Chemotherapy-induced neutropenia management in a patient with metastatic breast cancer and Shwachman-Diamond syndrome (SDS): a case report

Introduction

Background

Shwachman-Diamond syndrome (SDS) is an uncommon condition, occurring in approximately 1 in 76,000 individuals, and is inherited in an autosomal recessive manner (1). The syndrome primarily results from biallelic germline variants of the Shwachman-Bodian-Diamond syndrome (SBDS) gene (2,3). This complex disorder manifests as an inherited bone marrow failure syndrome (IBMFS) and is characterized by neutropenia, exocrine pancreatic dysfunction, and skeletal abnormalities (4). In about 35% of SDS cases, mild neutropenia often progresses to aplastic anemia, myelodysplastic syndrome (MDS), and/or acute myeloid leukemia (AML) by the age of 30 years (4). Hematologic malignancies in SDS cases have been attributed to clonal hematopoiesis due to biallelic loss of function in the tumor protein 53 (TP53) gene (3,5). While a few reported cases indicate the occurrence of solid tumors in SDS, these malignancies typically manifest after the age of 30 (4).

Rationale and knowledge gap

The available literature suggests that cytopenias associated with SDS pose challenges to administering optimal treatment, as chemotherapy can lead to myelosuppression and related complications such as infection. Consequently, cancer care presents a significant concern for these patients due to generally poor overall survival (OS).

Objective

In this report, we discuss the successful treatment of triple-positive [estrogen positive, progesterone positive, and human epidermal growth factor receptor 2 (HER2) positive] metastatic breast cancer using paclitaxel, trastuzumab, and pertuzumab, supported by granulocyte colony-stimulating factor (G-CSF) to achieve a complete response (CR) without severe complications. The objective of this case report is to underscore the adjustments made to therapeutic guidelines, aiming to facilitate the optimal management of this patient’s metastatic breast cancer. We present this article in accordance with the CARE reporting checklist (available at https://tbcr.amegroups.org/article/view/10.21037/tbcr-24-13/rc).

Case presentation

We identified a patient with SDS from the Alvin J. Siteman Cancer Center at Washington University in St. Louis School of Medicine who sought management of her metastatic breast cancer. She received chemotherapy with weekly paclitaxel with pertuzumab and trastuzumab (THP) every 3 weeks and was supported with twice-weekly G-CSF. Due to her SDS, docetaxel was substituted for paclitaxel to minimize neutropenia and G-CSF was added to help mitigate cytotoxic effects on her marrow. After nine cycles, she exhibited a CR and continued maintenance of pertuzumab and trastuzumab. Adverse effects of chemotherapy were managed medically, and the patient’s age, ethnicity, and clinical data are detailed in Table 1.

Patient

The patient is a 41-year-old Caucasian female with SDS who developed invasive ductal carcinoma (IDC) of the left breast. She is heterozygous for c.258+2 T>C and R126T mutations in the SBDS gene. Manifestations of her SDS included a lifelong history of thrombocytopenia without bleeding with normal hemoglobin and absolute neutrophil count (ANC), previously supplemented pancreatic insufficiency since childhood, longstanding arthralgias, short stature (151 cm), and femoral chondrodysplasia (refer to Table 1). As part of her initial hematology evaluation 10 years before her cancer diagnosis, she had a bone marrow biopsy which revealed a 30–40% marrow cellularity with erythroid hyperplasia but no dysplasia. Cytogenetics and next-generation sequencing were not performed on this sample. The patient did not have a repeat bone marrow biopsy before receiving chemotherapy.

The discovery of a mass in the upper inner quadrant of her left breast led to a mammogram confirming a 2 cm triple-positive IDC. A positron emission tomography-computed tomography (PET-CT) scan further identified a 2.0 cm × 2.2 cm left hepatic lesion, confirmed by biopsy to be metastatic breast cancer. A treatment plan was developed for her stage IV breast cancer (pT2 N1 M1) in the context of her SDS. Initially, the use of docetaxel was considered as per the Cleopatra trial (6). However, weekly paclitaxel was selected as a suitable alternative given the weekly dosing to allow for reduced risk and duration of myelosuppression allowing for more stringent monitoring of chemotherapy-induced cytopenias through weekly complete blood counts (CBCs). She consented to receive weekly paclitaxel (80 mg/m²) along with trastuzumab (8 mg/kg for cycle one only then at 6 mg/kg thereafter) with pertuzumab (840 mg for cycle one then 420 mg thereafter) every 21 days. Additional considerations for her underlying SDS included the use of G-CSF (filgrastim 300 mcg) support if her ANC fell below 1,500 cells/mm³ during chemotherapy. Traditionally, G-CSF is not used as part of the standard THP protocol. She established with hematology to address concerns about the risk of secondary hematologic malignancies given not only her history of SDS but also, the use of cytotoxic chemotherapy and potential use of G-CSF. Next-generation sequencing on peripheral blood using MyeloSeq testing of 49 genes and hotspots was targeted by the assay to assess her mutational landscape to provide a more personalized risk profile of her SDS. The MyeloSeq assay has a sensitivity of 2% variant allele frequency (VAF) for new variants and a VAF of >0.25% for previously reported variants. The assay does not utilize germline DNA. Based on her MyeloSeq panel, she was stratified as low risk for secondary hematological malignancies given that no variants were detected in the sequenced genes, including TP53 (detailed in Table 1).

During the initial cycle, chemotherapy was briefly interrupted due to significantly low post-chemotherapy ANC after cycle 1 day 8, prompting a 3-week paclitaxel hold and the administration of G-CSF (refer to Figure 1). The first dose of filgrastim was given on cycle 1 day 18 followed by three daily doses on cycle 2 days 2 to 4 due to persistent neutropenia (refer to Figure 2). She received two additional doses of filgrastim within the week before re-starting paclitaxel on cycle 2 day 15. A third dose of filgrastim was held due to leukocytosis. Thereafter, filgrastim was given every third and fifth day after receiving a dose of paclitaxel without the complication of bone pain. While receiving filgrastim with chemotherapy, all hematologic parameters remained stable.

Figure 1 Hematologic parameters before, during and after chemotherapy. C, cycle; D, day; ANC, absolute neutrophil count.

Figure 2 Filgrastim dosing and ANC during chemotherapy. C, cycle; D, day; ANC, absolute neutrophil count.

After six cycles of THP with twice weekly G-CSF support, a computed tomography (CT) of the chest abdomen and pelvis (CT-CAP) revealed no evidence of metastatic disease and a non-occlusive catheter-associated internal jugular vein thrombus, which led to the initiation of apixaban. She also developed hematuria (before initiation of apixaban) for which urology was consulted. Cystoscopy confirmed chronic inflammation, and she had a second episode of hematuria which was attributed to a urinary tract infection that was treated with trimethoprim-polymyxin B. Her cystitis resolved, and she did not develop recurrent hematuria. The development of peripheral sensory neuropathy after nine cycles of chemotherapy led to the discontinuation of paclitaxel. She then transitioned to maintenance TH every 3 weeks, and she initiated anastrozole and goserelin due to the relative contraindication of tamoxifen considering her history of the aforementioned internal jugular catheter-associated thrombus. A repeat CT-CAP after completing nine cycles of cytotoxic chemotherapy confirmed a CR.

Chemotherapy was well-tolerated throughout the treatment course without any impact on her cardiac function. She experienced chemotherapy-induced grade one to two diarrhea which was managed successfully with a combination of loperamide and diphenoxylate/atropine, and only required outpatient intravenous fluids on one occasion. She also had grade one oral mucositis, which was managed with magic mouthwash solution. She has maintained a CR for 18 months after treatment initiation. Regular CBC monitoring is ongoing. The patient has not had a post-chemotherapy bone marrow biopsy.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Key findings

In this case report, we treated a patient with SDS for metastatic triple-positive breast cancer using THP with G-CSF support, successfully achieving a CR. Close monitoring of hematologic markers through weekly CBCs early on facilitated prompt adjustments in management. Important considerations in this patient’s management included the risk of secondary hematological malignancy based on mutational status and the selection of appropriate cytotoxic chemotherapy given underlying myelosuppression. Notably, our patient did not experience severe infections during chemotherapy, distinguishing our case from previously reported solid tumor treatments in SDS (4).

Strengths and limitations

This unique case report highlights the possibility of successful treatment of a patient with metastatic breast cancer with SDS. It also helps to contextualize the risk versus benefit of G-CSF use in a population at increased risk of hematologic malignancies and the need for post-chemotherapy monitoring.

Our study is limited by a small sample size and its retrospective nature. Larger studies with longer-term follow-up are required to further elucidate the use of G-CSF in this population due to the potential development of hematological malignancies, especially in those deemed to be at high risk. This patient’s risk of hematologic malignancies due to the use of G-CSF and cytotoxic chemotherapy remains unknown, thus further monitoring is required.

Review of prior literature

SDS, one of the more common IBMFS is associated with neutropenia, exocrine pancreatic dysfunction, and skeletal abnormalities (3). Approximately 35% of SDS cases progress to hematologic malignancies, and our case supports a limited association with solid tumors, particularly breast cancer (4). Out of 10 reported solid tumor cases, breast cancer was predominant (n=4), with only two cases reporting somatic TP53 mutations (1,4,7-11). Ovarian (n=3) and pancreatic cancers (n=2) were also observed with no identified somatic or germline mutations in these patients. Notably, TP53 mutations did not clearly increase the risk of solid tumors, and age remains the primary risk factor occurring after age 30 (4). Only one patient (with esophageal carcinoma) was found to have a Harvey rat sarcoma viral oncogene homolog (HRAS) mutation though there is no known association with SDS. No other germline or somatic mutations were documented (4).

The effectiveness of chemotherapy in SDS differs in vitro versus in vivo. In vitro, downregulation of the SBDS protein increases cell death of breast cancer cells induced by anticancer drugs such as paclitaxel, cisplatin, and eribulin (12). Despite the demonstrated increased sensitivity of tumor cells to chemotherapy, this form of treatment has played a limited role in the management of cancers in SDS. Bone marrow mononuclear cells of SDS patients are predisposed to apoptosis through hyperactivation of the Fas-signaling pathway and have decreased telomere length resulting in increased vulnerability to organ toxicity (13). The management of hematologic malignancies has been associated with increased toxicity with complications such as bone marrow aplasia, infection, cardiac, and other organ toxicities (11). Cardiac dysfunction is usually associated with cyclophosphamide-containing regimens; however, it has been reported with other chemotherapeutic agents (13). Speculation has been made that some genotypes (such as c.297-300delAAGA deletion) may predispose to increased chemotoxicity; however, to date, no correlation has been made between clinical phenotype and genotype (13). The c.297-300delAAGA deletion was not reported in the reviewed literature or our case. Thus, we are unable to further comment on its significance in the setting of solid tumors (1,4,7-11). Current strategies include decreased chemotherapy doses or avoiding chemotherapy entirely. Only two other patients with SDS have been reported to have received chemotherapy in the current literature. One reported SDS case with esophageal carcinoma received FOLFOX, and carboplatin/paclitaxel was used to treat ovarian peritoneal carcinomatosis (4).

Underlying myelosuppression presents a significant obstacle in treating solid tumors in SDS. Pancytopenia, which is sometimes refractory, limits chemotherapeutic options due to cytotoxic effects. As an example, our literature review demonstrated a patient with breast cancer who was ineligible for chemotherapy due to transfusion refractory thrombocytopenia and underlying pancytopenia (11). In contrast, our patient with only mild thrombocytopenia received nine cycles of full-dose paclitaxel-containing chemotherapy (THP) with successful monitoring for cytopenias and response to G-CSF. G-CSF has been influential in treating severe congenital neutropenia, leading to increased ANC, reduced infections, and increased OS (14). In our case, G-CSF use during chemotherapy helped to maintain an appropriate ANC for the administration of cytotoxic chemotherapy. Although controversial due to concerns about accelerating progression to hematologic malignancies, especially in patients with TP53 mutations, our patient’s experience suggests benefits in reducing infection risk during chemotherapy. Additionally, her MyeloSeq panel did not demonstrate any somatic mutations, including TP53. In her case, the benefits outweighed the risk. Annual bone marrow surveillance is recommended for SDS patients who receive continuous G-CSF. This patient only received G-CSF in the context of chemotherapy and has demonstrated stable blood counts post-chemotherapy (15). A bone marrow biopsy will be considered as part of her routine surveillance for SDS (15).

Explanations of findings

Although G-CSF is commonly utilized in conjunction with chemotherapy regimens to bolster the ANC in the curative-intent setting, its use in patients with SDS remains controversial. Given G-CSF’s capacity to stimulate the bone marrow, a careful risk-benefit assessment is necessary given the theoretically accelerated progression of hematologic malignancies in SDS patients, particularly those harboring TP53 mutations (4,14). The SBDS protein is a cofactor for elongation factor 1 resulting in impaired growth and survival of hematopoietic stem cells (16). This deficiency in SDS leads to overstimulation of the p53 pathway due to ribosomal stress (5,16). Single TP53 mutations are acquired at an early age in SDS patients to alleviate the ribosomal stress on hematopoietic stem cells (5,17). A cohort study found that 48% (13/27) of patients with SDS had clonal hematopoiesis due to TP53 mutations but, these findings were not seen in healthy controls (0/17, P<0.001) or patients with severe congenital neutropenia (0/40, P<0.001) (5). MDS and AML are likely to develop due to the acquisition of biallelic mutations (5,17). Though this association has been described in hematologic malignancies, it has not been described in solid tumors (3). While G-CSF can correct neutropenia in patients with SDS, it may accelerate progression to MDS or AML in altered hematopoietic stem cells by rescuing malignant clones that would have otherwise undergone apoptosis (14). While the available data are limited, three patients to date have undergone G-CSF treatment for SDS, and an additional three patients including our case (two with TP53 mutations diagnosed by next-generation after neoadjuvant therapy) have received G-CSF either during or after chemotherapy (4,7,11) (refer to Tables 1,2). Our patient, as part of her palliative chemotherapy, received 17 doses of filgrastim 300 mcg to sustain her ANC with ongoing response to therapy (18 months of follow-up to date). The previously mentioned patients who received G-CSF in the neoadjuvant setting had a short OS (6 and 13 months) due to septic shock on a background of cancer-related organ failure (4). This precluded adequate follow-up time for the possible development of secondary hematological malignancies and post-chemotherapy TP53 testing was not pursued. A study identified two SDS patients who developed leukemia after 1 month and 2.2 years of receiving G-CSF at 6.0 and 4.3 mcg/kg/day, respectively (14,18). However, it was difficult to attribute the occurrence of leukemia to G-CSF use, particularly in the patient who developed leukemia after 1 month (18).

Implications and follow up

Continuous monitoring of our patient is warranted to monitor for the development of hematologic malignancies attributed to G-CSF and cytotoxic chemotherapy exposure.

Conclusions

In conclusion, this case report and literature review demonstrate the potential benefit of optimal chemotherapy dosing in a patient with SDS and metastatic breast cancer who received G-CSF. While the patient did not have a TP53 mutation, or mutations in any genes in the MyeloSeq panel, at baseline, ongoing monitoring is crucial to better understand the risk of G-CSF in this context. G-CSF use should be considered on an individual basis based on the risk-to-benefit ratio in each patient with SDS in the context of treatment decision-making.

Acknowledgments

The authors would like to thank the patient for her consent to publish this article. The authors would also like to thank Dr. Matthew Walter, MD, Division of Oncology, Department of Medicine at Washington University in St. Louis for his clinical care of the patient and for reviewing this manuscript.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tbcr.amegroups.org/article/view/10.21037/tbcr-24-13/rc

Peer Review File: Available at https://tbcr.amegroups.org/article/view/10.21037/tbcr-24-13/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.org/article/view/10.21037/tbcr-24-13/coif). A.A.D. serves as the unpaid editorial board member of Translational Breast Cancer Research from January 2024 to December 2025. A.A.D. has received grant funding from the Breast Cancer Alliance. A.A.D. has participated in scientific advisory boards for Pfizer and Biotheranostics and has been compensated to giving an OncLive lecture. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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