|LETTER TO THE EDITOR
|Ahead of print
An unusual durable response with palbociclib plus letrozole in hormone receptor positive metastatic breast cancer after multiple lines of therapy
Ilavarasi Vanidassane1, Ekta Dhamija2, Shailendra Singh Naik2, Atul Batra1
1 Department of Medical Oncology, AIIMS, New Delhi, India
2 Department of Radiodiagnosis, AIIMS, New Delhi, India
|Date of Submission||20-Jan-2019|
|Date of Decision||25-May-2019|
|Date of Acceptance||27-May-2019|
|Date of Web Publication||20-Jul-2020|
Department of Medical Oncology, AIIMS, New Delhi
Source of Support: None, Conflict of Interest: None
|How to cite this URL:|
Vanidassane I, Dhamija E, Naik SS, Batra A. An unusual durable response with palbociclib plus letrozole in hormone receptor positive metastatic breast cancer after multiple lines of therapy. Indian J Cancer [Epub ahead of print] [cited 2020 Aug 9]. Available from: http://www.indianjcancer.com/preprintarticle.asp?id=290274
Metastatic breast cancer (MBC) is incurable, and current therapy focuses on disease control and prolongation of life. Present treatment options in hormone receptor-positive and HER2 negative MBC include various endocrine therapies. The use of chemotherapy is being shifted to later lines of therapy. The various classes of drugs available for these patients are nonsteroidal and steroidal aromatase inhibitors such as anastrozole, letrozole, and exemestane; serum estrogen receptor modulators such as tamoxifen; estrogen receptor down-regulators such as fulvestrant, newer drugs including CDK 4/6 inhibitors such as palbociclib, and mTOR inhibitors such as everolimus.,, The expanding armamentarium of drugs has led to newer combinations such as everolimus and exemestane, palbociclib and letrozole, or fulvestrant in the management of MBC, which have improved the survival of these patients.,, The progression-free survival with subsequent lines of therapy decreases with further therapy and it is a challenge to achieve long-lasting response in heavily pretreated patients. We report a case of MBC who showed lasting response to the combination of palbociclib and letrozole as 6th line of therapy.
A 48-year-old premenopausal woman presented with left breast lump in 2006 and was diagnosed as invasive ductal carcinoma T2N0M0, stage IIA, estrogen receptor (ER), and progesterone receptor (PR) 60%, HER2 negative. She was treated with left-sided modified radical mastectomy, and received adjuvant 5-fluorouracil 500 mg/m2, epirubicin 75 mg/m2, and cyclophosphamide 500 mg/m2 (FEC) intravenously (IV) every 3 weeks for 6 cycles followed by adjuvant endocrine therapy with tamoxifen 20 mg per oral (PO) daily for 5 years. In December 2012, she developed a chest wall lesion, and imaging was suggestive of locoregional recurrence along with multiple bony metastases. A biopsy confirmed recurrence, and she was diagnosed as MBC ER/PR positive and HER2 negative. Because there was no visceral crisis, she was started on letrozole 2.5 mg PO continuously daily after confirming her postmenopausal status. On follow-up after 3 months, she developed cervical lymphadenopathy and new painful bone metastases and had clinical and radiological disease progression. In view of poor response to letrozole and painful bony lesions, she was started on capecitabine 1250 mg/m2 orally for day 1 to day 14 followed by 7 days rest period and docetaxel 75 mg/m2 on day 1 IV every 3 weeks. She achieved a partial response and became asymptomatic after 6 cycles of chemotherapy. Later, she was started on maintenance therapy with fulvestrant 500 mg intramuscularly (IM) on days 0, 14, and 28 followed by once in every 28 days and remained asymptomatic. After 2.5 years, she presented with cough. A contrast-enhanced computed tomography (CECT) of the thorax revealed bilateral lung metastases. Exemestane 25 mg PO plus everolimus 10 mg PO was initiated but everolimus had to be discontinued after 6 months owing to poor tolerance in spite of lowering the dose. After 8 months, in February 2017, the patient presented with worsening cough and dyspnea on exertion, and the imaging was suggestive of progressive lung metastases. She was then started on palbociclib 125 mg PO for 21 days followed by 7 day rest period and letrozole 2.5 mg PO once a day throughout the 28 days cycle. [Figure 1] depicts the treatment timeline of the patient.
|Figure 1: Treatment timeline of the patient. MBC – metastatic breast cancer, FEC - 5 fluorouracil, epirubicin, cyclophosphamide|
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Her symptoms improved markedly and imaging was suggestive of stable disease as per the response evaluation criteria in solid tumors (RECIST). She continues to have stable disease after 22 months of palbociclib plus letrozole [Figure 2]. Throughout this period, she tolerated the treatment well without significant adverse effects.
|Figure 2: Stable disease in a sequential scan (top row: at the time of starting palbociclib plus letrozole and bottom row: recent follow-up after 18 months). Axial CT images in soft tissue (a and b) and bone window (c and d) show lytic sclerotic changes involving an anterior aspect of 3rd, rib on the left side with associated mild soft tissue and also in the sternum. There is no significant interval change seen in the imaging findings of the two scans|
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This decade has witnessed landmark advances in the management of hormone receptor-positive MBC. These advances have prolonged the survival of these patients by years. However, resistance to endocrine therapy is being witnessed much more commonly than before as these patients live longer. Subsequent management of these patients after endocrine resistance remains a challenge. Common resistance mechanisms described in the literature are loss of expression of ER receptor, post-translational modification, differential binding of ER receptor, ER mutations, cross talk with HER2 signaling, P13K/AKT/mTOR pathway activation, and NFkB signaling increasing cyclins, CDKs leading to tumor survival using PI3K-AKT-mTOR pathway.
CDKs are key regulators of progression of cell cycle; CDK 4 links with the cyclin D1 and phosphorylates retinoblastoma (Rb) protein allowing cell cycle progression. Blocking of CDK4/6 phosphorylation of Rb leads to G1 cell cycle arrest. Three oral selective inhibitors of CDK4/6 are available palbociclib, abemaciclib, and ribociclib. Palbociclib plus letrozole was approved as the first line in hormone receptor-positive breast cancer after PALOMA-2 trail showed doubling in progression-free survival (PFS) when compared to letrozole alone group. In PALOMA-3 study, palbociclib and fulvestrant was compared with fulvestrant alone and showed significant improvement in PFS (HR 0.46; 95% CI 0.36-0.59; P < 0.0001) irrespective of PIK3CA mutational status, the endocrine resistance, and hormone receptor expression level. The combination is usually well tolerated without any major adverse effects. The common adverse events of this combination are neutropenia (66%), leukopenia (24%), anemia (5%), fatigue (2%), and febrile neutropenia (2%). In a retrospective review of 53 patients, this combination in the second line setting reported 6.3 months and 6.4 months of median time to treatment failure and progression-free survival, respectively.
This patient received palbociclib plus letrozole as 6th line therapy and continues to respond for more than 19 months with it. The overall survival since the diagnosis of metastatic disease is 6 years, and she continues to lead an active lifestyle. To the best of our knowledge, this is the first case report of a heavily treated hormone receptor positive MBC showing durable response with combination of palbociclib and letrozole beyond 2nd line setting.
To conclude, this case report supports the use of palbociclib with letrozole in postmenopausal hormone receptor-positive MBC patients who progressed on multiple therapies and did not receive this class of drug in frontline settings. In spite of limitations common to any anecdotal case, we believe that this case highlights palbociclib plus letrozole combination could achieve lasting control in heavily treated hormone receptor-positive MBC patients.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]