mama avançat; Receptor hormonalCáncer de mama avanzado; Receptor hormonalPurpose: To assess the efficacy and exploratory biomarkers of continuing palbociclib plus endocrine therapy (ET) beyond progression on prior palbociclib-based regimen in patients with hormone receptor–positive/HER2-negative (HR+/HER2−) advanced breast cancer (ABC). Patients and Methods: The multicenter, open-label, phase II BioPER trial included women who had experienced a progressive disease (PD) after having achieved clinical benefit on the immediately prior palbociclib plus ET regimen. Palbociclib (125 mg, 100 mg, or 75 mg daily orally for 3 weeks and 1 week off as per prior palbociclib-based regimen) plus ET of physician's choice were administered in 4-week cycles until PD or unacceptable toxicity. Coprimary endpoints were clinical benefit rate (CBR) and percentage of tumors with baseline loss of retinoblastoma (Rb) protein expression. Additional endpoints included safety and biomarker analysis. Results: Among 33 patients enrolled, CBR was 34.4% [95% confidence interval (CI), 18.6–53.2; P < 0.001] and 13.0% of tumors (95% CI, 5.2–27.5) showed loss of Rb protein expression, meeting both coprimary endpoints. Median progression-free survival was 2.6 months (95% CI, 1.8–6.7). No new safety signals were reported. A signature that included baseline mediators of therapeutic resistance to palbociclib and ET (low Rb score, high cyclin E1 score, ESR1 mutation) was independently associated with shorter median progression-free survival (HR, 22.0; 95% CI, 1.71–282.9; P = 0.018). Conclusions: Maintaining palbociclib after progression on prior palbociclib-based regimen seems to be a reasonable, investigational approach for selected patients. A composite biomarker signature predicts a subset of patients who may not derive a greater benefit from palbociclib rechallenge, warranting further validation in larger randomized controlled trials.This work was supported by Pfizer. The authors would like to thank the patients, their caregivers, and their families for participating in this study and all investigators and site personnel. The BioPER study was conceived and designed by Medica Scientia Innovation Research (MEDSIR) in collaboration with Pfizer Inc., which funded the study and provided palbociclib. J. Albanell acknowledges CIBERONC CB16/12/00241, PI21/00002, funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union, Generalitat de Catalunya (2017 SGR 507)

Differences in breast cancer risk after benign breast disease by type of screening diagnosis

Neoplàsies de mama; Detecció precoç del càncer; Factors de riscNeoplasias de mama; Detección precoz del cáncer; Factores de riesgoBreast neoplasms; Early cancer detection; Risk factorsIntroduction: We aimed to assess differences in breast cancer risk across benign breast disease diagnosed at prevalent or incident screens. Materials and methods: We conducted a retrospective cohort study with data from 629,087 women participating in a long-standing population-based breast cancer screening program in Spain. Each benign breast disease was classified as non-proliferative, proliferative without atypia, or roliferative with atypia, and whether it was diagnosed in a prevalent or incident screen. We used partly conditional Cox hazard regression to estimate the adjusted hazard ratios of the risk of breast cancer. Results: Compared with women without benign breast disease, the risk of breast cancer was significantly higher (p-value ¼ 0.005) in women with benign breast disease diagnosed in an incident screen (aHR, 2.67; 95%CI: 2.24e3.19) than in those with benign breast disease diagnosed in a prevalent screen (aHR, 1.87; 95%CI: 1.57e2.24). The highest risk was found in women with a proliferative benign breast disease with atypia (aHR, 4.35; 95%CI: 2.09e9.08, and 3.35; 95%CI: 1.51e7.40 for those diagnosed at incident and prevalent screens, respectively), while the lowest was found in women with non-proliferative benign breast disease (aHR, 2.39; 95%CI: 1.95e2.93, and 1.63; 95%CI: 1.32e2.02 for those diagnosed at incident and prevalent screens, respectively). Conclusion: Our study showed that the risk of breast cancer conferred by a benign breast disease differed according to type of screen (prevalent or incident). To our knowledge, this is the first study to analyse the impact of the screening type on benign breast disease prognosisThis study was supported by grants from Instituto de Salud Carlos III FEDER (grant numbers: PI15/00098 and PI17/00047), and by the Research Network on Health Services in Chronic Diseases (RD12/0001/0015

Identification and characterization of a novel population of memory B cells in the human intestine

We found that IgM+IgD- memory (ME-M) B cells formed a large reservoir of intestinal antigen-selected IgM+ lymphocytes distinct from antigen-naïve IgM+ lymphocytes. Human ME-M B cells colonized the intestine early in life, persisted throughout adulthood and inhabited Peyer’s patches and isolated lymphoid follicles. Intestinal ME-M B cells shared some commonalities with splenic IgM+IgDlowCD27+ marginal zone B cells, including phenotypic traits, multiple IgVH gene families and a pronounced reactivity against microbial carbohydrates and lipids. However, ME-M B cells expressed a gut-specific gene signature and an IgVH gene mutation profile consistent with a germinal center origin from gut inductive sites. Accordingly, ME-M B cells showed strong reactivity against mucus-embedded commensal antigens. Furthermore, ME-M B cells generated IgM+ or IgA+ plasma cells (PC) in response to T cell-dependent or independent signals and organized clonally coordinated IgM and IgA responses in ileum and colon. IgM+ PC emerging from ME-M B cells released IgM antibodies that along with IgA, coated intestinal bacteria and fungi.Hem descovert que les cèl·lules B de memòria IgM+IgD- (ME-M) formen una gran reserva intestinal de limfòcits preseleccionats diferents dels limfòcits verges. Les cèl·lules ME-M colonitzen l'intestí als inicis de la vida i hi perduren durant l’edat adulta en les plaques de Peyer i els fol·licles limfoides aïllats. Les cèl·lules ME-M comparteixen certes característiques amb les cèl·lules B IgM+IgDlleuCD27+ de la zona marginal esplènica, incloent trets fenotípics, famílies de gens IgVH i reactivitat pronunciada contra hidrats de carboni i lípids microbians. No obstant això, les cèl·lules ME-M expressen una signatura gènica específica del intestí i un perfil de mutació en els gens IgVH consistent amb un origen a centres germinals intestinals. En consequència, les cèl·lules ME-M mostren reactivitat enfront d'antígens comensals del moc intestinal. A més, les cèl·lules ME-M generen cèl·lules plasmàtiques (PC) IgM+ o IgA+ en resposta a senyals dependents i independents de cèl·lules T, i organitzen respostes clonals coordinades IgM i IgA en l'ili i el còlon. PC IgM+ derivades de cèl·lules ME-M, produeixen anticossos IgM que, juntament amb IgA, recobreixen bacteris i fongs del moc intestinal

Identification and characterization of a novel population of memory B cells in the human intestine

We found that IgM+IgD- memory (ME-M) B cells formed a large reservoir of intestinal antigen-selected IgM+ lymphocytes distinct from antigen-naïve IgM+ lymphocytes. Human ME-M B cells colonized the intestine early in life, persisted throughout adulthood and inhabited Peyer’s patches and isolated lymphoid follicles. Intestinal ME-M B cells shared some commonalities with splenic IgM+IgDlowCD27+ marginal zone B cells, including phenotypic traits, multiple IgVH gene families and a pronounced reactivity against microbial carbohydrates and lipids. However, ME-M B cells expressed a gut-specific gene signature and an IgVH gene mutation profile consistent with a germinal center origin from gut inductive sites. Accordingly, ME-M B cells showed strong reactivity against mucus-embedded commensal antigens. Furthermore, ME-M B cells generated IgM+ or IgA+ plasma cells (PC) in response to T cell-dependent or independent signals and organized clonally coordinated IgM and IgA responses in ileum and colon. IgM+ PC emerging from ME-M B cells released IgM antibodies that along with IgA, coated intestinal bacteria and fungi.Hem descovert que les cèl·lules B de memòria IgM+IgD- (ME-M) formen una gran reserva intestinal de limfòcits preseleccionats diferents dels limfòcits verges. Les cèl·lules ME-M colonitzen l'intestí als inicis de la vida i hi perduren durant l’edat adulta en les plaques de Peyer i els fol·licles limfoides aïllats. Les cèl·lules ME-M comparteixen certes característiques amb les cèl·lules B IgM+IgDlleuCD27+ de la zona marginal esplènica, incloent trets fenotípics, famílies de gens IgVH i reactivitat pronunciada contra hidrats de carboni i lípids microbians. No obstant això, les cèl·lules ME-M expressen una signatura gènica específica del intestí i un perfil de mutació en els gens IgVH consistent amb un origen a centres germinals intestinals. En consequència, les cèl·lules ME-M mostren reactivitat enfront d'antígens comensals del moc intestinal. A més, les cèl·lules ME-M generen cèl·lules plasmàtiques (PC) IgM+ o IgA+ en resposta a senyals dependents i independents de cèl·lules T, i organitzen respostes clonals coordinades IgM i IgA en l'ili i el còlon. PC IgM+ derivades de cèl·lules ME-M, produeixen anticossos IgM que, juntament amb IgA, recobreixen bacteris i fongs del moc intestinal

Palbociclib rechallenge for hormone receptor-positive/HER-negative advanced breast cancer: findings from the phase II BioPER trial

Purpose: to assess the efficacy and exploratory biomarkers of continuing palbociclib plus endocrine therapy (ET) beyond progression on prior palbociclib-based regimen in patients with hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer (ABC). Patients and methods: the multicenter, open-label, phase II BioPER trial included women who had experienced a progressive disease (PD) after having achieved clinical benefit on the immediately prior palbociclib plus ET regimen. Palbociclib (125 mg, 100 mg, or 75 mg daily orally for 3 weeks and 1 week off as per prior palbociclib-based regimen) plus ET of physician's choice were administered in 4-week cycles until PD or unacceptable toxicity. Coprimary endpoints were clinical benefit rate (CBR) and percentage of tumors with baseline loss of retinoblastoma (Rb) protein expression. Additional endpoints included safety and biomarker analysis. Results: among 33 patients enrolled, CBR was 34.4% [95% confidence interval (CI), 18.6-53.2; P < 0.001] and 13.0% of tumors (95% CI, 5.2-27.5) showed loss of Rb protein expression, meeting both coprimary endpoints. Median progression-free survival was 2.6 months (95% CI, 1.8-6.7). No new safety signals were reported. A signature that included baseline mediators of therapeutic resistance to palbociclib and ET (low Rb score, high cyclin E1 score, ESR1 mutation) was independently associated with shorter median progression-free survival (HR, 22.0; 95% CI, 1.71-282.9; P = 0.018). Conclusions: maintaining palbociclib after progression on prior palbociclib-based regimen seems to be a reasonable, investigational approach for selected patients. A composite biomarker signature predicts a subset of patients who may not derive a greater benefit from palbociclib rechallenge, warranting further validation in larger randomized controlled trials

Snail1 expression in endothelial cells controls growth, angiogenesis and differentiation of breast tumors

Snail1 is a transcriptional factor required for epithelial to mesenchymal transition and activation of cancer-associated fibroblasts (CAF). Apart from that, tumor endothelial cells also express Snail1. Here, we have unraveled the role of Snail1 in this tissue in a tumorigenic context. Methods: We generated transgenic mice with an endothelial-specific and inducible Snail1 depletion. This murine line was crossed with MMTV-PyMT mice that develop mammary gland tumors and the consequence of Snail1 depletion in the endothelium were investigated. We also interfere Snail1 expression in cultured endothelial cells. Results: Specific Snail1 depletion in the endothelium of adult mice does not promote an overt phenotype; however, it delays the formation of mammary gland tumors in MMTV-PyMT mice. These effects are associated to the inability of Snail1-deficient endothelial cells to undergo angiogenesis and to enhance CAF activation in a paracrine manner. Moreover, tumors generated in mice with endothelium-specific Snail1 depletion are less advanced and show a papillary phenotype. Similar changes on onset and tumor morphology are observed by pretreatment of MMTV-PyMT mice with the angiogenic inhibitor Bevacizumab. Human breast papillary carcinomas exhibit a lower angiogenesis and present lower staining of Snail1, both in endothelial and stromal cells, compared with other breast neoplasms. Furthermore, human breast tumors datasets show a strong correlation between Snail1 expression and high angiogenesis. Conclusion: These findings show a novel role for Snail1 in endothelial cell activation and demonstrate that these cells impact not only on angiogenesis, but also on tumor onset and phenotype.This study was funded by grants awarded to AGH by Agencia Estatal de Investigación (AEI) and Fondos FEDER (SAF2016-76461-R) and AEI (PID2019-104695RB-100/AEI/10.13039/501100011033). We also acknowledge support from the Instituto Carlos III / FEDER (PIE15/00008; PT17/0015/0011) and the "Xarxa de Bancs de tumors” sponsored by Pla Director d'Oncologia de Catalunya (XBTC). DCG was recipient of an FPU predoctoral fellowship from Ministerio de Educació

PD-L1 testing based on the SP142 antibody in metastatic triple-negative breast cancer: summary of an expert round-table discussion

Triple-negative breast cancer (TNBC) is more aggressive than other breast cancer subtypes. TNBC is characterized by increased expression of Programmed Death-ligand 1 (PD-L1), a signal used by many tumors to escape the immune response. Expression of PD-L1 is a positive predictor of response to immunotherapy; therefore, it should be investigated in TNBC in order to select patients who may benefit from anti-PD-L1 therapies. While many PD-L1 assays are available, only the VENTANA platform with the anti-PD-L1 (SP142) antibody is licensed as a companion diagnostic device for selecting patients with metastatic/advanced TNBC who are candidates for treatment with atezolizumab. In this article, we provide a summary of an expert round-table discussion about PD-L1 testing, using the SP142 antibody in metastatic TNBC

Glutamine-directed migration of cancer-activated fibroblasts facilitates epithelial tumor invasion

Tumors are complex tissues composed of transformed epithelial cells as well as cancer-activated fibroblasts (CAF) that facilitate epithelial tumor cell invasion. We show here that CAFs and other mesenchymal cells rely much more on glutamine than epithelial tumor cells; consequently, they are more sensitive to inhibition of glutaminase. Glutamine dependence drove CAF migration toward this amino acid when cultured in low glutamine conditions. CAFs also invaded a Matrigel matrix following a glutamine concentration gradient and enhanced the invasion of tumor cells when both cells were cocultured. Accordingly, glutamine directed invasion of xenografted tumors in immunocompromised mice. Stimulation of glutamine-driven epithelial tumor invasion by fibroblasts required previous CAF activation, which involved the TGFβ/Snail1 signaling axis. CAFs moving toward Gln presented a polarized Akt2 distribution that was modulated by the Gln-dependent activity of TRAF6 and p62 in the migrating front, and depletion of these proteins prevented Akt2 polarization and Gln-driven CAF invasion. Our results demonstrate that glutamine deprivation promotes CAF migration and invasion, which in turn facilitates the movement of tumor epithelial cells toward nutrient-rich territories. These results provide a novel molecular mechanism for how metabolic stress enhances invasion and metastasis. SIGNIFICANCE: Cancer-associated fibroblasts migrate and invade toward free glutamine and facilitate invasion of tumor epithelial cells, accounting for their movement away from the hostile conditions of the tumor towards nutrient-rich adjacent tissues. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/2/438/F1.large.jpg.We thank Drs. J. Moscat for advice, J. Yélamos, M. Birnbaum and L. Tío for cell lines and reagents and M. Iglesias for assistance. This study was funded by grants awarded by Ministerio de Ciencia, Innovación y Universidades -Agencia Estatal de Investigación (Retos de Investigación) and FEDER (SAF2016-76461-R and PID2019-104698RB-I00 to AGH and RTI2018-099719-B-100 to MD). We also acknowledge support from the Instituto Carlos III (PIE15/00008). AMF was funded by a Predoctoral FI Contract by the Secretaria d'Universitats i Recerca del Departament d'Empresa i Coneixement de la Generalitat de Catalunya (FI-DGR 2016); MBO and LAC were recipients of FPI contracts awarded by Ministerio de Ciencia y Tecnologia

Accuracy of sentinel node mapping in patients with biopsy-proven metastatic axillary lymph nodes and upfront surgery: preliminary results of the Multimodal Targeted Axillary Surgery (MUTAS) trial

Background: Some studies suggested that the patients included in the Z0011 trial may represent patients with ultrasound-negative axillary nodes and axillary invasion diagnosed by sentinel node (SN) biopsy. Nevertheless, the National Comprehensive Cancer Network (NCCN) guidelines recommend SN mapping if 1 or 2 suspicious lymph nodes are identified on axillary ultrasound (AU). The aim of this preliminary phase of the Multimodal Targeted Axillary Surgery (MUTAS) trial was to establish the accuracy of SN mapping in patients with axillary involvement undergoing upfront surgery. Methods: Between September 2019 and March 2022, we recruited patients with biopsy-proven metastatic axillary nodes and upfront surgery from a single center. We performed SN mapping in these patients before the surgical intervention, which included axillary lymph node dissection. The biopsy-proven metastatic node, SNs and the remaining axillary nodes were excised separately. SN status was considered representative of the status of the remaining axillary nodes. We calculated the sensitivity, specificity, negative predictive value and positive predictive value of the SN, overall and in patients with palpable nodes, in those with non-palpable nodes and an AU leading to diagnosis of axillary involvement, in those with 1 or 2 suspicious nodes on AU, and in patients with a single suspicious node on AU. We evaluated clinical, imaging and pathology features as predictors of the status of the remaining axillary nodes, false-negatives, and false-positives. Results: We included 25 patients in this phase. The false-negative rate of SN mapping was 28% overall, 21.42% for patients with palpable nodes, 36.36% for patients with non-palpable nodes and an AU diagnosis of axillary involvement, 28.75% for those with 1 or 2 suspicious nodes on AU, and 15.38% in patients with a single suspicious node on AU. The negative predictive value was highest in patients with a single suspicious node on AU (75%). The only significant predictive factor was that FN showed a higher Ki67 index score. Conclusions: In this study, SN mapping was not reliable in patients with biopsy-proven metastatic axillary nodes and upfront surgery for any of the subgroups studied. Further research should elucidate the best staging pathways in these patients to avoid premature de-escalation

LCOR mediates interferon-independent tumor immunogenicity and responsiveness to immune-checkpoint blockade in triple-negative breast cancer

Ligand-dependent corepressor (LCOR) mediates normal and malignant breast stem cell differentiation. Cancer stem cells (CSCs) generate phenotypic heterogeneity and drive therapy resistance, yet their role in immunotherapy is poorly understood. Here we show that immune-checkpoint blockade (ICB) therapy selects for LCORlow CSCs with reduced antigen processing/presentation machinery (APM) driving immune escape and ICB resistance in triple-negative breast cancer (TNBC). We unveil an unexpected function of LCOR as a master transcriptional activator of APM genes binding to IFN-stimulated response elements (ISREs) in an IFN signaling-independent manner. Through genetic modification of LCOR expression, we demonstrate its central role in modulation of tumor immunogenicity and ICB responsiveness. In TNBC, LCOR associates with ICB clinical response. Importantly, extracellular vesicle (EV) Lcor-messenger RNA therapy in combination with anti-PD-L1 overcame resistance and eradicated breast cancer metastasis in preclinical models. Collectively, these data support LCOR as a promising target for enhancement of ICB efficacy in TNBC, by boosting of tumor APM independently of IFN.This work was supported by the Instituto de Salud Carlos III-FSE (nos. MS17/00037 and PI18/00014) and the Cancer Research Institute, Clinic and Laboratory Integration Program (grant no. CRI2477 to T.C.-T). We also thank the AECC LAB (grant no. LABAE19007CELI) and the FERO foundation (to T.C.-T). This work was also supported by ISCIII (CIBERONC nos. CB16/12/00481, CB16/12/00241, PI18/00006 and PI21/00002), Generalitat de Catalunya (no. 2017 SGR 507) and the European Community through the Regional Development Funding Program to J. Albanell. Y.K. is supported by the Brewster Foundation, the Breast Cancer Research Foundation, the Susan G. Komen Foundation and the American Cancer Society. J. Arribas is funded by the Breast Cancer Research Foundation (no. BCRF-20-08), Instituto de Salud Carlos III (no. PI19/01181), Asociación Española Contra el Cáncer (no. GCAEC19017ARRI) and Fundación BBVA (no. CAIMI VHIO-FBBVA 2018-2021). M.M.A. is funded by MICINN and the Spanish Government (no. PGC2018-094091-B-I00). D.C. was funded by Instituto de Salud Carlos III (no. JR1800003). S.M. is funded by PERIS (no. SLT006/17/00040). The wotk of R.R.G. is funded by MICINN, the Spanish Government (no. PID2019-104948RB-I00) and the BBVA Foundation. S.B and J.P. acknowledge support from the Spanish Ministry of Science, the EMBL partnership and the CESO and CERCA Program