Sir,

Hormonal manipulation constitutes the backbone of management of advanced hormone-receptor-positive (HR+) breast cancer. The availability of cyclin-dependant kinase (CDK) 4/6 inhibitors has led to significant improvements in the outcome of this population. Palbociclib, ribociclib, and abemaciclib are now approved as first-line therapy for HR+ advanced breast cancer in combination with aromatase inhibitors (AIs) in postmenopausal women. Randomized Phase 3 trials have shown a significant increase in progression-free survival (PFS) of around 9–10 months when compared with anti-estrogen therapy alone when used in endocrine-naive patients [Table 1].[1] [2] [3] [4] When used in the second-line setting, the PFS gain is in the range of 6–7 months. The overall survival (OS) gain of 7 months (statistically nonsignificant) in the PALOMA 3 study could not answer the question of optimal sequencing of CDK 4/6 inhibitors, as 18% of patients received subsequent CDK 4/6 inhibitors in placebo arm.[5] Thus, we have a situation of an effective drug that can be sequenced in both the frontline and second-line settings, with no definitive evidence to suggest that a particular strategy of sequencing produces a definite survival benefit. To add to the clinician's dilemma, there are data from the FALCON trial which bring out single-agent fulvestrant as another treatment option in the endocrine-naive setting.[6] In addition, a recent publication highlights improved PFS and OS with a combination of fulvestrant plus anastrozole.[7] The subsequent lines could never be evidence based after that as there is no data on how AI + CDK4/6 inhibition will work after exposure to fulvestrant. Thus, it is likely that the recommendations of use in first line will remain the same in future.

| Figure 1  (a) Cyclin-dependent kinase 4/6 inhibitors in postmenopausal metastatic breast cancer: Comparison of cost and median progression-free survival. (b) Cyclin-dependent kinase 4/6 inhibitors in premenopausal metastatic breast cancer: comparison of cost and median progression-free survival

| Figure 2  Cyclin-dependent kinase 4/6 inhibitors – per-day expenditure

In palliative setting, treatment is continued indefinitely till progression. Thus, if two ways of sequencing therapies generate equivalent overall outcomes, a strategy which uses any expensive drug for a shorter duration should be the clear winner. While the first-line use of CDK antagonists leads to an unprecedented PFS of 2 years with apparent better quality of life and psychological benefit to the patients, it involves the use of an expensive drug for a median duration of around 2 years, which significantly escalates the total cost of therapy. The National Institute for Health and Care Excellence has approved the first-line use of palbociclib and ribociclib with a caveat of cost agreement.[8] [9] On the other hand, second-line use has a major advantage in terms of reduced costs [Figure 1a] and [b]. Further, endocrine resistance was present in 21.3% (111/521) of cases in the PALOMA 3 study, a subgroup where CDK inhibitor use was found to be ineffective in terms of improving survival. These patients may also be considered for fulvestrant alone or in a combination of exemestane and everolimus as the second-line regimen. Although it may be wise to choose exemestane + everolimus in this difficult set of patients, using this regimen indiscriminately as a cheaper option in the hormone-naive population may be counterproductive and may jeopardize survival, as there is some evidence to suggest that CDK 4/6 inhibition works poorly after mammalian target of rapamycin (mTOR) inhibitors, not to mention the increased toxicity concerns with mTOR inhibitors.[10]

The scientific evidence pertaining to CDK 4/6 inhibitors has created a challenging situation for health-care providers for optimizing the sequence of CDK 4/6 inhibitors. The financial aspects are important for any health-care system. When the treatment is out of pocket, placing CDK 4/6 inhibitors in the second line will definitely reduce the financial toxicity across the world, especially in resource-limited countries.

Conflict of Interest

There are no conflicts of interest.

• References

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1.  Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K. et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med 2016; 375: 1925-36
2.  Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J. et al. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol 2017; 35: 3638-46
3.  Tripathy D, Im SA, Colleoni M, Franke F, Bardia A, Harbeck N. et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): A randomised phase 3 trial. Lancet Oncol 2018; 19: 904-15
4.  Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S. et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med 2016; 375: 1738-48
5.  Turner NC, Slamon DJ, Ro J, Bondarenko I, Im SA, Masuda N. et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med 2018; 379: 1926-36
6.  Robertson JF, Bondarenko IM, Trishkina E, Dvorkin M, Panasci L, Manikhas A. 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
7.  Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR. et al. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med 2012; 367: 435-44
8.  Palbociclib with an Aromatase Inhibitor for Previously Untreated, Hormone Receptor-Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer | Guidance and Guidelines | NICE. Available from: https://www.nice.org.uk/guidance/ta495. [Last accessed on 2018 Dec 23]
9.  Ribociclib with An Aromatase Inhibitor for Previously Untreated, Hormone Receptor-Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer | Guidance and Guidelines | NICE. Available from: https://www.nice.org.uk/guidance/ta495. [Last accessed on 2018 Dec 23]
10.  Dhakal A, Matthews CM, Levine EG, Salerno KE, Zhang F, Takabe K. et al. Efficacy of palbociclib combinations in hormone receptor-positive metastatic breast cancer patients after prior everolimus treatment. Clin Breast Cancer 2018; 18: e1401-5

| Figure 1  (a) Cyclin-dependent kinase 4/6 inhibitors in postmenopausal metastatic breast cancer: Comparison of cost and median progression-free survival. (b) Cyclin-dependent kinase 4/6 inhibitors in premenopausal metastatic breast cancer: comparison of cost and median progression-free survival

| Figure 2  Cyclin-dependent kinase 4/6 inhibitors – per-day expenditure

1.  Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K. et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med 2016; 375: 1925-36
2.  Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J. et al. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol 2017; 35: 3638-46
3.  Tripathy D, Im SA, Colleoni M, Franke F, Bardia A, Harbeck N. et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): A randomised phase 3 trial. Lancet Oncol 2018; 19: 904-15
4.  Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S. et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med 2016; 375: 1738-48
5.  Turner NC, Slamon DJ, Ro J, Bondarenko I, Im SA, Masuda N. et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med 2018; 379: 1926-36
6.  Robertson JF, Bondarenko IM, Trishkina E, Dvorkin M, Panasci L, Manikhas A. 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
7.  Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR. et al. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med 2012; 367: 435-44
8.  Palbociclib with an Aromatase Inhibitor for Previously Untreated, Hormone Receptor-Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer | Guidance and Guidelines | NICE. Available from: https://www.nice.org.uk/guidance/ta495. [Last accessed on 2018 Dec 23]
9.  Ribociclib with An Aromatase Inhibitor for Previously Untreated, Hormone Receptor-Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer | Guidance and Guidelines | NICE. Available from: https://www.nice.org.uk/guidance/ta495. [Last accessed on 2018 Dec 23]
10.  Dhakal A, Matthews CM, Levine EG, Salerno KE, Zhang F, Takabe K. et al. Efficacy of palbociclib combinations in hormone receptor-positive metastatic breast cancer patients after prior everolimus treatment. Clin Breast Cancer 2018; 18: e1401-5