|Ahead of print publication
Metastatic hormone receptor-positive breast cancer in CDK 4/6 era: An outcome audit
Rajeev Krishnappa Lakkavalli, Jitendra Kumar Pehalajani, Venkatesh Tirumala, Govind K Babu, Dassappa Loknatha, Linu Abraham Jacob, Suresh M C Babu, AH Rudresha, Lokesh Nagendrappa Kadabur, Smitha C Saldanha, GV Giri
Department of Medical Oncology, Kidwai Cancer Institute, Bengaluru, Karnataka, India
|Date of Submission||13-Dec-2018|
|Date of Decision||12-Feb-2019|
|Date of Acceptance||19-May-2019|
|Date of Web Publication||31-Jan-2020|
Jitendra Kumar Pehalajani,
Department of Medical Oncology, Kidwai Cancer Institute, Marigowda Road, Bengaluru - 560 029, Karnataka
Source of Support: None, Conflict of Interest: None
Background: The treatment landscape of metastatic hormone receptor (HR) positive breast cancer has been changed in recent years. Availability of CDK 4/6 inhibitor and other hormone therapy has changed the treatment algorithm for these patient, we retrospectively analyzed our metastatic HR positive breast cancer patients.
Materials and Methods: In this study, we retrospectively analyzed the case records of hr positive metastatic breast cancer patient treated at department of medical oncology from October 2016 to September 2018. Demographical characteristics, site of metastasis, objective response and clinical benefit response and toxicity profile were analyzed.
Results: We treated a total of 178 patients of MBC with HT at our center during the study period. One hundred fifty-two patients received HT alone (control group) and 26 patients received HT and CDK 4/6 inhibitor (study group). The median age of patients was 56 and 58 years in the control group and study group. The ORR was 41.7 versus 57.9 (95% CI [1.01–2.56]), and the CBR was 66.1% versus 78.9%; (CI [1.18–3.56]) (P < 0.05) of the patients in control and study groups, respectively.
Conclusions: Among patients with HR-positive, advanced breast cancer, hormone therapy is efficacious addition of CDK 4/6 inhibitor improve the efficacy with tolerable side effects.
Keywords: CDK4/6 inhibitors, hormone receptor, metastatic breast cancer
|How to cite this URL:|
Lakkavalli RK, Pehalajani JK, Tirumala V, Babu GK, Loknatha D, Jacob LA, Babu SM, Rudresha A H, Kadabur LN, Saldanha SC, Giri G V. Metastatic hormone receptor-positive breast cancer in CDK 4/6 era: An outcome audit. J Can Res Ther [Epub ahead of print] [cited 2020 Oct 28]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=277465
| > Introduction|| |
The Globocan 2018 database states that breast cancer is the most common cancer in women. Metastatic breast cancer (MBC) remains an incurable disease despite therapeutic advancements. Screening and awareness have to lead to diagnosing patients in early stages of breast cancer (EBC) in the last decades. Despite all efforts, about 6% of breast cancer patients present with distant metastasis. Furthermore, around 20% of patients with upfront EBC will sooner or later develop distant metastases that need immediate and proper treatment. The choice of treatment for MBC depends on various factors such as biomarkers including human epidermal growth factor receptor 2 (Her-2) status and hormone receptor status (HR) and patient's clinical characteristics such as tumor burden, the timing of disease recurrence, and the type of earlier therapies. The prime intention of systemic treatment for patients with MBC is to improve symptoms and if possible prolonging survival. Patients with HR-positive MBC often respond well to hormone therapy (HT), alone or in combination with targeted agents. This approach can lessen the tumor burden, symptoms with similar efficacy, and fewer side effects than chemotherapy. Moreover, modern HT and targeted therapy appear to delay progression and possibly improve survival compared with older HT.,
Numerous prospective randomized clinical trials conducted in the last decade have established that other agents which mechanistically work in different pathways than HR interference can enhance the benefit seen with HT alone. Cyclin-dependent kinase (CDK) 4/6 inhibitors, particularly, in combination with HT are often effective. CDKs are a large family of serine–threonine kinases that play decisive roles in cell cycle regulation. They are an attractive therapeutic target implicated in breast cancer as well as multiple other malignancies. Three agents, palbociclib, ribociclib, and abemaciclib, have shown to improve progression-free survival (PFS) when added to HT as first-line or later therapies in MBC. Many food and drug administration authorities across the world have granted these treatments breakthrough therapy designation with accelerated approval for the reason of the extreme unmet need. Palbociclib was available in India from October 2016. Hence, we performed this study to evaluate its treatment outcomes and toxicity profile in the Indian population.
| > Materials and Methods|| |
This was a retrospective study carried out at the tertiary cancer center in southern India. We reviewed the case records of HR-positive MBC patients treated from October 2016 to September 2018 at our institution. We included patients treated with first-line HT with or without CDK 4/6 inhibitors in the study. We extracted data regarding demographic characteristics, site of metastasis, ER/PR/Her 2 status, and Ki-67 of the tumor. Patients received HT therapy alone or with palbociclib 125 mg once daily for 3 weeks, followed by 1 week off in the 28-day cycle. Tumor assessments were performed with computed tomography of chest, abdomen, and pelvis at baseline and every 12–16 weeks afterward. The Recist1.1 was used for response assessment. Objective response (overall response rate [ORR]) was defined as the percentage of patients who had a confirmed complete response (CR) or a partial response (PR). Clinical benefit response (CBR) was defined as the percentage of patients who had a confirmed CR, PR, or SD (stable disease) for ≥24 weeks. We monitored complete blood count before the start of palbociclib therapy, at the beginning of each cycle and on day 14 of the first two cycles. Toxicity profiles were recorded for both the groups and were compared. Statistical analysis was done using IBM SPSS 22.0® Bengaluru, India. PFS was assessed using the Kaplan–Meier method. HR and 95% confidence interval (CI) were derived from a Cox proportional hazards regression model.
| > Results|| |
The data cutoff date for analysis was November 2018. We treated a total of 178 patients of MBC with HT at our center during the study period. One hundred fifty-two patients received HT alone (control group) and 26 patients received HT and CDK 4/6 inhibitor (study group). The median age of patients was 56 and 58 years in the control group and study group. Patients with upfront metastatic disease were 54% in control arm and 50% in study arm. Visceral metastasis was seen in 48% and 46%, nonvisceral metastasis in 52% and 54%, and bone only metastasis in 55% and 50% of the patients in the control and study groups. Patients who received prior endocrine or chemotherapy were 28.2% and 26.9% in the control and study groups, respectively [Table 1].
The median follow-up for the control arm was 15.5 and 15 months for study arm. The ORR was 41.7 versus 57.9 (95% CI [1.01–2.56]), and the CBR was 66.1% versus 78.9%; (CI [1.18–3.56]) (P< 0.05) of the patients in control and study groups, respectively [Table 2]. The median PFS in the control arm was 13.2 months, but it was not reached in the study arm (1.64 [1.06–2.98]) (P = 0.01) as depicted in [Graph 1].
Any grade side effects reported in the control and study arm were 31% versus 85%. The most common side effect reported was neutropenia seen in 6% versus 77% of the patients in the control and study groups, respectively. Other common side effects were fatigue seen in 27% versus 38%, leucopenia (3% vs. 23%), infection (11.5% vs. 1.3%), and myalgia (23% vs. 9%) of the patients in control and study groups, respectively. The dose reduction due to neutropenia was in 23.07% patients in the study arm, 15.3% patients during the second cycle and others in the third cycle [Table 3].
| > Discussion|| |
HR-positive breast cancer remains the most common subtype of breast cancer. Historically, the most important therapeutic intervention to manage patients with HR-positive breast cancer has been the use of HT, including tamoxifen, aromatase inhibitors, and fulvestrant. MBC remains incurable with a median survival in the order of 3–4 years. In normal mammary tissue, cyclin D1 and CDK4, in particular, are important for luminal epithelial proliferation, and these dependencies are often seen in luminal breast cancers., Thus, the subtype for which CDK4/6 inhibition has the strongest rationale is estrogen receptor-positive disease in human breast cancer. These cancers almost always keep the retinoblastoma pathway intact at presentation, meaning that the principal pathway upon which these agents act is intact. The enzymatic activity of CDK4/6 is regulated by several mechanisms. Several mitogenic signaling pathways that are active in breast cancers positively regulate CDK4/6 activity by increasing CCND1 expression or increasing cyclin D1 protein stability., Orally active inhibitors of CDK4/6 have only become available as cancer therapeutics in the last decade. They directly block the action of the cyclin D–CDK4/6 holoenzyme. These agents act to restrain the proliferation of sensitive tumor cells, in particular preventing cell cycle progression from the G1 to the S phase of the cell cycle. Thus, CDK4/6 inhibition typically induces a phenotype resembling cellular senescence in sensitive cells. This principal had been well validated by various clinical trials. Usually, patients treated in practice are clinically diverse from patients in randomized control trials. This study was undertaken to examine patient characteristics, dosing, treatment patterns, and neutropenia among patients with MBC treated with palbociclib in combination with HT.
We observed that the ORR in the palbociclib arms was 57.9%, which is consistent with the rates of ORR reported for the other clinical trials on the same scenario (PALOMA-1 55% and PALOMA-2 55%). CBR was 78.9% in the palbociclib arm, which is comparable with the rates of CBR reported for the clinical trials (PALOMA-1 81% and PALOMA-2 85%)., This showed the improvement in the efficacy of adding CDK 4 inhibitors to HT in MBC patients. The combination strategies are a way forward to improve outcomes in HR-positive MBC patients.
We observed 34.61% of dose reductions of palbociclib as compared to dose reductions reported in the clinical trials 37.1%, 36%, 52%. The rate of Grade 3 and 4 neutropenia by laboratory value was 65.38% which are consistent with the rates of Grade 3 and 4 neutropenia reported for the clinical trials 62%, 76%, 66%. The other side effects noted in our study were also comparable to the other studies. There were no new side effects observed in our study. The safety profiles of these novel agents are albeit different, but predictable and manageable in clinical practice.,,
The main limitation of this study is its retrospective nature with the potential to get incomplete care history because the breast cancer diagnosis and information for this study was obtained from case records only. In addition, we were unable to assess the clinical benefit of palbociclib, given that enough time had not elapsed to dependably estimate PFS or overall survival. These limitations are similar to those observed in various other retrospective analyses.
| > Conclusions|| |
This study confirmed that palbociclib combined with HT results in longer PFS than that with HT alone among women with HR-positive MBC. It provides more evidence about the efficacy and safety of inhibition of CDK4 and CDK6 as first-line treatment. Addition of palbociclib to HT therapy resulted in higher rates of myelotoxic effects than the rates with HT. By far, these effects have been successfully managed with appropriate supportive care and dose reductions.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.
O'Shaughnessy J. Extending survival with chemotherapy in metastatic breast cancer. Oncologist 2005;10 Suppl 3:20-9.
Sledge GW Jr., Hu P, Falkson G, Tormey D, Abeloff M. Comparison of chemotherapy with chemohormonal therapy as first-line therapy for metastatic, hormone-sensitive breast cancer: An Eastern Cooperative Oncology Group Study. J Clin Oncol 2000;18:262-6.
Lindström LS, Karlsson E, Wilking UM, Johansson U, Hartman J, Lidbrink EK, et al.
Clinically used breast cancer markers such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 are unstable throughout tumor progression. J Clin Oncol 2012;30:2601-8.
Wilcken N, Hornbuckle J, Ghersi D. Chemotherapy alone versus endocrine therapy alone for metastatic breast cancer. Cochrane Database of Systematic Reviews 2003, Issue 2. Art. No.: CD002747. DOI: 10.1002/14651858.CD002747.
Chlebowski RT. Changing concepts of hormone receptor-positive advanced breast cancer therapy. Clin Breast Cancer 2013;13:159-66.
Saux OL, Lardy-Cleaud A, Frank S, Cottu PH, Pistilli B, Debled M, et al
. Assessment of multiple endocrine therapies for metastatic breast cancer in a multicenter national observational study. J Clin Oncol 2017;35:1052.
Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, et al.
Palbociclib in hormone-receptor-positive advanced breast cancer. N
Engl J Med 2015;373:209-19.
Yu Q, Sicinska E, Geng Y, Ahnström M, Zagozdzon A, Kong Y, et al.
Requirement for CDK4 kinase function in breast cancer. Cancer Cell 2006;9:23-32.
Yanagawa M, Ikemot K, Kawauchi S, Furuya T, Yamamoto S, Oka M, et al.
Luminal A and luminal B (HER2 negative) subtypes of breast cancer consist of a mixture of tumors with different genotype. BMC Res Notes 2012;5:376.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin 2017;67:7-30.
Bonotto M, Gerratana L, Poletto E, Driol P, Giangreco M, Russo S, et al.
Measures of outcome in metastatic breast cancer: Insights from a real-world scenario. Oncologist 2014;19:608-15.
Sicinski P, Donaher JL, Parker SB, Li T, Fazeli A, Gardner H, et al.
Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 1995;82:621-30.
Jeselsohn R, Brown NE, Arendt L, Klebba I, Hu MG, Kuperwasser C, et al.
Cyclin D1 kinase activity is required for the self-renewal of mammary stem and progenitor cells that are targets of MMTV-erbB2 tumorigenesis. Cancer Cell 2010;17:65-76.
Knudsen ES, Witkiewicz AK. The strange case of CDK4/6 inhibitors: Mechanisms, resistance, and combination strategies. Trends Cancer 2017;3:39-55.
Diehl JA, Cheng M, Roussel MF, Sherr CJ. Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 1998;12:3499-511.
Vora SR, Juric D, Kim N, Mino-Kenudson M, Huynh T, Costa C, et al.
CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell 2014;26:136-49.
Narita M, Nũnez S, Heard E, Narita M, Lin AW, Hearn SA, et al.
Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 2003;113:703-16.
Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, 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.
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.
Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, 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;17:425-39.
[Table 1], [Table 2], [Table 3]