Symptomatic bone marrow involvement by metastatic occult HR+/HER2- breast cancer treated with ribociclib and letrozole: A case report

Abstract

Visceral crisis (VC) occurs in less than about 15% of patients with de novo metastatic breast cancer (BC). We present a case of a 59-years-old woman who presented with history of bone pain, fatigue, dyspnea on exertion, and weight loss; on physical examination was found no breast nodules, enlarged lymph nodes, or enlarged viscera were palpable. Laboratory tests revealed hemoglobin 5.8 g/dl. PET CT scan showed multiple osteolytic lesions. A bone marrow biopsy was performed, which identified infiltration by an epithelial tumor lesion. Immunohistochemistry showed positivity for CK1/3, CK7, Gata-3, and estrogen and progesterone receptors. HER2 negative (0+). The diagnosis of de novo occult HR+/HER2- metastatic BC was made. Systemic treatment with ribociclib and letrozole was started; the patient experienced clinical improvement of the symptoms, weight gain and improvement in hemoglobin levels. VC in HR+/HER2- metastatic BC is a challenging situation from its definition to its management. In case of availability and quick access, a free CT regimen with CDK4/6i + endocrine therapy could be a option to consider in this patients. This also represents a challenge in terms of cost-effectiveness in the health systems of low-income countries.

Introduction

Breast cancer (BC) is the most frequently diagnosed tumor and represents the leading cause of cancer death worldwide among women [1]. About 10% are diagnosed with advanced stage disease, of which approximately 60% are hormone receptor positive (HR+) HER2 negative (HER2-) tumors [2,3].

Occult breast cancer (OBC) is a rare disease and reported to comprise 0.3%-1.0% of all BC [4]. Patients with OBC are defined as a group of patients for whom the primary lesion in the breast gland cannot be found through clinical tests and imaging (mammography and ultrasonography) and the metastasis of axillary lymph nodes (ALNs) or other organs is mainly taken as the first symptom; for these patients, other metastatic sites need to be confirmed as the source of BC lesions [5].

Visceral crisis (VC) occurs in less than about 15% of patients with de novo metastatic BC [6]. The concept of VC was oftentimes revisited in recent years and nowadays there is not a widely accepted definition: according to the Advanced Breast Cancer (ABC) international consensus guidelines 6 and 7 define a VC as “severe organ dysfunction as assessed by signs, symptoms, and laboratory studies, resulting from rapid progression of neoplastic disease and indicative of substantial visceral compromise, which may serve as an indication for more aggressive therapeutic intervention”. However, there are no objective criteria for defining VC [6]. This guideline provides more specific details only for hepatic VC (elevated bilirubin >1.5 times the upper limit of normal in the absence of obstruction) and pulmonary VC (resting dyspnea in the absence of pleural effusion). Nonetheless, other scenarios have been classified as VC in different studies, based on the clinical perception that the aggressive disease presentation may preclude further treatment if initial management fails. These clinical scenarios include bowel obstruction due to peritoneal carcinomatosis, hypercalcemia of malignancy, superior vena cava syndrome, cardiac tamponade and cytopenias due to bone marrow infiltration [7]. Here we present a case of symptomatic bone marrow involvement by de novo metastatic occult HR+/HER2- BC treated with ribociclib and letrozole.

Case report

A 59-year-old woman with controlled arterial hypertension, no surgical history, no family history and nonsmoker was referred to our institution's hematology service with a 1-year history of bone pain, fatigue, dyspnea on exertion, and a 20-kilogram weight loss. On physical examination, the patient was found to have lost weight, Eastern Cooperative Oncology Group (ECOG) Performance Status 2 (capable of all self-care but unable to carry out any work activities. Up and about for more than 50% of their waking hours), no breast nodules, enlarged lymph nodes, or enlarged viscera were palpable. Laboratory tests revealed hemoglobin 5.8 g/dl, albumin 2.7 g/dL; the other laboratory tests including leukocytes, platelet count, alanine aminotransferase, aspartate aminotransferase, total bilirubin, alkaline phosphatase, gamma-glutamyl transferase, lactate dehydrogenase, prothrombin time test, activated partial thromboplastin time, hepatitis B surface antigen, hepatitis C virus, HIV were normal. Upper and lower gastrointestinal endoscopy showed no evidence of primary tumors, ulcers, or bleeding. Bone marrow flow cytometry: no cell populations expressing immunophenotypes suspicious for neoplasia were identified. PET CT scan showed multiple osteolytic lesions in the axial and appendicular skeleton with morphometabolic characteristics of malignancy. No suspicious lesions were observed in the breasts or lymph node areas (Fig. 1A). Breast and axillary lymph node ultrasound did not show any nodules, masses, or lymph nodes suspicious for malignancy (Fig. 2). A bone marrow biopsy was performed, which identified infiltration by an epithelial tumor lesion with extensive cytoplasm, hyperchromatic nuclei, and frequent nucleoli. Immunohistochemistry showed positivity for CK1/3, CK7, CAM5.2, Gata-3, estrogen and progesterone receptors. HER2 negative (0+). Negative for CK20, CK5/6, CD45, TTF1, and CDX2 (Fig. 3). The patient was referred to our institution's oncology service. The diagnosis of de novo metastatic HR+/HER2- breast cancer was made. After discussion in the tumor committee, systemic treatment with ribociclib 600 mg once daily for 21 consecutive days, followed by 7 days off, letrozole 2.5 mg per day on a continuous schedule and denosumab was started. Written informed consent for publication of this case and accompanying images was obtained from the patient. The patient experienced clinical improvement of the symptoms, weight gain of 5 kilograms and improvement in hemoglobin levels (9.6 g/dl) in the first 2 months. PET/CT performed 4 months after the start of treatment showed a decrease in the number and metabolism of osteolytic lesions in the axial and appendicular skeleton (Fig. 1B). After 9 months of treatment, the patient continues to respond to the prescribed treatment.

Fig. 1.

(A) PET/CT scan showing multiple osteolytic lesions in the axial and appendicular skeleton with morphometabolic characteristics of malignancy. No suspicious lesions were observed in the breasts or lymph node areas and (B) PET/CT showing decreased number and metabolism of osteolytic lesions in the axial and appendicular skeleton.

Fig. 2.

Breast (A and B) and axillary lymph node (C and D) ultrasound did not show any nodules, masses, or lymph nodes suspicious for malignancy.

Fig. 3.

(A) Bone marrow biopsy: infiltration by epithelial tumor lesion (H&E. 10 and 40X.) (B) IHC showing membranous positivity for CK7. 10 and 40x. (C) IHC showing membranous positivity for GATA3. 10 and 40x. (D) IHC showing nuclear positivity for ER. 10 and 40x. (E) IHC showing nuclear positivity for PR. 10 and 40x. (F) Negative IHC for HER2. 10 and 40x. H&E: Hematoxylin and eosin; IHC: Immunohistochemistry.

Discussion

This case report of symptomatic bone marrow involvement by de novo metastatic occult HR+/HER2- breast cancer treated with ribociclib and letrozole is an unusual presentation of a frequent pathology.

In patients with OBC, magnetic resonance imaging (MRI) is significantly more sensitive in detecting a primary lesion that mammography or ultrasound; identifying a primary in 72% of cases that were deemed occult [8]. Walter et al. [9] reported the sensitivity of MRI and PET-CT for breast disease was 89 and 63%, respectively, the specificity was 74 and 91%, respectively. In the case of our patient, a breast MRI was not performed since it would not influence the therapeutic approach and because a PET CT was performed. Multiple case reports of de novo metastatic occult breast cancer without lymph node involvement have been published [[10], [11], [12]]. Bitencourt A. et al. [13] reported in a series of 597 patients with de novo metastatic breast cancer who underwent pretreatment PET/CT; 14.2% showed no regional lymph node involvement, most of whom were HR-positive.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have revolutionized the treatment of HR+/HER2- advanced BC (aBC) by significantly improving progression-free survival (PFS) [[14], [15], [16]] and, in some cases, overall survival (OS) [14].

The paradigm of treating VC in patients with HR+/HER2- aBC was for years chemotherapy (CT). This recommendation, based on the idea that CT could provide more rapid and higher response rates (RR) than endocrine therapy, was adopted in the pre-CDK4/6i era. Multiple data published in recent years have challenged this paradigm supporting the possibility to use CDK4/6i also in this poor prognostic context, at least if patients present with a severe clinical condition that does not represent per se an obstacle to CDK4/6i prescription. Pangarsa E. et al. [17] report their experience in a premenopausal female with HR+/HER2- aBC and visceral crisis, which involved bone marrow infiltration and liver metastasis with preserved liver function successfully treated with letrozole, ribociclib, and leuprorelin injection. Schettini F. et al. [18] report their experience in a 52 years old female with HR+/HER2- aBC with lymphangitis carcinomatosis successfully treated with upfront ribociclib + fulvestrant. The patient experienced a complete symptomatic and radiologic remission of the lymphangitis with a partial response as best response. The PFS was of 20 months. In RIGHT Choice trial, 222 pre/perimenopausal patients were randomized to ribociclib plus ET or combination CT, 67.6% had symptomatic visceral metastases, 18.5% had rapid disease progression per investigator's judgment, and 14.0% had symptomatic nonvisceral disease. Overall, 47.7% patients had investigator-assessed visceral crisis. The median PFS was 21.8 months in ribociclib plus ET arm versus 12.8 months in combination CT arm. No diferences were found in overall RR and the median time to response in the ribociclib versus CT arms [19]. The study used an old definition of visceral crisis (ABC guidelines 3). It was not reported whether patients with bone marrow infiltration were included. In the same sense, frontline combination of CDK4/6i and ET for patients with aggressive HR+/HER2- BC was also evaluated in the ABIGAIL trial, a phase 2, noninferiority study. Patients were randomised to receive abemaciclib plus ET (letrozole or fulvestrant) or paclitaxel for 12 weeks followed by abemaciclib plus ET. The 12-week overall RR was 58.8% in patients treated with abemaciclib plus ET compared to 40.2% in patients treated with CT [20]. The inclusion criteria for “aggressive HR+/HER2- BC” were broad, and the proportion of patients with VC and whether patients with bone marrow infiltration were included were not reported.

The pattern of VC rather than VC itself might guide the selection of the most proper treatment, according to systemic agents' side effects and pharmacokinetic profile. For example, patients with medullary infiltration and neutropenia/pancytopenia might be considered candidates to receive abemaciclib instead of other CDK4/6i, since the former is characterized by lower rates of hematotoxicity than palbociclib/ribociclib and is potentially less myelodisruptive than standard CT, or, in moderate–severe liver dysfunction cases, considering the preferential liver metabolism of all the 3 approved CDK4/6i, other agents which have been proven to be safely administrable in patients with impaired hepatic function, such as capecitabine or platinum agents should be preferred [18].

In conclusion, VC in HR+/HER2- aBC is a challenging situation from its definition to its management. After multidisciplinary discussion, availability and quick access, a free CT regimen with CDK4/6i + ET could be a option to consider in this patients. This also represents a challenge in terms of cost-effectiveness in the health systems of low-income countries.

Patient consent

The authors of this manuscript declare that an informed consent for publication of this case was obtained from the patient.