Abstract
Background/Aim: Currently, there is no recommendation for the treatment of breast cancer (BC) with bone-marrow cell infiltration (BMI). We evaluated the efficacy and safety of weekly-paclitaxel in this population. Patients and Methods: This retrospective study included all BC patients with BMI receiving weekly-paclitaxel between January 2014 and May 2018. Overall-survival (OS) was the primary endpoint. Secondary endpoints were progression-free-survival (PFS) and safety. Results: BMI was diagnosed in 26 patients. This infiltration was suggested by peripheral blood smear in 73% of cases. All patients had anemia, and 77% had thrombocytopenia. OS and PFS were 7.2 months [95% confidence interval (CI)=2.6-20.7] and 3.3 months (95%CI=1.6-7.2), respectively. Good performance-status, absence of thrombocytopenia and presence of less than 5% of circulating erythroblasts at BMI diagnosis, were associated with better survival. One patient presented grade 5 febrile neutropenia but no episodes of bleeding were reported. Conclusion: Weekly-paclitaxel is an effective therapeutic option with limited toxicity for BC with BMI.
Breast cancer (BC) is the most common cancer in females worldwide with 2.088.849 new cases in 2018 (1). Bone marrow infiltration (BMI) by cancer cells is not a rare event in BC. Braun et al. have found occult bone marrow (BM) micrometastases in nearly a third of patients with localized BC (2). However, symptomatic BM metastasis is an uncommon presentation of metastatic BC, occurring in less than 0.2% of patients in Kopp study (3). The gold standard for BMI diagnosis is BM biopsy. It is unclear if BM aspiration alone or leucoerythroblastosis in peripheral blood could be an alternative to BM biopsy in the absence of other evident etiology. But Kopp et al. have shown a sensitivity of 75% for the diagnosis of BMI by blood smear (3). BMI can result in cytopenia which can complicate treatment choice (4). To date, there is little data concerning BC with symptomatic BMI evolution and no therapeutic guidelines are clearly established. In our center, weekly-paclitaxel is usually prescribed in this situation. We report here the results of a retrospective analysis of BC patients with symptomatic BMI treated with weekly-paclitaxel.
Patients and Methods
Study design. We carried out a descriptive retrospective monocentric study at the cancer center in Caen, France. Eligible patients were men or women, over 18 years old, with metastatic BC associated with symptomatic BMI. Patients must have received weekly-paclitaxel chemotherapy and were selected using the CHIMIO® software. BMI had to be confirmed by BM biopsy or by the presence of erythroblasts in peripheral blood smear in association with cytopenia defined by Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Symptomatic BMI, was defined by BMI associated with cytopenia (affecting at least one cell line). Exclusion criteria included presence of non symptomatic BMI, blood sample abnormalities attributed to others causes (infection, BM regeneration, etc.) and treatment other than weekly-paclitaxel. In accordance with the regulations regarding research involving human subjects, registration in the CIL register was carried out for this study. Patients' non-opposition to the use of their data was sought after verification of vital status. All data were anonymized for statistical analysis.
Efficacy and safety measures. Tumors were assessed by computed tomography or bone scan as per the oncologist's discretion. Hematologic analyses were performed weekly. Adverse events were graded for severity according to the CTCAE Version 5.0.
Patient characteristics at initial diagnosis of breast cancer.
End points. The primary end point was overall survival (OS) which was evaluated from the symptomatic BMI diagnosis until the occurrence of death or the end of the follow-up. Secondary end points were progression-free survival (PFS) (defined as the time from the symptomatic BMI diagnosis until disease progression or death), cytopenia evolution after 2 months of chemotherapy and safety.
Statistical analysis. OS and PFS and their corresponding 95% confidence intervals (CIs) were estimated with the Kaplan–Meier method. Log-rank test was used for comparisons. OS and PFS were calculated using the nonparametric method of Kaplan-Meier and compared with log-rank tests, given the small population size. Exploratory subgroup analyses were performed on subgroups identified in the literature as associated with prognosis. All statistical tests were two-sided, and statistical analyses were conducted using Stata for Windows version 15.0 (StataCorp, College Station, TX, USA). All p-values were considered statistically significant at a level of <0.05.
Results
Between January 2014 and May 2018, a total of 465 patients received weekly-paclitaxel chemotherapy for metastatic BC. Among these patients, 26 (1 male and 25 females) were identified with symptomatic BMI.
Patient characteristics at initial diagnosis of BC. Ten patients had metastatic disease, and among them 4 had symptomatic BMI. Invasive carcinoma of no special type (NST) was the most common histology (n=15). Most tumors were estrogen receptor positive (n=23), including seven that were progesterone receptor negative. Two patients had triple negative BC. HER2 receptor was overexpressed in 2 patients. Twelve percent of tumors were grade 1, 65% were grade 2 and 23% were grade 3. Characteristics at initial diagnosis of BC are summarized in Table I.
Patient characteristics at diagnosis of symptomatic BMI. Median patient age at symptomatic BMI diagnosis was 63 years (range=36-77 years). BMI was diagnosed by BM biopsy in 7 cases and by peripheral blood smear in 19 cases. The median time from initial diagnosis of BC to diagnosis of symptomatic BMI was 96.5 months (range=0-341 months). All patients had other metastatic sites. The median time from metastatic development to symptomatic BMI diagnosis was 5.5 months (range=0-83 months). Bone was the most frequent metastatic site (n=25). Other metastatic sites included the liver (n=9) and the lung (n=9). As per the selection criteria, all patients had at least one cytopenia. Anemia was present in all patients, and in combination with thrombocytopenia in 58% of cases. Five patients had pancytopenia. In most patients, analysis of blood smear showed less than 5% erythroblasts. Characteristics at diagnosis of BMI are summarized in Table II.
Patient characteristics at first diagnosis of bone marrow infiltration from breast cancer.
Treatment. All patients received at least one infusion of paclitaxel 80 mg/m2/w. One patient with HER2-overexpressing tumor, received targeted therapy with weekly-paclitaxel. Eleven patients had initial reduction in paclitaxel dosage, according to the clinician evaluation.
Efficacy. With a median follow-up of 101 months, median OS was 7.2 months (95%CI=2.6-20.7), and the median PFS was 3.3 months (95%CI=1.6-7.2). Figure 1 illustrates OS and PFS.
After 2 months of treatment, 8 patients died and 18 patients achieved stable disease. In these 18 patients, hemoglobin increased in 9, decreased in 4 and was stable in 5. Among patients with initially normal platelet levels, one presented a decrease in platelet count (which remained grade 1). For patients with thrombocytopenia, 3 had improvement of platelet levels, 5 remained at the same grade and 2 had the platelet levels decrease. Among the five patients with pancytopenia at diagnosis, one died before two months, one had worsening of neutropenia but the other three patients improved with neutrophils count normalization.
Subgroup analysis. We identified three statistically significant factors associated with OS improvement. Patients with good PS (0-1) at BMI diagnosis had a better OS, estimated at 15.5 months (95%CI=7.2-29.3) versus 1.41 months (95%CI=0.62-4.5) for patients with poorer PS (p=0.0002). The second factor was the platelet levels at BMI diagnosis. OS was 24.4 months (95%CI=13.5-30.0) for patients without thrombocytopenia, 4.5 months (95%CI=3.1-20.7) with grade 1 thrombocytopenia and 0.8 months (95%CI=0.5-3.2) for deeper thrombocytopenia (p=0.013). Circulating erythroblast count at BMI diagnosis was also a prognostic factor for survival. OS was 15.5 months (95%CI=4.5-28.6), 3.7 months (95%CI=1.4-8.3) and 0.8 months (95%CI=0.5-2.0) for patients with erythroblasts <5%, with 5 to 10% erythroblasts and with >10% erythroblasts, respectively (p=0.00001). Other factors were not associated with differences in survival. Subgroup analysis is summarized in Table III. Figure 2 illustrates OS according to subgroups.
Overall survival (OS) (A) and progression-free survival (PFS) (B) after symptomatic bone marrow infiltration (BMI) diagnosis.
Subgroup analysis.
Safety. One patient developed febrile neutropenia and died. No patient experienced bleeding complications. Following paclitaxel infusion, there was no significant increase in red blood cell or platelet transfusion.
Discussion
We conducted this monocentric retrospective study to assess efficacy and safety of weekly-paclitaxel in the management of BC complicated by symptomatic BMI. Our choice of weekly-paclitaxel chemotherapy is based on several points: recognized efficacy of paclitaxel in BC treatment (5), efficacy upon rechallenge (6, 7), and its safety especially on the hematological function with low myelosuppression when administered weekly (8). Median OS was 7.2 months and PFS was 3.3 months. To our knowledge this study is the largest series of patients who have received the same systemic therapy for BC with BMI.
Overall survival (OS) after symptomatic bone marrow infiltration (BMI) diagnosis according to performance status (PS) (A), thrombocytopenia (B), and erythroblasts count (C). G: Grade according to CTCAE definition.
We highlighted 3 factors significantly influencing OS: PS, platelet count and erythroblast count in peripheral blood at diagnosis of BMI. Poor PS was associated with poorer survival irrespective of the chemotherapy dose received. This is consistent with Hung et al.'s results (9). Previous studies on solid cancer BMI have found a prognostic impact of platelet count on OS (9, 10). Hung et al. have shown improved survival in patients with platelet levels greater than 50×109/l. In our study, we confirmed the impact of platelet count on survival. OS was reduced as soon as thrombocytopenia appeared, even grade 1. Finally, we demonstrated a correlation between OS and the initial erythroblast count. Erythroblast count is strongly correlated with BMI (11, 12). However, to our knowledge, the impact of erythroblast on OS has not been previously described.
All patients had anemia at BMI diagnosis. The red blood cell line is usually the first hematologic cell line affected by BMI (3, 13, 14). After chemotherapy, we noticed improvement in blood cell count in many patients. This justifies the use of chemotherapy to improve BM function by destroying cancer cells.
Paclitaxel safety was acceptable. No patient experienced hemorrhagic syndrome and only one presented a febrile neutropenia causing death. However, this patient had poor PS and previously received eight lines of chemotherapy in metastatic setting and was probably not a good candidate for paclitaxel. In our study, most patients were hormone receptor (HR) positive and had bone metastases which is similar to previously published studies (3, 13). One of the hypotheses to explain this preferential metastatic involvement of bone is the concept of sleeper cells, secondary to “homing” in an osteogenic niche (15). This hypothesis also explains late relapse in HR positive tumor (16, 17).
Apart from our study, two Japanese teams have reported 2 cases of paclitaxel use in BMI due to BC with survival ranges between 4 and 12 months (18, 19). Other treatments have been evaluated in breast cancer BMI. Kopp et al. have reported a series of 22 patients who received different chemotherapy regimens with 11 months of OS (95%CI=10.5-27.5) (3). However, Kopp's population differed from ours. Patients were selected as soon as they presented BMI which was not always symptomatic. Only 40% of patients had any grade thrombocytopenia, compared to 77% in our study. Our population had more advanced BMI, which may explain survival differences. Concerning safety, 5 cases of febrile neutropenia and 5 cases of hemorrhagic syndrome grade 3/4 were reported in Kopp's study. Weekly-paclitaxel seems to be better tolerated. Ardavanis et al. have reported a series of 5 patients who received low-dose capecitabine with 7 to 24 months of survival without major toxicity (20).
Despite being the largest published in BC with BMI, our study has certain limitations. Because of its retrospective monocentric nature and small number of patients, the results should be interpreted with caution. In 73% of cases, BMI diagnosis was made by peripheral blood smear. Although this isn't the gold standard for BMI diagnosis, it represents common practice in oncology. In addition, all patients had metastatic evolution requiring chemotherapy, irrespective of BMI.
Symptomatic BMI is a rare metastatic disorder during breast cancer and has a poor prognosis. Patients with symptomatic BMI are usually excluded from therapeutic trials, due to biological impairment, and few data are available for this population. Weekly-paclitaxel seems to be an effective option with an acceptable safety. Good PS, no thrombocytopenia and less than 5% erythroblasts at BMI diagnosis were associated with improvement of OS. Therefore, it seems essential to select patients who could benefit from chemotherapy. In this population with poor prognosis metastatic disease the primary objective must remain quality of life. Finally, noting that the vast majority of this population is HR positive and HER2 negative, another valid option could be based on a combination of endocrine therapy with cyclin-dependent kinase 4-6 inhibitors. The risk of neutropenia could be a limiting factor but may be reduced with a less hematotoxic compounds such as abemaciclib. Designing prospective trials to test this approach seems of interest.
Footnotes
Authors' Contributions
A.D collected, analyzed, and interpreted the data and was a major contributor in writing the manuscript. G.E was the second reviewer for data analysis and interpretation, as well as manuscript preparation. I.L also participated in data analysis and risk of bias assessment. All Authors read and approved the final manuscript.
Conflicts of Interest
None to declare in relation to that article.
- Received April 10, 2020.
- Revision received April 16, 2020.
- Accepted April 17, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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