Skip to main content

Advertisement

SpringerLink
Log in

Correlative studies investigating effects of PI3K inhibition on peripheral leukocytes in metastatic breast cancer: potential implications for immunotherapy

  • Clinical trial
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

Patients with localized breast cancer have a 5-year survival rate > 99% compared to patients with metastatic breast cancer (MBC) that have a 5-year survival rate of ~ 27%. Unregulated PI3K/AKT signaling is a common characteristic of MBC, making it a desirable therapeutic target for tumors with activating mutations in this pathway. Interestingly, inhibition of the PI3K/AKT pathway can affect signaling in immune cells, which could potentially alter the immune phenotype of patients undergoing therapy with these drugs. The purpose of this study is to evaluate how PI3K inhibition affects the immune cells of MBC patients during treatment.

Methods

We investigated the effects of PI3K inhibition on the immune cell populations in peripheral blood of MBC patients enrolled in 4 different clinical trials utilizing PI3K inhibitors. Peripheral blood was drawn at different points in patient treatment cycles to record immune cell fluctuations in response to therapy.

Results

MBC patients who responded to treatment with a positive fold-change in cytotoxic T cell population, had an average duration of treatment response of 31.4 months. In contrast, MBC patients who responded to treatment with a negative fold-change in cytotoxic T-cell population, had an average duration of therapeutic response of 5 months. These data suggest that patients with a more robust, initial anti-tumor T cell response may have a longer therapeutic response compared to patients who do not have a robust, initial anti-tumor T cell response.

Conclusions

These results highlight the potential for PI3K inhibition to sensitize tumors to immune checkpoint inhibitors, thus providing additional therapeutic options for patients with MBC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Breast Cancer Statistics (2019) In: Control DoCPa (ed). CDC Website, vol 2019

  2. Weigelt B, Peterse JL, van’t Veer LJ (2005) Breast cancer metastasis: markers and models. Nat Rev Cancer 5:591–602

    Article  CAS  Google Scholar 

  3. Campbell IG, Russell SE, Choong DY, Montgomery KG, Ciavarella ML, Hooi CS et al (2004) Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res 64:7678–7681

    Article  CAS  Google Scholar 

  4. Costa RLB, Han HS, Gradishar WJ (2018) Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: a review. Breast Cancer Res Treat 169:397–406

    Article  CAS  Google Scholar 

  5. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI et al (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943–1947

    Article  CAS  Google Scholar 

  6. Ooms LM, Binge LC, Davies EM, Rahman P, Conway JR, Gurung R et al (2015) The inositol polyphosphate 5-phosphatase PIPP regulates AKT1-dependent breast cancer growth and metastasis. Cancer Cell 28:155–169

    Article  CAS  Google Scholar 

  7. Jean S, Kiger AA (2014) Classes of phosphoinositide 3-kinases at a glance. J Cell Sci 127:923–928

    Article  CAS  Google Scholar 

  8. Polyak K, Metzger Filho O (2012) SnapShot: breast cancer. Cancer Cell 22(562–562):e561

    Google Scholar 

  9. Fruman DA, Meyers RE, Cantley LC (1998) Phosphoinositide kinases. Annu Rev Biochem 67:481–507

    Article  CAS  Google Scholar 

  10. Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT (2017) The PI3K pathway in human disease. Cell 170:605–635

    Article  CAS  Google Scholar 

  11. Okkenhaug K, Graupera M, Vanhaesebroeck B (2016) Targeting PI3K in cancer: impact on tumor cells, their protective stroma, angiogenesis, and immunotherapy. Cancer Discov 6:1090–1105

    Article  CAS  Google Scholar 

  12. Orditura M, Della Corte CM, Diana A, Ciaramella V, Franzese E, Famiglietti V et al (2018) Three dimensional primary cultures for selecting human breast cancers that are sensitive to the anti-tumor activity of ipatasertib or taselisib in combination with anti-microtubule cytotoxic drugs. Breast 41:165–171

    Article  CAS  Google Scholar 

  13. Andre F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS et al (2019) Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med 380:1929–1940

    Article  CAS  Google Scholar 

  14. Baird RD, van Rossum AGJ, Oliveira M, Beelen K, Gao M, Schrier M et al (2019) POSEIDON trial phase 1b results: safety, efficacy and circulating tumor DNA response of the beta isoform-sparing PI3K inhibitor taselisib (GDC-0032) combined with tamoxifen in hormone receptor positive metastatic breast cancer patients. Clin Cancer Res 25:6598–6605

    Article  CAS  Google Scholar 

  15. Baselga J, Im SA, Iwata H, Cortes J, De Laurentiis M, Jiang Z et al (2017) Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 18:904–916

    Article  CAS  Google Scholar 

  16. Baselga J, Dent SF, Cortés J, Im Y-H, Diéras V, Harbeck N et al (2018) Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) v FULV in patients (pts) with estrogen receptor (ER)-positive, PIK3CA-mutant (MUT), locally advanced or metastatic breast cancer (MBC): primary analysis from SANDPIPER. J Clin Oncol 36:LBA1006

    Article  Google Scholar 

  17. Dickler MN, Saura C, Richards DA, Krop IE, Cervantes A, Bedard PL et al (2018) Phase II study of taselisib (GDC-0032) in combination with fulvestrant in patients with HER2-negative, hormone receptor-positive advanced breast cancer. Clin Cancer Res 24:4380–4387

    Article  CAS  Google Scholar 

  18. Hoeflich KP, Guan J, Edgar KA, O’Brien C, Savage H, Wilson TR et al (2016) The PI3K inhibitor taselisib overcomes letrozole resistance in a breast cancer model expressing aromatase. Genes Cancer 7:73–85

    Article  CAS  Google Scholar 

  19. Juric D, Krop I, Ramanathan RK, Wilson TR, Ware JA, Sanabria Bohorquez SM et al (2017) Phase I dose-escalation study of taselisib, an oral PI3K inhibitor, in patients with advanced solid tumors. Cancer Discov 7:704–715

    Article  CAS  Google Scholar 

  20. Mayer IA, Abramson VG, Formisano L, Balko JM, Estrada MV, Sanders ME et al (2017) A phase Ib study of alpelisib (BYL719), a PI3Kalpha-specific inhibitor, with letrozole in ER+/HER2-metastatic breast cancer. Clin Cancer Res 23:26–34

    Article  CAS  Google Scholar 

  21. Saura C, Roda D, Rosello S, Oliveira M, Macarulla T, Perez-Fidalgo JA et al (2017) A first-in-human phase I study of the ATP-competitive AKT inhibitor ipatasertib demonstrates robust and safe targeting of AKT in patients with solid tumors. Cancer Discov 7:102–113

    Article  CAS  Google Scholar 

  22. Saura C, Hlauschek D, Oliveira M, Zardavas D, Jallitsch-Halper A, de la Pena L et al (2019) Neoadjuvant letrozole plus taselisib versus letrozole plus placebo in postmenopausal women with oestrogen receptor-positive, HER2-negative, early-stage breast cancer (LORELEI): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 20:1226–1238

    Article  CAS  Google Scholar 

  23. Ndubaku CO, Heffron TP, Staben ST, Baumgardner M, Blaquiere N, Bradley E et al (2013) Discovery of 2-{3-[2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide (GDC-0032): a beta-sparing phosphoinositide 3-kinase inhibitor with high unbound exposure and robust in vivo antitumor activity. J Med Chem 56:4597–4610

    Article  CAS  Google Scholar 

  24. Moore HM, Savage HM, O’Brien C, Zhou W, Sokol ES, Goldberg ME et al (2019) Predictive and pharmacodynamic biomarkers of response to the phosphatidylinositol 3-kinase inhibitor taselisib in breast cancer preclinical models. Mol Cancer Ther 19(1):292–303

    Article  Google Scholar 

  25. Rinnerthaler G, Gampenrieder SP, Greil R (2018) ASCO 2018 highlights: metastatic breast cancer. Memo 11:276–279

    Article  Google Scholar 

  26. Rodon J, Curigliano G, Delord JP, Harb W, Azaro A, Han Y et al (2018) A Phase Ib, open-label, dose-finding study of alpelisib in combination with paclitaxel in patients with advanced solid tumors. Oncotarget 9:31709–31718

    Article  Google Scholar 

  27. Sharma P, Abramson VG, O’Dea A, Pathak HB, Pessetto ZY, Wang YY et al (2018) Clinical and biomarker results from phase I/II study of PI3K inhibitor BYL 719 (alpelisib) plus nab-paclitaxel in HER2-negative metastatic breast cancer. J Clin Oncol 36:1018

    Article  Google Scholar 

  28. Morgillo F, Della Corte CM, Diana A, Mauro CD, Ciaramella V, Barra G et al (2017) Phosphatidylinositol 3-kinase (PI3Kalpha)/AKT axis blockade with taselisib or ipatasertib enhances the efficacy of anti-microtubule drugs in human breast cancer cells. Oncotarget 8:76479–76491

    Article  Google Scholar 

  29. De Henau O, Rausch M, Winkler D, Campesato LF, Liu C, Cymerman DH et al (2016) Overcoming resistance to checkpoint blockade therapy by targeting PI3Kgamma in myeloid cells. Nature 539:443–447

    Article  Google Scholar 

  30. Kaneda MM, Messer KS, Ralainirina N, Li H, Leem CJ, Gorjestani S et al (2017) Corrigendum: PI3Kgamma is a molecular switch that controls immune suppression. Nature 542:124

    Article  CAS  Google Scholar 

  31. Sai J, Owens P, Novitskiy SV, Hawkins OE, Vilgelm AE, Yang J et al (2017) PI3K inhibition reduces mammary tumor growth and facilitates antitumor immunity and anti-PD1 responses. Clin Cancer Res 23:3371–3384

    Article  CAS  Google Scholar 

  32. Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B (2010) The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol 11:329–341

    Article  CAS  Google Scholar 

  33. Chan A (2017) TILs in metastatic breast cancer-no surprises, but more questions. Lancet Oncol 18:5–6

    Article  Google Scholar 

  34. Teixeira-Carvalho A, Martins-Filho OA, Andrade ZA, Cunha-Mello JR, Wilson RA, Correa-Oliveira R (2002) The study of T-cell activation in peripheral blood and spleen of hepatosplenic patients suggests an exchange of cells between these two compartments in advanced human Schistosomiasis mansoni infection. Scand J Immunol 56:315–322

    Article  CAS  Google Scholar 

  35. Yan Y, Kumar AB, Finnes H, Markovic SN, Park S, Dronca RS et al (2018) Combining immune checkpoint inhibitors with conventional cancer therapy. Front Immunol 9:1739

    Article  Google Scholar 

  36. Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H et al (2018) Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med 379:2108–2121

    Article  CAS  Google Scholar 

  37. Liu C, Hu Q, Hu K, Su H, Shi F, Kong L et al (2019) Increased CD8+CD28+ T cells independently predict better early response to stereotactic ablative radiotherapy in patients with lung metastases from non-small cell lung cancer. J Transl Med 17:120

    Article  Google Scholar 

  38. Song G, Wang X, Jia J, Yuan Y, Wan F, Zhou X et al (2013) Elevated level of peripheral CD8(+)CD28(−) T lymphocytes are an independent predictor of progression-free survival in patients with metastatic breast cancer during the course of chemotherapy. Cancer Immunol Immunother 62:1123–1130

    Article  CAS  Google Scholar 

  39. Liu C, Wu S, Meng X, Liu G, Chen D, Cong Y et al (2017) Predictive value of peripheral regulatory T cells in non-small cell lung cancer patients undergoing radiotherapy. Oncotarget 8:43427–43438

    Article  Google Scholar 

  40. Retseck J, VanderWeele R, Lin HM, Lin Y, Butterfield LH, Tarhini AA (2016) Phenotypic and functional testing of circulating regulatory T cells in advanced melanoma patients treated with neoadjuvant ipilimumab. J Immunother Cancer 4:38

    Article  Google Scholar 

  41. Chen X, Zhang W, Qian D, Guan Y, Wang Y, Zhang H et al (2019) Chemoradiotherapy-induced CD4(+) and CD8(+) T-cell alterations to predict patient outcomes in esophageal squamous cell carcinoma. Front Oncol 9:73

    Article  CAS  Google Scholar 

Download references

Funding

Funding were provided by National Cancer Institute (Grant Nos.: CA34590, P50CA098131, 5T32CA009592 30, 1T32CA217834-01A1), Breast Cancer Research Foundation (Grant No.: IIDRP-16-001), U.S. Department of Veterans Affairs (Grant No. 5101BX000196-04), National Institutes of Health (CA90625) and Vanderbilt University (Grant No. P30 CA68485, Brock Family Fellowship).

Author information

Authors and Affiliations

  1. Department of Veteran Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA

    Carly Bess Williams, Caroline A. Nebhan, Jinming Yang, Chi Yan, Anna E. Vilgelm & Ann Richmond

  2. Department of Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN, 37232, USA

    Carly Bess Williams, Jinming Yang, Chi Yan, Anna E. Vilgelm & Ann Richmond

  3. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA

    Sheau-Chiann Chen & Gregory Dan Ayers

  4. Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Caroline A. Nebhan, Vandana Abramson & Ingrid A. Mayer

  5. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA

    Lauren S. Starnes

Authors
  1. Carly Bess Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Caroline A. Nebhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jinming Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lauren S. Starnes
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chi Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anna E. Vilgelm
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sheau-Chiann Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gregory Dan Ayers
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Vandana Abramson
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ingrid A. Mayer
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ann Richmond
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ann Richmond.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 313 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Williams, C.B., Nebhan, C.A., Yang, J. et al. Correlative studies investigating effects of PI3K inhibition on peripheral leukocytes in metastatic breast cancer: potential implications for immunotherapy. Breast Cancer Res Treat 184, 357–364 (2020). https://doi.org/10.1007/s10549-020-05846-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-020-05846-5

Keywords

Search

Navigation