Neoadjuvant palbociclib on ER+ breast cancer (N007): clinical response and EndoPredict's value
Louis W C Chow, Satoshi Morita, Christopher Y C Chow, Wai-Kuen Ng, Masakazu Toi, Louis W C Chow, Satoshi Morita, Christopher Y C Chow, Wai-Kuen Ng, Masakazu Toi
Abstract
The purpose of the study was to test the efficacy of neoadjuvant palbociclib therapy and to evaluate its impact on cell cycle arrest and changes in EndoPredict (EP) scores before and after treatment. Postmenopausal women with histologically proven ER+ve, HER2-ve invasive breast cancer, 2 cm or greater, were enrolled in an open-label, single-arm study. Twenty eligible patients were given letrozole 2.5 mg per day together with palbociclib 125 mg per day for 3 out of 4 weeks in repeated cycles for 16 weeks (4 cycles) before surgery. The primary end points were clinical response rates (cRR) and preoperative endocrine prognostic index (PEPI). The secondary end points were pathologic response and gene expression testing with EP test on collected tumor samples. The following results were obtained. 17 patients showed a clinical response of 50% or more, including 8 complete responses and 9 partial responses. There was significant reduction in area (P < 0.0001) and volume (P = 0.017) of the cancer. Pathologic complete response (pCR) was achieved in one patient; all cancers were downgraded after treatment. Ki67 (P = 0.044) and EP scores (P < 0.0001) were significantly reduced after treatment. Analysis of the relative gene expression levels showed that all proliferative genes, IL6ST and RBBP8 were decreased after palbociclib treatment. 6 patients with intermediate and three patients with high PEPI risk scores were found to have low EPclin scores. All patients with high PEPI relapse risk score had high EPclin score. In conclusion, effective clinical response was demonstrated by neoadjuvant letrozole in combination with palbociclib. Compared with PEPI, EPclin might be a better parameter to estimate prognosis after neoadjuvant therapy.
Keywords: EndoPredict; breast cancer; letrozole; neoadjuvant; palbociclib.
© 2018 The authors.
Figures
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5763422/bin/erc-25-123-g001.jpg)
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5763422/bin/erc-25-123-g002.jpg)
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5763422/bin/erc-25-123-g003.jpg)
![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5763422/bin/erc-25-123-g004.jpg)
Figure 5
Distribution of PEPI scores. A…
Figure 5
Distribution of PEPI scores. A PEPI score of 0 predicts a low risk…
Figure 6
Distribution of EPclin scores. EPclin…
Figure 6
Distribution of EPclin scores. EPclin score
Figure 7
Neutropenia during the course of…
Figure 7
Neutropenia during the course of treatment. AE, adverse events.
- Serum thymidine kinase 1 activity as a pharmacodynamic marker of cyclin-dependent kinase 4/6 inhibition in patients with early-stage breast cancer receiving neoadjuvant palbociclib.Bagegni N, Thomas S, Liu N, Luo J, Hoog J, Northfelt DW, Goetz MP, Forero A, Bergqvist M, Karen J, Neumüller M, Suh EM, Guo Z, Vij K, Sanati S, Ellis M, Ma CX. Bagegni N, et al. Breast Cancer Res. 2017 Nov 21;19(1):123. doi: 10.1186/s13058-017-0913-7. Breast Cancer Res. 2017. PMID: 29162134 Free PMC article.
- Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer (NA-PHER2): an exploratory, open-label, phase 2 study.Gianni L, Bisagni G, Colleoni M, Del Mastro L, Zamagni C, Mansutti M, Zambetti M, Frassoldati A, De Fato R, Valagussa P, Viale G. Gianni L, et al. Lancet Oncol. 2018 Feb;19(2):249-256. doi: 10.1016/S1470-2045(18)30001-9. Epub 2018 Jan 8. Lancet Oncol. 2018. PMID: 29326029 Clinical Trial.
- Randomized Phase II Study Evaluating Palbociclib in Addition to Letrozole as Neoadjuvant Therapy in Estrogen Receptor-Positive Early Breast Cancer: PALLET Trial.Johnston S, Puhalla S, Wheatley D, Ring A, Barry P, Holcombe C, Boileau JF, Provencher L, Robidoux A, Rimawi M, McIntosh SA, Shalaby I, Stein RC, Thirlwell M, Dolling D, Morden J, Snowdon C, Perry S, Cornman C, Batten LM, Jeffs LK, Dodson A, Martins V, Modi A, Osborne CK, Pogue-Geile KL, Cheang MCU, Wolmark N, Julian TB, Fisher K, MacKenzie M, Wilcox M, Huang Bartlett C, Koehler M, Dowsett M, Bliss JM, Jacobs SA. Johnston S, et al. J Clin Oncol. 2019 Jan 20;37(3):178-189. doi: 10.1200/JCO.18.01624. Epub 2018 Dec 6. J Clin Oncol. 2019. PMID: 30523750 Clinical Trial.
- FDA Approval: Palbociclib for the Treatment of Postmenopausal Patients with Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer.Beaver JA, Amiri-Kordestani L, Charlab R, Chen W, Palmby T, Tilley A, Zirkelbach JF, Yu J, Liu Q, Zhao L, Crich J, Chen XH, Hughes M, Bloomquist E, Tang S, Sridhara R, Kluetz PG, Kim G, Ibrahim A, Pazdur R, Cortazar P. Beaver JA, et al. Clin Cancer Res. 2015 Nov 1;21(21):4760-6. doi: 10.1158/1078-0432.CCR-15-1185. Epub 2015 Aug 31. Clin Cancer Res. 2015. PMID: 26324739 Review.
- The safety and efficacy of palbociclib in the treatment of metastatic breast cancer.Ettl J, Harbeck N. Ettl J, et al. Expert Rev Anticancer Ther. 2017 Aug;17(8):661-668. doi: 10.1080/14737140.2017.1347506. Epub 2017 Jul 12. Expert Rev Anticancer Ther. 2017. PMID: 28649895 Review.
- Comparative Analysis of Transcriptomic Changes including mRNA and microRNA Expression Induced by the Xenoestrogens Zearalenone and Bisphenol A in Human Ovarian Cells.Márton É, Varga A, Penyige A, Birkó Z, Balogh I, Nagy B, Szilágyi M. Márton É, et al. Toxins (Basel). 2023 Feb 9;15(2):140. doi: 10.3390/toxins15020140. Toxins (Basel). 2023. PMID: 36828454 Free PMC article.
- Systemic therapy for early-stage breast cancer: learning from the past to build the future.Agostinetto E, Gligorov J, Piccart M. Agostinetto E, et al. Nat Rev Clin Oncol. 2022 Dec;19(12):763-774. doi: 10.1038/s41571-022-00687-1. Epub 2022 Oct 17. Nat Rev Clin Oncol. 2022. PMID: 36253451 Free PMC article. Review.
- Cyclin-dependent kinase 4 and 6 inhibitors in combination with neoadjuvant endocrine therapy in estrogen receptor-positive early breast cancer: a systematic review and meta-analysis.Guan Y, Shen G, Fang Q, Xin Y, Huo X, Li J, Zhao F, Ren D, Liu Z, Li Z, Zhao J. Guan Y, et al. Clin Exp Med. 2022 Mar 19. doi: 10.1007/s10238-022-00814-3. Online ahead of print. Clin Exp Med. 2022. PMID: 35304677 Review.
- Patient-derived scaffolds as a drug-testing platform for endocrine therapies in breast cancer.Gustafsson A, Garre E, Leiva MC, Salerno S, Ståhlberg A, Landberg G. Gustafsson A, et al. Sci Rep. 2021 Jun 25;11(1):13334. doi: 10.1038/s41598-021-92724-9. Sci Rep. 2021. PMID: 34172801 Free PMC article.
- The Present and Future of Neoadjuvant Endocrine Therapy for Breast Cancer Treatment.Martí C, Sánchez-Méndez JI. Martí C, et al. Cancers (Basel). 2021 May 21;13(11):2538. doi: 10.3390/cancers13112538. Cancers (Basel). 2021. PMID: 34064183 Free PMC article. Review.
-
- Borg A, Zhang QX, Alm P, Olsson H, Sellberg G. 1992. The retinoblastoma gene in breast cancer: allele loss is not correlated with loss of gene protein expression. Cancer Research 52 2991–2994. - PubMed
- Clinical Trial
- Research Support, Non-U.S. Gov't
- Aged
- Aged, 80 and over
- Antineoplastic Agents / therapeutic use*
- Breast Neoplasms / drug therapy*
- Breast Neoplasms / genetics
- Breast Neoplasms / pathology
- Female
- Humans
- Middle Aged
- Neoadjuvant Therapy
- Piperazines / therapeutic use*
- Protein Kinase Inhibitors / therapeutic use*
- Pyridines / therapeutic use*
- Receptors, Estrogen
- Treatment Outcome
- Tumor Burden / drug effects
- Antineoplastic Agents
- Piperazines
- Protein Kinase Inhibitors
- Pyridines
- Receptors, Estrogen
- palbociclib
- Full Text Sources
- Other Literature Sources
- Medical
- Research Materials
- Miscellaneous
![Figure 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5763422/bin/erc-25-123-g005.jpg)
![Figure 6](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5763422/bin/erc-25-123-g006.jpg)
Figure 7
Neutropenia during the course of…
Figure 7
Neutropenia during the course of treatment. AE, adverse events.
![Figure 7](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5763422/bin/erc-25-123-g007.jpg)
References
- Borg A, Zhang QX, Alm P, Olsson H, Sellberg G. 1992. The retinoblastoma gene in breast cancer: allele loss is not correlated with loss of gene protein expression. Cancer Research 52 2991–2994.
- Bosco EE, Wang Y, Xu H, Zilfou JT, Knudsen KE, Aronow BJ, Lowe SW, Knudsen ES. 2007. The retinoblastoma tumor suppressor modifies the therapeutic response of breast cancer. Journal of Clinical Investigation 117 218–228. (10.1172/JCI28803)
- Cariou S, Donovan JC, Flanagan WM, Milic A, Bhattacharya N, Slingerland JM. 2000. Down-regulation of p21WAF1/CIP1 or p27Kip1 abrogates antiestrogen-mediated cell cycle arrest in human breast cancer cells. PNAS 97 9042–9046. (10.1073/pnas.160016897)
- Chano T, Kontani K, Teramoto K, Okabe H, Ikegawa S. 2002. Truncating mutations of RB1CC1 in human breast cancer. Nature Genetics 31 285–288. (10.1038/ng911)
- Chow LW, Yip AY, Loo WT, Lam CK, Toi M. 2008. Celecoxib anti-aromatase neoadjuvant (CAAN) trial for locally advanced breast cancer. Journal of Steroid Biochemistry and Molecular Biology 111 13–17. (10.1016/j.jsbmb.2008.04.004)
- Dubsky P, Brase JC, Jakesz R, Rudas M, Singer CF, Greil R, Dietze O, Luisser I, Klug E, Sedivy R, et al. 2013. The EndoPredict score provides prognostic information on late distant metastases in ER+/HER2- breast cancer patients. British Journal of Cancer 109 2959–2964. (10.1038/bjc.2013.671)
- Ellis MJ, Tao Y, Luo J, A’Hern R, Evans DB, Bhatnagar AS, Chaudri Ross HA, von Kameke A, Miller WR, Smith I, et al. 2008. Outcome prediction for estrogen receptor-positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics. Journal of the National Cancer Institute 100 1380–1388. (10.1093/jnci/djn309)
- Ellis MJ, Suman VJ, Hoog J, Lin L, Snider J, Prat A, Parker JS, Luo J, DeSchryver K, Allred DC, et al. 2011. Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype – ACOSOG Z1031. Journal of Clinical Oncology 29 2342–2349. (10.1200/JCO.2010.31.6950)
- Filipits M, Rudas M, Jakesz R, Dubsky P, Fitzal F, Singer CF, Dietze O, Greil R, Jelen A, Sevelda P, et al. 2011. A new molecular predictor of distant recurrence in ER-positive, HER2-negative breast cancer adds independent information to conventional clinical risk factors. Clinical Cancer Research 17 6012–6020. (10.1158/1078-0432.CCR-11-0926)
- Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, Ginther C, Atefi M, Chen I, Fowst C, et al. 2009. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Research 11 R77 (10.1186/bcr2419)
- Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M, et al. 2015. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncology 16 25–35. (10.1016/S1470-2045(14)71159-3)
- Fusco C, Reymond A, Zervos AS. 1998. Molecular cloning and characterization of a novel retinoblastoma-binding protein. Genomics 51 351–358. (10.1006/geno.1998.5368)
- Klahan S, Wong HS, Tu SH, Chou WH, Zhang YF, Ho TF, Liu CY, Yih SY, Lu HF, Chen SC, et al. 2017. Identification of genes and pathways related to lymphovascular invasion in breast cancer patients: a bioinformatics analysis of gene expression profiles. Tumour Biology 39 1–7.
- Ma CX, Gao F, Northfelt D, Goetz M, Forero A, Naughton M, Ademuyiwa F, Suresh R, Anderson KS, Margenthaler J, et al. 2015. A phase II trial of neoadjuvant palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with anastrozole for clinical stage 2 or 3 estrogen receptor positive HER2 negative (ER+HER2-) breast cancer (BC). Cancer Research 76 (4 Supplement) abstract S6-05. (10.1158/1538-7445.SABCS15-S6-05)
- Musgrove EA, Lilischkis R, Cornish AL, Lee CS, Setlur V, Seshadri R, Sutherland RL. 1995. Expression of the cyclin-dependent kinase inhibitors p16INK4, p15INK4B and p21WAF1/CIP1 in human breast cancer. International Journal of Cancer 63 584–591. (10.1002/ijc.2910630420)
- Nair BC, Vadlamudi RK. 2008. Regulation of hormonal therapy resistance by cell cycle machinery. Gene Therapy and Molecular Biology 12 395.
- Oesterreich S, Fuqua SA. 1999. Tumor suppressor genes in breast cancer. Endocrine-Related Cancer 6 405–419. (10.1677/erc.0.0060405)
- Pietiläinen T, Lipponen P, Aaltomaa S, Eskelinen M, Kosma VM, Syrjänen K. 1995. Expression of retinoblastoma gene protein (Rb) in breast cancer as related to established prognostic factors and survival. European Journal of Cancer 31A 329–333.
- Slamon DJ, Hurvitz SA, Applebaum S, Glaspy JA, Allison MK, DiCarlo BA, Courtney RD, Kim ST, Randolph S, Finn RS. 2010. Phase I study of PD 0332991, cyclin-D kinase (CDK) 4/6 inhibitor in combination with letrozole for first-line treatment of patients with ER-positive, HER2-negative breast cancer. Journal of Clinical Oncology 28 (Supplement 15) abstract 3060 (10.1200/jco.2010.28.15_suppl.3060)
- Turnbull AK, Arthur LM, Renshaw L, Larionov AA, Kay C, Dunbier AK, Thomas JS, Dowsett M, Sims AH, Dixon JM. 2015. Accurate prediction and validation of response to endocrine therapy in breast cancer. Journal of Clinical Oncology 33 2270–2278. (10.1200/JCO.2014.57.8963)
- Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, et al. 2015. Palbociclib in hormone-receptor-positive advanced breast cancer. New England Journal of Medicine 373 209–219. (10.1056/NEJMoa1505270)
- Yu Q, Sicinska E, Geng Y, Ahnström M, Zagozdzon A, Kong Y, Gardner H, Kiyokawa H, Harris LN, Stål O, et al. 2006. Requirement for CDK4 kinase function in breast cancer. Cancer Cell 9 23–32. (10.1016/j.ccr.2005.12.012)
- Zhou R, Frum R, Deb S, Deb SP. 2005. The growth arrest function of the human oncoprotein mouse double minute-2 is disabled by downstream mutation in cancer cells. Cancer Research 65 1839–1848. (10.1158/0008-5472.CAN-03-3755)
Source: PubMed