Complete Response to Single Agent Palbociclib in Metastatic Breast Cancer: A Case Report

Introduction

Breast cancer is the most common malignancy diagnosed in women and it is the second leading cause of cancer-related death in United States.¹ Estrogen and Progesterone receptor (ER/PR)-positive, human epidermal growth factor receptor 2 (HER2)-negative is the most common subtype of breast cancer.² While most patients in Western societies present with early stage breast cancer and will likely survive their disease, some patients suffer a recurrence, and other present with de novo metastatic disease. Once metastatic, breast cancer is rarely cured, with a 5-year survival rate of only 24%.¹

Endocrine manipulations are an integral part of treatment of patients with advanced ER/PR-positive breast cancer.³ Unfortunately, patients with metastatic disease will eventually suffer disease progression despite endocrine therapy either due to primary or secondary resistance. Depending on initial response, most women will be transitioned to chemotherapy following 1–3 lines of endocrine therapy.⁴ In contrast to endocrine therapy, chemotherapy is associated with many adverse effects, and once initiated women are expected to have more frequent office visits and laboratory tests. Therefore, there has been a search to improve efficacy of endocrine therapy, to delay the administration of chemotherapy, and to maintain the quality of life of these patients.

Palbociclib, is an orally active, selective, and reversible inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Palbociclib is approved by the Food and Drug Administration (FDA) for the treatment of postmenopausal women with hormone receptor-positive, HER2-negative disease in combination with endocrine therapy.⁵ It is approved in combination with aromatase inhibitors as an initial treatment based on the results of PALOMA-1 and PALOMA-2 studies.^6,7 Palbociclib is also approved with fulvestrant in women with disease progression following first line endocrine therapy based on PALOMA-3.^8,9 We report here a case of a post-menopausal woman with metastatic breast cancer who had substantial clinical benefit with single agent palbociclib as second line therapy.

Case report

A 73-year-old woman presented for treatment recommendations for recurrent metastatic breast cancer in 2010. She was initially diagnosed with ductal carcinoma in-situ in 2000, following an abnormal mammogram. Her past medical history was significant for hypertension, hyperthyroidism, and a hysterectomy and unilateral salpingo-oophorectomy at age 28. Her home medications were hydrochlorothiazide and levothyroxine, and a prolonged use of oral hormone replacement therapy. Her family history was significant for ovarian cancer in her mother and maternal aunt and prostate and colon cancer in her father. Given the family history of ovarian cancer and her desire to continue hormone replacement therapy, she underwent bilateral mastectomy with breast reconstruction and an oophorectomy. Pathology of the left breast revealed a high grade, 1 cm ductal carcinoma in-situ. She declined genetic testing and received no further therapy.

In 2010, the patient underwent an assessment in preparation for an extensive reconstructive foot surgery, which required bone marrow harvesting and stem cell engraftment. A PET-CT revealed a single hypermetabolic mass of 2.3 x1.8 cm in the right lobe of her liver. A biopsy revealed this was a poorly differentiated adenocarcinoma, consistent with a breast primary. It was ER/PR-positive, HER2-negative. She stopped her hormone replacement therapy when the diagnosis of metastatic disease was made. Her physical examination was unremarkable except for prior bilateral mastectomies and implant-based reconstruction. The patient was started on endocrine therapy with exemestane. She described multiple symptoms and was not able to tolerate the medication. She was prescribed anastrozole, which was associated with a syncopal episode.

Since the patient had an oligo-metastasis, she underwent a partial hepatectomy in April 2010, which revealed metastatic adenocarcinoma carcinoma. Following the hepatic resection, she declined endocrine therapy. She was followed regularly with clinical examination and PET-CT imaging every 3 to 6 months. After 3 years of follow up, PET-CT revealed a new single hypodense lesion in the liver measuring 2.6 × 2.8 cm. The patient underwent a second hepatic resection in June 2013.

The patient again declined endocrine therapy and was with no evidence of disease until June 2014 when multiple new hepatic lesions were seen on PET-CT. Since she was not a candidate for resection, the patient started letrozole and has taken the medication despite significant bone pain and dry mouth for approximately one year when a PET-CT in June 2015 demonstrated disease progression with multiple hepatic nodules and mediastinal lymph nodes (Figure 1). The patient was started on fulvestrant and palbociclib in July 2015. She received one injection of fulvestrant and described significant flu-like symptoms, including a cough and diffuse aches. She declined day 15 dose, and did not take her palbociclib. She was agreeable to a second dose of fulvestrant about one month following the first injection and also started palbociclib. She again described significant side effects and declined endocrine therapy. She also declined chemotherapy and asked to remain on single agent palbociclib. Given few available options, the patient was maintained on palbociclib, which was adjusted to 100 mg by mouth daily for 2 weeks with a 2-week break based on her complete blood cell counts. She tolerated this dose and schedule well with no neutropenia. An initial follow up PET-CT in September 2015 revealed near complete metabolic resolution of the metastatic disease (Figure 2). She remained on palbociclib alone and was monitored with clinical evaluation and PET-CTs every 3 to 6 months. However, after progression free interval of 20 months her PET CT, in June of 2017 revealed disease progression in the liver and locoregional lymph nodes.

Figure 1. PET-CT images prior to initiating palbociclib.

Maximum Intensity Projection PET image (A) demonstrate multiple focally hypermetabolic lymph nodes in the mediastinum/hilum (yellow arrows) and patchy nodular activity in segment 7 of the liver (red arrow). Axial PET-CT images (B and C) demonstrate patchy nodular hypermetabolic disease in liver segment 7 (red arrows).

Figure 2. PET-CT images following 3 months of single-agent palbociclib.

Maximum Intensity Projection PET image (A) demonstrates near complete metabolic resolution of lymph nodes in the mediastinum/hilum (yellow arrows) and lesions in segment 7 of the liver (red arrow). Axial PET-CT images (B and C) demonstrates metabolic resolution of multiple liver lesions in segment 7 with post treatment calcification (red arrows).

Discussion

CDKs are key regulators of cell cycle and RNA transcription. Inhibition of CDK prevent phosphorylation of retinoblastoma protein (Rb) downstream and arrests cell cycle in G1 phase in vitro and tumor regression in vivo.^10,11 Animal studies have demonstrated that oral administration of palbociclib as a single agent is associated with inhibition of cell growth and suppression of DNA replication by preventing cell from entering S phase. Oral administration of palbociclib is also associated with significant tumor regression against multiple human tumor xenografts in mice.¹²

In a phase II trial of single agent palbociclib, investigators enrolled 37 women with metastatic breast cancer with positive staining for Rb (>1+ staining intensity in primary or metastatic tumor). The majority of the patients (84%) had hormone receptor-positive, HER2-negative disease and received 2 or more prior cytotoxic regimens (76%) and endocrine therapies (65%). Overall, the investigators reported a clinical benefit rate of 21% in patients with hormone receptor-positive disease, which increased to 29% among those who had progressed through at least 2 prior lines of endocrine therapy. This study suggested that palbociclib may have single agent activity, primarily in women with acquired endocrine resistance. However, the median progression-free survival (PFS) in hormone receptor-positive, HER2-negative disease was only 3.8 months (95% confidence interval [CI] 1.9 – 5.8).¹³

Our patient received only one line of endocrine therapy prior to initiating palbociclib. Her PFS on letrozole was similar to that observed in the control arms of PALOMA-1 and 2. PALOMA-1, a randomized, open label, phase 2 multicenter trial, and PALOMA-2, a phase 3, randomized double-blind study, enrolled postmenopausal women with advanced hormone-receptor positive, HER2-negative breast cancer who have not received prior therapies to letrozole with palbociclib or placebo. In PALOMA-1, the median PFS was 10.2 months in the letrozole group and 20.2 months for the palbociclib and letrozole group (HR 0.488, 95% CI 0.319–0.748; p=0.0004).⁶ In PALOMA-2, the median PFS was 14.5 months (95% CI, 12.9 to 17.1) in the placebo-letrozole, as compared with 24.8 months (95% CI 22.1 to not estimable) in the palbociclib and letrozole group (HR for disease progression or death, 0.58; 95% CI, 0.46 to 0.72; P<0.001).⁷

Our patient had prolonged response to palbociclib alone, longer than the benefit she experienced with letrozole alone, and longer than the median PFS seen in PALOMA-3 with the combination of palbociclib and fulvestrant and in the single agent palbociclib trial. In the phase 3 randomized PALOMA-3, women aged 18 years or older with hormone receptor positive, HER2-negative metastatic breast cancer received fulvestrant with or without palbociclib.⁸ A median PFS of 9.5 months (95% CI 9.2–11.0) was observed in the fulvestrant and palbociclib group compared to 4.6 months (95% CI 3.5–5.6) in the fulvestrant and placebo group (HR 0.46, 95% CI 0.36–0.59, p<0.0001). These 3 studies demonstrated significant improvement in PFS when palbociclib was added to endocrine therapy, however, our patient was not taking concomitant endocrine therapy.

Two additional CDK inhibitors have been recently approved for individuals with advanced breast cancer. Ribociclib, was approved in combination of AI for first line therpay of women with advanced hormone receptor-positive, HER2-negative breast cancer. Single agent ribociclib administered to heavily pretreated patients with solid tumors or lymphomas was associated with modest activity including one partial response in a patient with a PIK3CAmutant, CCND1-amplified, ER-positive breast cancer, and several stable diseases in patients with breast cancer.¹⁴ Abemaciclib was approved for second or later-line therapy in combination with fulvestrant based on the results of MONARCH-2, and as a single agent for third or later-line therapy for women and men based on MONARCH-1.^15,16

Another observation is that our patient had a family history of ovarian cancer but has declined genetic testing. It is possible that individuals with germline mutations may be particularly sensitive to CDK 4/6 inhibition. Future mechanistic studies can help further investigate this hypothesis.

Our case report suggests that single agent palbociclib may provide benefit to select patients. Future studies should consider patient populations who may be candidates for this approach, which may help delay administration of chemotherapy while providing good disease control. Further large multicenter trials are needed to see the effect of single agent palbociclib on disease progression.

Conclusion

This is the first report to our knowledge of a patient treated with single agent palbociclib for metastatic breast cancer in clinical practice. Further studies are needed to assess response to single agent palbociclib instead of combination with endocrine therapy in patients who either cannot tolerate endocrine therapy or had disease progression on endocrine therapy.

Clinical practice points.

• Palbociclib combined with endocrine therapy is currently approved for the treatment of metastatic hormone receptor-positive breast cancer.

• The effect of single agent palbociclib is not well known, however a benefit may be observed in patients who cannot tolerate endocrine therapy.