Unexpected thrombocytopenia of a rare tamoxifen-induced complication in breast cancer therapy: A case report

Abstract

BACKGROUND

Tamoxifen, a selective estrogen receptor modulator, is pivotal in managing hormone receptor-positive breast cancer. While its common side effects are well-documented, tamoxifen-induced thrombocytopenia is a rare, serious adverse event requiring drug discontinuation.

CASE SUMMARY

We report a case of tamoxifen-induced thrombocytopenia in a 51-year-old premenopausal woman with breast cancer, occurring within 4 weeks of initiating adjuvant tamoxifen therapy. Platelet counts normalized after drug cessation, but thrombocytopenia recurred upon rechallenge, leading to permanent discontinuation.

CONCLUSION

This case underscores the need for regular complete blood count monitoring in patients on tamoxifen to detect rare hematologic adverse events promptly.

Key Words: Tamoxifen; Drug-induced thrombocytopenia; Breast cancer; Selective estrogen receptor modulator; Case report

Core Tip: This case report describes a rare instance of tamoxifen-induced thrombocytopenia in a 51-year-old woman with breast cancer. Thrombocytopenia developed 4 weeks after starting tamoxifen and resolved upon discontinuation, only to recur after rechallenge, confirming causality. The case highlights the need for regular blood count monitoring during tamoxifen therapy to detect rare hematologic adverse effects early. As tamoxifen is not typically associated with thrombocytopenia, this case underscores the importance of clinician awareness and individualized risk-benefit evaluation in managing such patients.

INTRODUCTION

Tamoxifen, a selective estrogen receptor modulator (SERM) synthesized in 1962, exerts antiestrogenic and antitumor effects on breast tissue by competitively binding estrogen receptors, slowing the cell cycle via downstream signaling[1]. It is United States Food and Drug Administration (FDA)-approved for hormone receptor-positive breast cancer in men and women, risk reduction of invasive breast cancer in high-risk patients, and adjuvant therapy post-surgery and radiation for ductal carcinoma in situ[2-4]. The discovery of tamoxifen, as the first non-cytotoxic small molecule therapy in oncology, was a major milestone and its success ushered in the era of molecular targeting cancer treatments. Tamoxifen played a major role in reducing the breast cancer mortality[5]. Common side effects include hot flashes, peripheral edema, irregular menstruation, vaginal discharge, hypertension, mood changes, skin rashes, nausea, vomiting, arthralgia, fatigue, and pharyngitis[1]. Less frequent effects include insomnia, weight gain, diarrhea, urinary tract infections, alopecia, and cataracts[6]. Tamoxifen carries a black box warning for uterine malignancies, pulmonary embolism, and stroke in patients treated for breast cancer risk reduction[7]. While tamoxifen typically induces a hypercoagulable state, increasing thrombosis risk, thrombocytopenia is a rare adverse effect.

We present a rare report of tamoxifen-induced thrombocytopenia in a patient receiving adjuvant therapy for breast cancer, highlighting its clinical presentation, management, and implications.

CASE PRESENTATION

Chief complaints

A 51-year-old premenopausal woman presented with a 4-month history of a progressively enlarging lump in her left breast. She had no significant medical history, no known allergies, and no family history of breast cancer. She was a non-smoker, non-drinker, and employed as a homemaker. Psychosocially, she reported mild anxiety about her diagnosis but was supported by her family.

History of present illness

The patient’s illness timeline was as follows. At month 0, the patient noticed a left breast lump and sought medical evaluation 4 months later. At month 4, she was diagnosed with invasive ductal carcinoma (cT2N0M0, estrogen receptor (ER)/progesterone receptor (PR)-positive, human epidermal growth factor receptor 2 (HER2)-negative) via sono-mammography and trucut biopsy, and underwent left modified radical mastectomy. At month 5, postoperative histopathology confirmed pT2N0Mx and no lymphovascular/perineural invasion. The patient was lost to follow-up for over a year, At month 17, she returned for restaging (no recurrence), and started tamoxifen 20 mg/day after correction of iron-deficiency anemia (hemoglobin: 7.1 g/dL). At month 18, the patient developed grade III thrombocytopenia (platelets: 43000/μL) 4 weeks after starting tamoxifen. The tamoxifen was stopped, and platelets normalized within 3 weeks. At month 19, a rechallenge with tamoxifen led to the recurrence of thrombocytopenia (platelets: 77000/μL), so the drug was permanently discontinued. At month 20, follow-up showed a normal complete blood count (CBC). The patient has remained asymptomatic and has been on letrozole 2.5 mg per day (1 year at the time of reporting), which she is tolerating fairly well (Table 1).

Table 1 Timeline of key clinical events.

Month	Event	Clinical findings	Interventions	Outcomes
0	Symptom onset	Left breast lump (4 cm × 4 cm), painless, progressive	None	Patient delayed seeking care
4	Diagnosis and surgery	BIRADS 5 Lesion, invasive ductal carcinoma (cT2N0M0, ER/PR+, HER2-)	Left modified radical mastectomy	Histopathology: PT2N0Mx, no invasion; uneventful recovery
5	Post-surgery	No complications	None (lost to follow-up)	Adjuvant therapy delayed
17	Restaging and treatment start	No recurrence; anemia (hemoglobin: 7.1 g/dL, platelets: 159000/μL)	Parenteral iron, tamoxifen 20 mg/day	Anemia corrected; tamoxifen initiated
18	Thrombocytopenia	Grade III thrombocytopenia (platelets: 43000/μL), no bleeding	Tamoxifen withheld; diagnostic workup	Platelets normalized (165000/μL) in 3 weeks
19	Rechallenge	Recurrent thrombocytopenia (platelets: 77000/μL)	Tamoxifen permanently discontinued	Thrombocytopenia confirmed as tamoxifen-related
20	Follow-up	Normal CBC (platelets: 165000/μL), asymptomatic	Referral for alternative ET	Patient stable, satisfied with care

Chronological summary of the patient’s clinical course, highlighting diagnosis, treatment, adverse events, and outcomes. BIRADS: Breast Imaging Report and Data System; CBC: Complete blood count; ER: Estrogen receptor; ET: Essential thrombocythemia; HER2: Human epidermal growth factor receptor 2; PR: Progesterone receptor.

History of past illness

The patient’s past medical history has no direct connection with the current disease.

Personal and family history

No significant personal or family history.

Physical examination

Physical examination revealed a 4 cm × 4 cm well-defined, firm mass in the lower outer quadrant of the left breast, with no axillary lymphadenopathy. Baseline vital signs were normal (blood pressure: 120/80 mmHg, heart rate: 78 bpm, temperature: 36.7 °C).

Laboratory examinations

Baseline CBC was normal (platelets: 159000/μL, hemoglobin: 7.1 g/dL, leukocytes: 4560/μL with normal differentials).

Imaging examinations

Sono-mammography indicated a Breast Imaging Report and Data System 5 Lesion (> 95% malignancy risk) with satellite nodules.

FINAL DIAGNOSIS

Baseline CBC was normal (platelets: 159000/μL, hemoglobin: 7.1 g/dL, leukocytes: 4560/μL with normal differentials). Sono-mammography indicated a Breast Imaging Report and Data System 5 Lesion (> 95% malignancy risk) with satellite nodules. Tru-cut biopsy confirmed invasive ductal carcinoma, ER/PR-positive, HER2-negative by immunohistochemistry and fluorescence in situ hybridization. Systemic imaging (chest X-ray, abdominal ultrasound, bone scan) showed no metastases (cT2N0M0). Serum follicle-stimulating hormone and luteinizing hormone confirmed premenopausal status. At 4 weeks post-tamoxifen initiation, CBC revealed grade III thrombocytopenia (platelets: 43000/μL, per Common Terminology Criteria for Adverse Events v5.0) without bleeding. Diagnostic workup excluded splenomegaly (ultrasound), infectious causes (negative dengue/malaria serology), consumption coagulopathy (normal coagulation parameters), and hemolysis (normal serum lactate dehydrogenase, indirect bilirubin, renal function tests, and reticulocyte count). Peripheral smear showed reduced platelets with occasional large forms with no schistocytes. Bone marrow examination was declined by the patient. The Naranjo adverse drug reaction probability score was 7, indicating a probable causal relationship with tamoxifen.

TREATMENT

The patient received parenteral iron for anemia before starting oral tamoxifen 20 mg/day. Upon detecting thrombocytopenia, tamoxifen was withheld, leading to platelet recovery within 3 weeks. Rechallenge with tamoxifen (20 mg/day) was attempted to confirm causality, but thrombocytopenia recurred, prompting permanent discontinuation. No platelet transfusions or corticosteroids were required, as the patient remained asymptomatic.

OUTCOME AND FOLLOW-UP

At 1-month post-discontinuation, CBC was normal (platelets: 165000/μL), and the patient reported no bleeding or other symptoms. She was referred for alternative adjuvant therapy (aromatase inhibitors considered, pending menopausal status reassessment). No adverse events related to iron therapy or surgery were noted. The patient adhered to follow-up visits post-event and expressed satisfaction with her care. Patient perspective: “I noticed the breast lump but delayed seeking help due to fear. After surgery, I felt relieved, but starting tamoxifen was worrying because of potential side effects. When my doctor told me my platelet count was low, I wasn’t alarmed, as it was explained as a possible drug reaction. Stopping the medication resolved the issue, and I felt supported by my medical team. Due to the doctor’s clarification, I have realized the importance of compliance to regular follow up visits and continuation of therapy. I’m now doing well and grateful for the care I received”.

DISCUSSION

Drug-induced thrombocytopenia (DITP) results from impaired platelet production or accelerated destruction, often via drug-dependent antibodies binding platelet glycoproteins (e.g., glycoprotein IIb-IIIa, glycoprotein Ib-IX)[8,9]. More than 300 drugs, including quinine, are implicated[9]. Classical DITP is sudden, severe, and associated with bleeding. Tamoxifen, while typically associated with a prothrombotic state due to partial estrogen receptor agonism, rarely causes thrombocytopenia through immune and non-immune mechanisms[10]. Candido et al[11] demonstrated drug-dependent platelet antibodies in a tamoxifen-induced case using immunofluorescence, positive only in the presence of patient sera or shortly after drug exposure. Non-immune mechanisms include reduced platelet function via decreased peroxynitrite, increased nitric oxide, inhibition of the phospholipase C-like 2-protein kinase C-p38 mitogen-activated protein kinase-thromboxane A2 cascade, and megakaryocytic hypoplasia[12-14]. With extensive literature search, we failed to identify any plausible genetic polymorphism associated with this unique side effect of tamoxifen. Literature reports variable onset of tamoxifen-induced thrombocytopenia. Nasiroğlu et al[10] described a case 1.5 years post-initiation, resolving without rechallenge. Pathak et al[15] reported onset after 3 years, managed with steroids and continued tamoxifen. Our case, with onset within 4 weeks, aligns with Candido et al’s report[11]. A case of tamoxifen-induced pancytopenia due to bone marrow suppression exists, but our patient’s isolated thrombocytopenia and rapid recovery suggest a peripheral mechanism[16]. The recurrence of thrombocytopenia with the rechallenge, confirms the causality related to tamoxifen and makes our case unique. A search on FDA Adverse Event Reporting System and EudraVigilance failed to show other any reports of this unique side effect of tamoxifen.

Due to its rarity, there is no consensus regarding the continuation of tamoxifen in those who develop thrombocytopenia. While Pathak et al[15], continued tamoxifen in their patient along with oral prednisolone 20 mg/day which was gradually tapered, Nasiroğlu et al[10] concluded that substituting tamoxifen with either anastrozole, letrozole or exemestane may be a better alternative. Although guidelines are lacking regarding the frequency of monitoring the CBC while the patient is on tamoxifen, the physician should always be watchful for symptoms of thrombocytopenia and agranulocytosis at each clinical encounter and monitor accordingly. The decision to restart tamoxifen in such cases should be considered after carefully weighing the risk-benefit ratio. Thrombocytopenia is not commonly encountered with the use of other SERMs. Layton et al[17] reported the occurrence of thrombocytopenia in 3 patients who were prescribed raloxifene, a second-generation SERM, for prophylaxis of osteoporosis and osteopenia in post-menopausal women, and amongst which only 1 case was assessed as possibly related. Aromatase inhibitors including anastrozole, letrozole, and exemestane are approved for postmenopausal women with hormone receptor-positive breast cancer in both the adjuvant and metastatic settings, and thrombocytopenia appears to be a common side effect with the use of letrozole. In an analysis of the spontaneous reports submitted to the FDA Adverse Event Reporting System, the incidence of serious thrombocytopenia was relatively high in the letrozole group compared to the other aromatase inhibitors, with a reporting odds ratio of 4.09[18]. This case confirms causality via rechallenge and Naranjo scoring, supported by a thorough diagnostic workup. However, there are still some limitations including the lack of bone marrow examination restricts mechanistic insights. In addition, antibody testing was unavailable due to resource constraints.

CONCLUSION

Tamoxifen-induced thrombocytopenia is a rare, reversible adverse event requiring prompt recognition and drug discontinuation. Its variable onset (weeks to years) necessitates regular CBC monitoring. Clinicians should include DITP in the differential diagnosis of thrombocytopenia in patients treated with tamoxifen.