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Review Article

Editor's Choice - Free Access

Incorporating CDK4/6 Inhibitors in the Treatment of Advanced Luminal Breast Cancer

Echavarria I. · Jerez Y. · Martin M. · López-Tarruella S.

Author affiliations

Department of Medical Oncology, Instituto de Investigación Sanitaria Gregorio Marañon (IiSGM), Universidad Complutense de Madrid, CiberOnc, Madrid, Spain

Corresponding Author

Dr. Isabel Echavarria

Department of Medical Oncology

Instituto de Investigación Sanitaria Gregorio Marañon (IiSGM)

Dr Esquerdo 46, 28006 Madrid, Spain

iechavarriadg@gmail.com

Related Articles for ""

Breast Care 2017;12:296-302

Abstract

After optimizing endocrine monotherapy modalities in the setting of advanced luminal breast cancer (BC), dual endocrine/targeted therapy combinations have been tested with positive results, and are transforming this BC subtype treatment landscape. Cell cycle deregulation is a hallmark of cancer that has become a key druggable target in hormone receptor (HR)-positive BC due to its role in endocrine resistance mechanisms. Cyclin dependent kinase (CDK)4/6 inhibitors have experienced a fast development in combination with endocrine therapy and have already been commercialized in some countries. In this review, we will summarize the development of these CDK4/6 inhibitors in luminal BC, from the preclinical data to the pivotal phase III trials that led to their approval, focusing on the efficacy and safety data for each of the treatment settings. Moreover, we will consider the challenges CDK4/6 inhibitors face in their positioning in the algorithm of treatment for advanced luminal BC and the considerations physicians should take into account when selecting these therapies for their patients. However, we are still in need of reliable predictive biomarkers in order to identify patients who will derive the greatest benefit from these drug combinations that are not exempt from toxicity.

© 2017 S. Karger GmbH, Freiburg


Introduction

Both de novo and acquired endocrine resistance mechanisms represent a challenge in hormone receptor (HR)-positive breast cancer (BC) [1]. Dual targeting strategies in advanced luminal BC have emerged as a promising way to overcome this resistance and enhance the sensitivity to endocrine therapy (ET) [2].

CDK4/6 Inhibitors as a Target of Interest in Luminal BC

Cell cycle deregulation is a hallmark of cancer, conferring a proliferative advantage as well as genomic and chromosomal instability on cells [3]. Cyclin dependent kinases (CDKs) modulated by activators (cyclins) and inhibitors closely regulate the cell cycle. For instance, the G1/S checkpoint of the cell cycle (restriction point) is tightly controlled by CDK4/6 and cyclin D interactions. Different mitogenic signals converge at this level leading to the phosphorylation of the Rb protein by CDK4/6 and the subsequent release of the E2F transcription factor from pRb. E2F then triggers cell cycle progression through the transcription of key genes involved in the G1/S transition [4,5].

The cyclin D/CDK4 axis deregulation is of significant relevance in estrogen receptor-positive (ER+) BC, as cyclin D1 is an ER gene product and there is significant crosstalk between steroidal HRs and the cell cycle [6]. Cyclin D1 is overexpressed in up to 50% of all BC [7], and luminal tumors are particularly enriched in CCND1 amplifications and/or CDK4 gains. In particular, luminal A tumors have low expression of CDKN2C and high expression of RB1[8]. Rb dysfunction has been associated with endocrine resistance in luminal BC [9]. CDK4/6 inhibitors have been shown to induce G1 arrest and decrease the phosphorylation of the Rb protein, with a subsequent down-regulation of E2F downstream effectors.

The CDK inhibitor development has been a long and challenging process [4,10], until the arrival of CDK4/6 inhibitors [5,9]. Palbociclib (Ibrance®, Pfizer, New York, NY, USA), Ribociclib (Kisqali®, Novartis, Basel. Switzerland), and Abemaciclib (Lilly, Indianapolis, IN, USA) are members of this new generation of serine/threonine kinase inhibitors, and their combination with ET in luminal BC has provided promising results which we will review below.

Development of CDK4/6 Inhibitors in BC

First Steps of CDK4/6 Inhibitors at the Preclinical Level

Palbociclib (PD0332991) is a potent and highly selective CDK4/6 inhibitor (table 1). In vivo trials revealed antitumor activity in a variety of tumors, including BC, although palbociclib was found to be inactive in Rb-negative BC tumors [11]. Among a large panel of BC cell lines, ER+ cell lines, including luminal HER2+, showed the greatest sensitivity in contrast to basal subtypes. In addition to luminal markers, sensitive cell lines showed overexpression of RB1 and cyclin D1, as well as underexpression of p16 [12].

Table 1

Preclinical data and early-phase trial dosage results

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Ribociclib (LEE011) is a selective CDK4/6 inhibitor with preclinical activity via the induction of cytostasis and senescence [13,14]. Enhanced tumor growth inhibition in BC was observed when combined with ET, and was further improved with PI3K inhibitor triple combination [15].

Abemaciclib (LY2835219) is a selective CDK inhibitor with a higher selectivity towards CDK4 than towards CDK6 [16]. Abemaciclib's activity was observed only in Rb-proficient cells [16,17], inducing reversible cell cycle arrest and senescence [18]. Abemaciclib has been shown to cross the blood-brain barrier in a more effective way than palbociclib [19].

Early-Phase Clinical Trials with CDK4/6 Inhibitors Focused on Luminal BC

The first-in-human trial of palbociclib was conducted in a population of Rb-positive advanced solid tumors and lymphomas [20]. Palbociclib 125 mg per day was evaluated in a 3-weeks-on/1-week-off (3/4 wk) schedule phase I trial [21] demonstrating an adequate safety profile. Subsequent studies in combination with ET confirmed a favorable safety and efficacy profile [22].

A first-in-human trial of single-agent ribociclib established the recommended dose for expansion at 600 mg/day on a 3/4 wk schedule [23]. The combination of ribociclib and ET also showed a favorable safety and efficacy profile [24,25]. Triple combination trials with PI3K/Akt/mTOR inhibitors are currently ongoing (NCT01872260 and NCT01857193).

A dose-escalation trial fixed the maximum tolerated dose for single-agent abemaciclib at continuous 200 mg twice daily, and the combination of fulvestrant and abemaciclib showed a similar safety profile [26]. Resistance to abemaciclib was associated with TP53 mutations, and no impact of PI3KCA mutation was observed in terms of response to abemaciclib.

CDK4/6 Inhibitor Development in the Clinical Setting of Advanced Luminal BC: Phase II-III Trials

Following promising early-phase trial results, the agents were evaluated in phase II-III studies. We will review the most relevant data for each of the drugs currently available (table 2), as well as provide a summary of ongoing trials (table 3).

Table 2

Main phase II-III clinical trials evaluating CDK4/6 inhibitors in advanced luminal breast cancer (BC) patients with data reported by June 2017

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Table 3

Selection of ongoing phase II-III clinical trials evaluating CDK4/6 inhibitors in advanced luminal breast cancer patients

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Palbociclib

This agent was the first CDK4/6 inhibitor approved by the regulatory authorities. The PALOMA-1 trial [27] was a randomized phase II trial designed to evaluate the addition of palbociclib to letrozole in HR+/HER2- advanced BC (ABC) patients with no prior treatment for metastatic disease. While patients who received mono-ET obtained a median progression-free survival (PFS) of 10.2 months, letrozole plus palbociclib treatment reached a PFS of 20.2 months (hazard ratio (HR) 0.488, p < 0.001).

The PALOMA-2 trial [28] was a randomized phase III trial designed to confirm and add to the results of PALOMA-1. This trial allocated 666 HR+/HER2- ABC patients with no prior treatment for advanced disease to receive letrozole plus palbociclib or placebo. Palbociclib increased PFS from 14.5 to 24.8 months (HR 0.58, p < 0.001). Neutropenia occurred in 79% of patients in the palbociclib arm and was the most common grade (G) 3-4 adverse event (AE) (66.4 vs. 1.4%).

The PALOMA-3 trial [29,30] was a double-blind randomized trial that assigned 521 patients (2:1) to fulvestrant plus palbociclib or placebo. Eligibility criteria included ER+/HER2- ABC patients who had progressed during ET for advanced disease or within 12 months of completing adjuvant therapy. Median PFS was 9.5 versus 4.6 months in the palbociclib and control arm, respectively (HR 0.46, p < 0.001), with a similar benefit among premenopausal women [31]. G 3-4 neutropenia occurred in 65% of the patients in the palbociclib arm, with a less than 1% febrile neutropenia rate [32].

The TREND trial [33] was a randomized phase II trial comparing single-agent palbociclib versus palbociclib in combination with the same ET that patients were receiving prior to disease progression. This trial included ER+/HER2- ABC patients who had previously received 1 or 2 lines of ET (only 1 for ABC). The primary endpoint was the clinical benefit rate, which was similar for both arms (54 and 60% in the combination and monotherapy groups, respectively). However, median duration of clinical benefit was 11.5 versus 6 months (HR 0.35, p = 0.002), and median PFS was 10.8 versus 6.5 months (HR 0.69, p = 0.12). This trial suggests that palbociclib could reverse acquired resistance and that palbociclib monotherapy harbors clinical activity in moderately pretreated patients.

Both the PALOMA-2 and the PALOMA-3 trial explored ER positivity as a biomarker of response, and while ER+ tumors did benefit from palbociclib, the level of ER expression did not discriminate for this benefit [30,34]. CCND1 amplification, loss of p16, or Ki67 levels did not help in predicting response to palbociclib [27,34]. ESR1 mutations were related to worse outcomes, and despite a reduction in the ESR1 mutational burden along treatment, it did not predict for PFS benefit, nor was the PIK3CA mutational status discriminative [30]. A decrease in circulating tumor (ct)DNA levels at day 15 was significantly associated with PFS [35].

Ribociclib

Ribociclib was the second CDK4/6 inhibitor to be commercialized. The MONALEESA-2 trial [36] was a double-blind phase III trial that randomized 668 ER+/HER2- ABC patients with no prior treatment for advanced disease to receive letrozole plus or placebo. Median PFS was 25.3 versus 16 months (HR 0.58, p < 0.001) [37]. The most common G 3-4 AE was neutropenia (59.3 vs. 0.9%), and QTcF interval increases (> G 2) occurred in 3% of the patients.

Parallel with the palbociclib data, biomarker analysis of the MONALEESA-2 trial did not demonstrate the value of Rb, p16, or ki-67 levels, or CDKN2A, CCND1 or ESR1 gene expression levels, as biomarkers of ribociclib benefit [38].

Abemaciclib

In October 2015, abemaciclib obtained the designation of Innovative Therapy by the Food and Drug Administration (FDA). The MONARCH-1 [39] phase II trial of single-agent abemaciclib included ER+/HER2- ABC women who had progressed on or after ET and had received no more than 3 lines of chemotherapy for advanced disease. The primary endpoint was the overall response rate (ORR). At 12 months of follow-up, the ORR was 19.7% and PFS was 6 months.

The MONARCH-2 trial [40] was a double-blind phase III study that included ER+/HER2- ABC patients who had progressed while receiving or within 12 months of completion of adjuvant/neoadjuvant ET, or during first-line ET for metastatic disease. Patients were randomized to receive fulvestrant plus abemaciclib or placebo. Median PFS were 16.4 and 9.3 months in the abemaciclib and placebo arms, respectively (HR 0.553, p < 0.001). The most frequent AEs were gastrointestinal (GI) symptoms and neutropenia. Diarrhea occurred in 73% of patients in the abemaciclib arm (13.4% G 3); this was an early event and was easily managed with antidiarrheal medication. Increases in serum creatinine levels occurred in 25% of the patients in the abemaciclib group, with no renal impairment.

A phase II trial evaluated the potential benefit of abemaciclib in brain metastases (NCT02308020) (HR+ BC, melanoma, and non-small cell lung cancer) with preliminary evidence of antitumor activity [41].

Advanced Luminal BC - Current Treatment Status: CDK4/6 Inhibitors in Context

The advanced luminal BC landscape is continuously evolving, and CDK4/6 inhibitors are promising drugs that have come to stay. Palbociclib has rapidly progressed from its accelerated FDA approval [27] to its inclusion in international treatment guidelines for HR+/HER2- ABC [42,43]. Similarly, ribociclib has just been approved by the FDA in 2017 [36], and abemaciclib is heading towards its final approval.

ABC treatment goals should be present when evaluating the expansion of our treatment armamentarium [44,45]. To date, international ABC guidelines for HR+/HER2- patients uniformly recommended endocrine-based regimens over chemotherapy unless there is a visceral crisis in need of rapid response [43,46]. The balance between disease-specific characteristics and patient-related factors forms the basis for the decision-making process; however, other external factors such as social support, healthcare coverage, and research opportunities are also worth considering. In view of the significant gains in PFS with CDK4/6 inhibitors [27,28,30,36,40], the mono-ET paradigm is being challenged, although overall survival (OS) data are still too immature to draw solid conclusions. So far, the PALOMA-1 trial is the only trial to report a non-statistically significant increase in OS for the combination of letrozole and palbociclib [47]. Nevertheless, this co-targeting strategy has demonstrated the ability to delay the use of chemotherapy [47] and global quality of life deterioration [48].

The benefits of new CDK4/6 inhibitor/ET combinations should be counterbalanced with the AEs derived from their use. While palbociclib dose-limiting toxicities were mainly hematologic, ribociclib added liver alterations and QTc prolongation as relevant AEs, and in contrast, fatigue, anorexia, and GI AEs appeared in the toxicity spectrum of abemaciclib more commonly than with the other inhibitors. Hematologic toxicity is a key issue to be aware of, but it is manageable with dose delays and reductions, does not require routine use of granulocyte-colony stimulating factor, and is associated with a low rate of febrile neutropenia and severe infections. This probably is the result of palbociclib's bone marrow suppression mechanism, through a temporary cell cycle arrest, as opposed to permanent DNA damage or cell death with cytotoxic chemotherapy [49]. Close monitoring of blood counts and signs of infection is a necessary precaution during palbociclib treatment. Precautions to be observed with the use of ribociclib include electrocardiogram, serum electrolyte, and liver function monitoring, adding to the previous set of recommendations. Given the abemaciclib toxicity profile, diarrhea and GI toxicity management strategies need to be implemented to optimize treatment dose intensity.

Many of the ABC luminal population is over 60 years of age, and with an increased prevalence of comorbidities and polypharmacy, close monitoring of concomitant medication is mandatory.

Finally, financial toxicity is an unavoidable barrier for the widespread use of CDK4/6 inhibitors over mono-ET strategies, and must be addressed in the treatment individualization process [50].

Future Prospects and Open-Ended Questions for CDK4/6 Inhibitors in Luminal BC Treatment

CDK4/6 inhibitors have opened a new chapter in the luminal ABC treatment historical timeline, although many unanswered questions remain. In the ABC setting, do we need to adopt combination strategies or is there still a role for mono-ET? We have long been searching for the right endocrine sequence, and the current advances, with the integration of mTOR and CDK4/6 inhibitors, just expand the picture. The arrival of new CDK4/6 combinations opens the possibility to delay the development of endocrine resistance but also to overcome this resistance once established. Up to this point, the 3 CDK4/6 inhibitors have followed a parallel development strategy, but there is no head-to-head comparison that allows us to decide between the different options. With positive data from palbociclib and ribociclib in the frontline setting, they represent a valuable option that can be offered to many patients, with benefit either for visceral or non-visceral involvement and irrespective of the interval from the end of adjuvant ET. However, as we are still awaiting OS results, single-agent ET still has a role in this setting, particularly fulvestrant in non-visceral recurrences for ET-naïve patients [51]. The benefits obtained with fulvestrant and either palbociclib or abemaciclib in the resistant setting indicate that treatment with CDK4/6 inhibitors should seriously be considered at some point in advanced luminal BC. Besides, the definition of the optimal therapy upon progression on CDK4/6 inhibitors plus aromatase inhibitors (AIs) in the first line is still pending, and the combination of everolimus and ET is still a valuable choice in the resistant setting before moving on to chemotherapy [2,52].

In addition, data from direct comparisons of CDK4/6 inhibitor plus ET versus chemotherapy are limited, and clinical trials either in the first-line real-world setting (PADMA, EudraCT 2016-004482-89) or in a non-steroidal AI-resistant population (PEARL, NCT02028507) are still underway.

More importantly, will these achievements be translated into the early luminal BC setting? There is intensive work currently in progress in a potentially curable population, which is undoubtedly the ultimate and most important goal to attain. Currently, there are ongoing adjuvant trials with palbociclib (PENELOPE-B/NCT01864746 and PALLAS/NCT02513394), ribociclib (EarLEE-1/NCT03078751 and EarLEE-2/NCT03081234), and abemaciclib (monarchE/NCT03155997), and the final results are eagerly awaited.

Finally, advances in biomarker identification beyond clinical criteria will enable us to select the best treatment regimen for each patient. This constitutes an unmet clinical need in this area, and many efforts are devoted to this aspect. Nevertheless, ER expression remains the best marker to select patients for CDK4/6 inhibition. Further insights into the resistance mechanisms of this new family of drugs (reviewed in this same issue by Migliaccio et al.) will surely enhance their future development by indicating new potential strategies to overcome the problem.

Disclosure Statement

SLC: Advisory role - Novartis, Pfizer, Astra Zeneca; travel grant - Pfizer, Novartis. MM: speaker's honoraria - Pfizer, Lilly, Novartis; research funding - Novartis. IE and YJ have nothing to disclose.


References

  1. Hart CD, Migliaccio I, Malorni L, Guarducci C, Biganzoli L, Di Leo A: Challenges in the management of advanced, ER-positive, HER2-negative breast cancer. Nat Rev Clin Oncol 2015;12:541-552.
  2. Baselga J, Campone M, Piccart M, et al.: Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012;366:520-529.
  3. Malumbres M, Barbacid M: Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 2009;9:153-166.
  4. Asghar U, Witkiewicz AK, Turner NC, Knudsen ES: The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov 2015;14:130-146.
  5. Ingham M, Schwartz GK: Biology of neoplasia: cell-cycle therapeutics come of age. J Clin Oncol 2017;35:2949-2959.
  6. Zwijsen RM, Wientjens E, Klompmaker R, van der Sman J, Bernards R, Michalides RJ: CDK-independent activation of estrogen receptor by cyclin D1. Cell 1997;88:405-415.
  7. Barnes DM, Gillett CE: Cyclin D1 in breast cancer. Breast Cancer Res Treat 1998;52:1-15.
  8. Cancer Genome Atlas Network: Comprehensive molecular portraits of human breast tumours. Nature 2012;490:61-70.
  9. O'Leary B, Finn RS, Turner NC: Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol 2016;13:417-430.
  10. Whittaker SR, Mallinger A, Workman P, Clarke PA: Inhibitors of cyclin-dependent kinases as cancer therapeutics. Pharmacol Ther 2017;173:83-105.
  11. Fry DW, Harvey PJ, Keller PR, et al.: Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther 2004;3:1427-1438.
  12. Finn RS, Dering J, Conklin D, et al.: 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 Res 2009;11:R77.
  13. Rader J, Russell MR, Hart LS, et al.: Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin Cancer Res 2013;19:6173-6182.
  14. Kim S, Loo A, Chopra R, Caponigro G, Huang A, Vora S, et al.: LEE011: an orally bioavailable, selective small molecule inhibitor of CDK4/6-reactivating Rb in cancer. Mol Cancer Ther 2013;12:abstr PR02.
  15. O'Brien NA, Tomaso ED, Ayala R, et al.: In vivo efficacy of combined targeting of CDK4/6, ER and PI3K signaling in ER+ breast cancer. Cancer Res 2014;74:abstr 4756.
  16. Gelbert LM, Cai S, Lin X, et al.: Preclinical characterization of the CDK4/6 inhibitor LY2835219:in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs 2014;32:825-837.
  17. Tate SC, Cai S, Ajamie RT, et al.: Semi-mechanistic pharmacokinetic/pharmacodynamic modeling of the antitumor activity of LY2835219, a new cyclin-dependent kinase 4/6 inhibitor, in mice bearing human tumor xenografts. Clin Cancer Res 2014;20:3763-3774.
  18. Lallena MJ, Boehnke K, Torres R, et al.: In-vitro characterization of abemaciclib pharmacology in ER+ breast cancer cell lines. Cancer Res 2015;75:abstr 3101.
  19. Raub TJ, Wishart GN, Kulanthaivel P, et al.: Brain exposure of two selective dual CDK4 and CDK6 inhibitors and the antitumor activity of CDK4 and CDK6 inhibition in combination with temozolomide in an intracranial glioblastoma xenograft. Drug Metab Dispos Biol Fate Chem 2015;43:1360-1371.
  20. Schwartz GK, LoRusso PM, Dickson MA, et al.: Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1). Br J Cancer 2011;104:1862-1868.
  21. Flaherty KT, LoRusso PM, DeMichele A, et al.: Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer. Clin Cancer Res 2012;18:568-576.
  22. Finn R, Hurvitz S, Allison M, et al.: Phase I study of PD 0332991, a novel, oral, cyclin-D kinase (CDK) 4/6 inhibitor in combination with letrozole, for first-line treatment of metastatic post-menopausal, estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Cancer Res 2009;69:5069-5069.
  23. Infante JR, Cassier PA, Gerecitano JF, et al.: A phase I study of the cyclin-dependent kinase 4/6 inhibitor ribociclib (LEE011) in patients with advanced solid tumors and lymphomas. Clin Cancer Res 2016;22:5696-5705.
  24. Juric D, Munster PN, Campone M, et al.: Ribociclib (LEE011) and letrozole in estrogen receptor-positive (ER+), HER2-negative (HER2-) advanced breast cancer (aBC): phase Ib safety, preliminary efficacy and molecular analysis. J Clin Oncol 2016;34(suppl):568.
  25. Tolaney SM, Forero-Torres A, Boni V, et al.: Ribociclib + fulvestrant in postmenopausal women with HR+, HER2- advanced breast cancer (ABC). Cancer Res 2017;77:abstr P4-22-12.
  26. Patnaik A, Rosen LS, Tolaney SM, et al.: Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. Cancer Discov 2016;6:740-753.
  27. Finn RS, Crown JP, Lang I, et al.: 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 Oncol 2015;16:25-35.
  28. Finn RS, Martin M, Rugo HS, et al.: Palbociclib and letrozole in advanced breast cancer. N Engl J Med 2016;375:1925-1936.
  29. Turner NC, Ro J, André F, et al.: Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med 2015;373:209-219.
  30. Cristofanilli M, Turner NC, Bondarenko I, et al.: Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 2016;17:425-439.
  31. Loibl S, Turner NC, Ro J, et al.: Standard endocrine therapy options for PreM women with MBC are limited and better options are needed. PALOMA-3 is the first large registrational study to include PreM women with HR+ MBC. J Clin Oncol 2016;34(suppl):abstr 524.
  32. Verma S, Bartlett CH, Schnell P, et al.: Palbociclib in combination with fulvestrant in women with hormone receptor-positive/HER2-negative advanced metastatic breast cancer: detailed safety analysis from a multicenter, randomized, placebo-controlled, phase III study (PALOMA-3). Oncologist 2016;21:1165-1175.
  33. Malorni L, Curigliano G, Minisini AM, et al.: A phase II trial of the CDK4/6 inhibitor palbociclib (P) as single agent or in combination with the same endocrine therapy (ET) received prior to disease progression, in patients (pts) with hormone receptor positive (HR+) HER2 negative (HER2-) metastatic breast cancer (mBC) (TREnd trial). J Clin Oncol 2017;35:1002-1002.
  34. Finn R, Jiang Y, Rugo H, et al.: Biomarker analyses from the phase 3 PALOMA-2 trial of palbociclib (P) with letrozole (L) compared with placebo (PLB) plus L in postmenopausal women with ER+/HER2- advanced breast cancer (ABC). Ann Oncol 2016;27(suppl):LBA15.
  35. O'Leary B, Hrebien S, Morden JP, et al.: Predicting sensitivity to palbociclib with early circulating tumor DNA dynamics in the PALOMA-3 trial. J Clin Oncol 2017;35(suppl):abstr 1018.
  36. Hortobagyi GN, Stemmer SM, Burris HA, et al.: Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med 2016;375:1738-1748.
  37. Hortobagyi GN, Stemmer SM, Burris HA, et al.: Updated results from MONALEESA-2, a phase 3 trial of first-line ribociclib + letrozole in hormone receptor-positive (HR+), HER2-negative (HER2-), advanced breast cancer (ABC). J Clin Oncol 2017;35(suppl):abstr 1038.
  38. Campone M, Marschner N, Villanueva C, et al.: First-line ribociclib + letrozole in HR+, HER2- ABC: Efficacy by baseline tumor markers. Ann Oncol 2017;28(suppl):mdx137.
  39. Dickler MN, Tolaney S, Rugo HS, et al.: MONARCH 1, a phase 2 study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2- metastatic breast cancer. Clin Cancer Res 2017;23:5218-5224.
  40. Sledge GW, Toi M, Neven P, et al.: MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol 2017;35:2875-2884.
  41. Tolaney SM, Lin NU, Thornton D, et al.: Abemaciclib for the treatment of brain metastases (BM) secondary to hormone receptor positive (HR+), HER2 negative breast cancer. J Clin Oncol 2017;35(suppl):abstr 1019.
  42. Rugo HS, Rumble RB, Macrae E, et al.: Endocrine therapy for hormone receptor-positive metastatic breast cancer: American Society of Clinical Oncology guideline. J Clin Oncol 2016;34:3069-3103.
  43. Cardoso F, Costa A, Senkus E, et al.: 3rd ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 3). Ann Oncol 2017;28:16-33.
  44. Booth CM, Tannock I: Reflections on medical oncology: 25 years of clinical trials - where have we come and where are we going? J Clin Oncol 2008;26:6-8.
  45. Smith I: Goals of treatment for patients with metastatic breast cancer. Semin Oncol 2006;33:S2-5.
  46. Wilcken N, Hornbuckle J, Ghersi D: Chemotherapy alone versus endocrine therapy alone for metastatic breast cancer. Cochrane Database Syst Rev 2003; CD002747.
  47. Finn RS, Crown J, Lang I, et al.: Overall survival results from the randomized phase II study of palbociclib (P) in combination with letrozole (L) vs letrozole alone for frontline treatment of ER+/HER2- advanced breast cancer (PALOMA-1; TRIO-18). J Clin Oncol 2017;35:1001-1001.
  48. Harbeck N, Iyer S, Turner N, et al.: Quality of life with palbociclib plus fulvestrant in previously treated hormone receptor-positive, HER2-negative metastatic breast cancer: patient-reported outcomes from the PALOMA-3 trial. Ann Oncol 2016;27:1047-1054.
  49. Hu W, Sung T, Jessen BA, et al.: Mechanistic investigation of bone marrow suppression associated with palbociclib and its differentiation from cytotoxic chemotherapies. Clin Cancer Res 2016;22:2000-2008.
  50. Del Paggio JC, Sullivan R, Schrag D, et al.: Delivery of meaningful cancer care: a retrospective cohort study assessing cost and benefit with the ASCO and ESMO frameworks. Lancet Oncol 2017;18:887-894.
  51. Robertson JFR, Bondarenko IM, Trishkina E, et al.: Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet 2016;388:2997-3005.
  52. Kornblum N, Manola J, Klein P, et al.: PrECOG 0102: a randomized, double-blind, phase II trial of fulvestrant plus everolimus or placebo in post-menopausal women with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC) resistant to aromatase inhibitor (AI) therapy. Cancer Res 2017;77:abstr S1-02.

Author Contacts

Dr. Isabel Echavarria

Department of Medical Oncology

Instituto de Investigación Sanitaria Gregorio Marañon (IiSGM)

Dr Esquerdo 46, 28006 Madrid, Spain

iechavarriadg@gmail.com


Article / Publication Details

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Published online: October 19, 2017
Issue release date: October 2017

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ISSN: 1661-3791 (Print)
eISSN: 1661-3805 (Online)

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References

  1. Hart CD, Migliaccio I, Malorni L, Guarducci C, Biganzoli L, Di Leo A: Challenges in the management of advanced, ER-positive, HER2-negative breast cancer. Nat Rev Clin Oncol 2015;12:541-552.
  2. Baselga J, Campone M, Piccart M, et al.: Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012;366:520-529.
  3. Malumbres M, Barbacid M: Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 2009;9:153-166.
  4. Asghar U, Witkiewicz AK, Turner NC, Knudsen ES: The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov 2015;14:130-146.
  5. Ingham M, Schwartz GK: Biology of neoplasia: cell-cycle therapeutics come of age. J Clin Oncol 2017;35:2949-2959.
  6. Zwijsen RM, Wientjens E, Klompmaker R, van der Sman J, Bernards R, Michalides RJ: CDK-independent activation of estrogen receptor by cyclin D1. Cell 1997;88:405-415.
  7. Barnes DM, Gillett CE: Cyclin D1 in breast cancer. Breast Cancer Res Treat 1998;52:1-15.
  8. Cancer Genome Atlas Network: Comprehensive molecular portraits of human breast tumours. Nature 2012;490:61-70.
  9. O'Leary B, Finn RS, Turner NC: Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol 2016;13:417-430.
  10. Whittaker SR, Mallinger A, Workman P, Clarke PA: Inhibitors of cyclin-dependent kinases as cancer therapeutics. Pharmacol Ther 2017;173:83-105.
  11. Fry DW, Harvey PJ, Keller PR, et al.: Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther 2004;3:1427-1438.
  12. Finn RS, Dering J, Conklin D, et al.: 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 Res 2009;11:R77.
  13. Rader J, Russell MR, Hart LS, et al.: Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin Cancer Res 2013;19:6173-6182.
  14. Kim S, Loo A, Chopra R, Caponigro G, Huang A, Vora S, et al.: LEE011: an orally bioavailable, selective small molecule inhibitor of CDK4/6-reactivating Rb in cancer. Mol Cancer Ther 2013;12:abstr PR02.
  15. O'Brien NA, Tomaso ED, Ayala R, et al.: In vivo efficacy of combined targeting of CDK4/6, ER and PI3K signaling in ER+ breast cancer. Cancer Res 2014;74:abstr 4756.
  16. Gelbert LM, Cai S, Lin X, et al.: Preclinical characterization of the CDK4/6 inhibitor LY2835219:in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs 2014;32:825-837.
  17. Tate SC, Cai S, Ajamie RT, et al.: Semi-mechanistic pharmacokinetic/pharmacodynamic modeling of the antitumor activity of LY2835219, a new cyclin-dependent kinase 4/6 inhibitor, in mice bearing human tumor xenografts. Clin Cancer Res 2014;20:3763-3774.
  18. Lallena MJ, Boehnke K, Torres R, et al.: In-vitro characterization of abemaciclib pharmacology in ER+ breast cancer cell lines. Cancer Res 2015;75:abstr 3101.
  19. Raub TJ, Wishart GN, Kulanthaivel P, et al.: Brain exposure of two selective dual CDK4 and CDK6 inhibitors and the antitumor activity of CDK4 and CDK6 inhibition in combination with temozolomide in an intracranial glioblastoma xenograft. Drug Metab Dispos Biol Fate Chem 2015;43:1360-1371.
  20. Schwartz GK, LoRusso PM, Dickson MA, et al.: Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1). Br J Cancer 2011;104:1862-1868.
  21. Flaherty KT, LoRusso PM, DeMichele A, et al.: Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer. Clin Cancer Res 2012;18:568-576.
  22. Finn R, Hurvitz S, Allison M, et al.: Phase I study of PD 0332991, a novel, oral, cyclin-D kinase (CDK) 4/6 inhibitor in combination with letrozole, for first-line treatment of metastatic post-menopausal, estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Cancer Res 2009;69:5069-5069.
  23. Infante JR, Cassier PA, Gerecitano JF, et al.: A phase I study of the cyclin-dependent kinase 4/6 inhibitor ribociclib (LEE011) in patients with advanced solid tumors and lymphomas. Clin Cancer Res 2016;22:5696-5705.
  24. Juric D, Munster PN, Campone M, et al.: Ribociclib (LEE011) and letrozole in estrogen receptor-positive (ER+), HER2-negative (HER2-) advanced breast cancer (aBC): phase Ib safety, preliminary efficacy and molecular analysis. J Clin Oncol 2016;34(suppl):568.
  25. Tolaney SM, Forero-Torres A, Boni V, et al.: Ribociclib + fulvestrant in postmenopausal women with HR+, HER2- advanced breast cancer (ABC). Cancer Res 2017;77:abstr P4-22-12.
  26. Patnaik A, Rosen LS, Tolaney SM, et al.: Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. Cancer Discov 2016;6:740-753.
  27. Finn RS, Crown JP, Lang I, et al.: 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 Oncol 2015;16:25-35.
  28. Finn RS, Martin M, Rugo HS, et al.: Palbociclib and letrozole in advanced breast cancer. N Engl J Med 2016;375:1925-1936.
  29. Turner NC, Ro J, André F, et al.: Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med 2015;373:209-219.
  30. Cristofanilli M, Turner NC, Bondarenko I, et al.: Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 2016;17:425-439.
  31. Loibl S, Turner NC, Ro J, et al.: Standard endocrine therapy options for PreM women with MBC are limited and better options are needed. PALOMA-3 is the first large registrational study to include PreM women with HR+ MBC. J Clin Oncol 2016;34(suppl):abstr 524.
  32. Verma S, Bartlett CH, Schnell P, et al.: Palbociclib in combination with fulvestrant in women with hormone receptor-positive/HER2-negative advanced metastatic breast cancer: detailed safety analysis from a multicenter, randomized, placebo-controlled, phase III study (PALOMA-3). Oncologist 2016;21:1165-1175.
  33. Malorni L, Curigliano G, Minisini AM, et al.: A phase II trial of the CDK4/6 inhibitor palbociclib (P) as single agent or in combination with the same endocrine therapy (ET) received prior to disease progression, in patients (pts) with hormone receptor positive (HR+) HER2 negative (HER2-) metastatic breast cancer (mBC) (TREnd trial). J Clin Oncol 2017;35:1002-1002.
  34. Finn R, Jiang Y, Rugo H, et al.: Biomarker analyses from the phase 3 PALOMA-2 trial of palbociclib (P) with letrozole (L) compared with placebo (PLB) plus L in postmenopausal women with ER+/HER2- advanced breast cancer (ABC). Ann Oncol 2016;27(suppl):LBA15.
  35. O'Leary B, Hrebien S, Morden JP, et al.: Predicting sensitivity to palbociclib with early circulating tumor DNA dynamics in the PALOMA-3 trial. J Clin Oncol 2017;35(suppl):abstr 1018.
  36. Hortobagyi GN, Stemmer SM, Burris HA, et al.: Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med 2016;375:1738-1748.
  37. Hortobagyi GN, Stemmer SM, Burris HA, et al.: Updated results from MONALEESA-2, a phase 3 trial of first-line ribociclib + letrozole in hormone receptor-positive (HR+), HER2-negative (HER2-), advanced breast cancer (ABC). J Clin Oncol 2017;35(suppl):abstr 1038.
  38. Campone M, Marschner N, Villanueva C, et al.: First-line ribociclib + letrozole in HR+, HER2- ABC: Efficacy by baseline tumor markers. Ann Oncol 2017;28(suppl):mdx137.
  39. Dickler MN, Tolaney S, Rugo HS, et al.: MONARCH 1, a phase 2 study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2- metastatic breast cancer. Clin Cancer Res 2017;23:5218-5224.
  40. Sledge GW, Toi M, Neven P, et al.: MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol 2017;35:2875-2884.
  41. Tolaney SM, Lin NU, Thornton D, et al.: Abemaciclib for the treatment of brain metastases (BM) secondary to hormone receptor positive (HR+), HER2 negative breast cancer. J Clin Oncol 2017;35(suppl):abstr 1019.
  42. Rugo HS, Rumble RB, Macrae E, et al.: Endocrine therapy for hormone receptor-positive metastatic breast cancer: American Society of Clinical Oncology guideline. J Clin Oncol 2016;34:3069-3103.
  43. Cardoso F, Costa A, Senkus E, et al.: 3rd ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 3). Ann Oncol 2017;28:16-33.
  44. Booth CM, Tannock I: Reflections on medical oncology: 25 years of clinical trials - where have we come and where are we going? J Clin Oncol 2008;26:6-8.
  45. Smith I: Goals of treatment for patients with metastatic breast cancer. Semin Oncol 2006;33:S2-5.
  46. Wilcken N, Hornbuckle J, Ghersi D: Chemotherapy alone versus endocrine therapy alone for metastatic breast cancer. Cochrane Database Syst Rev 2003; CD002747.
  47. Finn RS, Crown J, Lang I, et al.: Overall survival results from the randomized phase II study of palbociclib (P) in combination with letrozole (L) vs letrozole alone for frontline treatment of ER+/HER2- advanced breast cancer (PALOMA-1; TRIO-18). J Clin Oncol 2017;35:1001-1001.
  48. Harbeck N, Iyer S, Turner N, et al.: Quality of life with palbociclib plus fulvestrant in previously treated hormone receptor-positive, HER2-negative metastatic breast cancer: patient-reported outcomes from the PALOMA-3 trial. Ann Oncol 2016;27:1047-1054.
  49. Hu W, Sung T, Jessen BA, et al.: Mechanistic investigation of bone marrow suppression associated with palbociclib and its differentiation from cytotoxic chemotherapies. Clin Cancer Res 2016;22:2000-2008.
  50. Del Paggio JC, Sullivan R, Schrag D, et al.: Delivery of meaningful cancer care: a retrospective cohort study assessing cost and benefit with the ASCO and ESMO frameworks. Lancet Oncol 2017;18:887-894.
  51. Robertson JFR, Bondarenko IM, Trishkina E, et al.: Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet 2016;388:2997-3005.
  52. Kornblum N, Manola J, Klein P, et al.: PrECOG 0102: a randomized, double-blind, phase II trial of fulvestrant plus everolimus or placebo in post-menopausal women with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC) resistant to aromatase inhibitor (AI) therapy. Cancer Res 2017;77:abstr S1-02.
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