Abstract
Background/Aim: Breast cancer is the most commonly diagnosed malignancy among women worldwide. While survival outcomes have improved substantially over time, recurrence remains a significant concern, especially in estrogen receptor-positive (ER+) disease. Although most recurrences occur within five years of initial treatment, ER+ tumors carry a persistent risk of late relapse due to tumor dormancy. Very late recurrences occurring decades after remission are rare and poorly characterized.
Case Report: We present the case of a 96-year-old female with a history of right-sided breast cancer treated with mastectomy and adjuvant radiation therapy at age 50, who presented 46 years later with a palpable chest wall mass near her prior mastectomy scar. Imaging revealed an irregular hypoechoic lesion extending into the pectoralis muscle (BIRADS-5). Core biopsy demonstrated moderately differentiated infiltrating lobular carcinoma that was strongly ER+, progesterone receptor-negative, and HER2 non-amplified. Staging studies revealed no evidence of distant metastatic disease. Given the patient’s advanced age, comorbidities, and prior radiation exposure, surgical and radiation approaches were deferred. Following multidisciplinary tumor board discussion and shared decision-making, primary endocrine therapy with tamoxifen was initiated. The patient demonstrated clinical regression within three months and tolerated therapy well.
Conclusion: This case represents one of the longest reported intervals between initial remission and breast cancer recurrence, highlighting the prolonged biologic potential of dormant ER-positive tumor cells. Clinicians should maintain vigilance for recurrence even decades after treatment, particularly in hormone receptor-positive disease.
Introduction
Breast cancer is the most prevalent malignancy among women worldwide. According to the American Cancer Society, the lifetime risk of developing breast cancer is approximately 1 in 8, accounting for nearly 32% of all new cancer diagnoses in women (1). Although the incidence of breast cancer has steadily increased since the 2000s, survival outcomes have significantly improved. The overall 5-year survival rate for breast cancer in the US is now approximately 91%, though this varies substantially based on the stage at diagnosis (1).
Breast cancer remission is defined as the absence of detectable disease following treatment and is most often indicated by a pathologic complete response (pCR). pCR is defined as the absence of residual invasive carcinoma in the breast and regional lymph nodes following completion of neoadjuvant systemic therapy, corresponding to ypT0/Tis ypN0 in the current American Joint Committee on Cancer (AJCC) staging system (2). Since the 1980s, pCR has been widely adopted as a meaningful endpoint for assessing treatment response, reflecting its association with improved long-term outcomes. Before this, remission was evaluated primarily through clinical and radiologic findings. Recurrence is defined as the reappearance of cancer, whether locoregional or distant, after a period during which the patient was presumed to be disease–free based on restaging and surveillance protocols. The majority of breast cancer recurrences occur within 2 to 5 years following pCR (3). Late recurrences, occurring 10 to 20 years after remission, have been increasingly recognized, particularly among estrogen receptor-positive (ER+) breast cancer subtypes.
Importantly, many patients treated in earlier eras of breast cancer management lacked comprehensive tumor characterization, including hormone receptor and HER2 status, and were managed under treatment paradigms that differed substantially from current standards of care. The absence of receptor-guided systemic therapy and the limited availability of adjuvant endocrine or targeted treatments in prior decades may contribute to late recurrence risk and reflect the long-term outcomes of historical treatment approaches.
In this context, the persistence of residual tumor cells following initial treatment provides a biologic framework for understanding late recurrence. One proposed mechanism underlying late recurrence involves the persistence of residual tumor cells, often in the form of disseminated tumor cells, that enter a dormant or quiescent state. These non-proliferative cells may evade conventional cytotoxic therapies that primarily target actively dividing cells (4). Established risk factors for recurrence include high anatomic stage, particularly the presence of four or more positive lymph nodes, primary tumor size greater than 20 mm, high tumor grade (>3), and adverse genomic features such as FGFR1(8p11) amplification and BRCA2 mutations (5-8).
We present a rare case of breast cancer recurrence occurring 46 years after initial remission, representing one of the longest reported latency intervals to recurrence in the literature. This case outlines the diagnostic evaluation and management of late recurrence and explores potential biologic mechanisms underlying tumor dormancy. It further highlights the importance of maintaining clinical vigilance in elderly patients with a remote history of malignancy and underscores broader implications for survivorship care and surveillance strategies.
Case Report
A 96-year-old female with a history of right-sided breast cancer, osteoporosis, and toxic multinodular goiter presented to her primary care physician for evaluation of a palpable 1 cm nodule along the lateral anterior chest wall near the superior aspect of her prior mastectomy scar. The patient reported gradual enlargement of the lesion over time. She endorsed recent unintentional weight loss but denied fevers, night sweats, or other systemic symptoms. The patient’s family history was notable for melanoma in two sisters; there was no known family history of breast cancer.
At age 50, the patient was diagnosed with carcinoma of the right breast. The original tumor stage, grade, and receptor status were not documented. Treatment consisted of a right mastectomy with axillary lymph node dissection followed by external beam radiation therapy (EBRT) to the chest wall. No systemic therapy was administered, consistent with standard treatment practices at the time. Histopathologic details from the original diagnosis were unavailable.
The patient underwent surveillance with bilateral mammography for over four decades without evidence of malignancy. Two months before her current presentation, a routine screening mammogram revealed calcifications in the lower inner quadrant of the left breast, categorized as BIRADS-3, and a six-month follow-up recommended. Subsequent diagnostic left mammography confirmed a 0.4 cm cluster of round calcifications in the same region. Left breast ultrasound identified a faint cystic structure measuring 0.3×0.1×0.3 cm at the 7 o’clock position, 5 cm from the nipple. These findings were again categorized as BIRADS-3, and a six-month follow-up was advised. No abnormalities were identified in the right breast on imaging at that time.
On physical examination during her current evaluation, a palpable 1.0×1.2 cm nodular mass was noted in the right upper outer quadrant at the 10 o’clock position along the chest wall. There was no palpable axillary, supraclavicular, infraclavicular, or cervical lymphadenopathy bilaterally.
Right breast ultrasound revealed a 1.9×0.9×1.5 cm irregular, hypoechoic mass in the upper chest wall, with associated skin retraction and extension into the underlying pectoralis muscle. Mild right axillary lymphadenopathy was also noted, with cortical thickness measuring 3 mm. The lesion was classified as BIRADS-5, and ultrasound-guided core biopsy was recommended.
Histopathologic examination of the chest wall mass revealed a moderately differentiated, grade 2 infiltrating lobular carcinoma measuring 11 mm in greatest dimension. Immunohistochemical analysis revealed strong ER positivity (100%), progesterone receptor (PR) negativity, and HER2 non-amplification. Clinical staging was determined to be rcT1c cN0 cM0 (Stage IA).
A positron emission tomography/computed tomography (PET/CT) scan performed for staging identified a minimally hypermetabolic right chest wall nodule measuring 1.1 cm (SUV max 1.7), corresponding to the known lesion, as well as a mildly hypermetabolic right thyroid nodule. Ultrasound evaluation of thyroid was recommended. No additional hypermetabolic lesions were identified in the chest, abdomen, or pelvis.
Given the patient’s age, comorbidities, and prior radiation exposure, multiple management options were discussed in a multidisciplinary setting. Sentinel lymph node biopsy and axillary core needle sampling were deferred due to marginal cortical thickening, deep nodal location, and limited anticipated impact on overall treatment strategy. Surgical excision with adjuvant radiation or chemotherapy was also discussed; however, operative risk was deemed high given the patients’ age, comorbidities, and previous history of radiation therapy. Oncotype DX testing to assess potential benefit from chemotherapy was discussed, but ultimately not pursued due to limited clinical utility given the patient’s poor candidacy for systemic chemotherapy.
Given the patient’s overall prognosis and goals of care, management with primary endocrine therapy was proposed. Following multidisciplinary tumor board review and shared decision-making with the patient, treatment with tamoxifen 20 mg daily was initiated. At one-month follow-up, the patient was tolerating tamoxifen without adverse effects and demonstrated mild clinical regression of the lesion. By three months, further regression was observed, with no new lesions identified on surveillance CT imaging. Given this favorable response and the patient’s preference to avoid invasive interventions, surgical and radiation therapies were deferred. She continued tamoxifen therapy with ongoing clinical monitoring.
Ethical approval is not required for this study per institution guidelines.
Discussion
Breast cancer recurrence remains a clinical concern even years after initial remission, particularly among patients with hormone receptor-positive disease. While the majority of recurrences occur within the first five years following diagnosis, patients with ER+ tumors face a persistent risk of late recurrence extending well beyond ten years (9, 10). This case represents an extreme example, a 46-year latency period between initial treatment and recurrence, revealing the biological complexity and long-term clinical implications of tumor dormancy in ER+ breast cancer.
Infiltrating lobular carcinoma, as observed in this case, exhibits distinct biologic behavior compared with ductal carcinoma, including a more indolent course, diffuse growth patterns, and a higher likelihood of late recurrence (11). These characteristics may further explain the prolonged dormancy observed in this case. Additionally, lobular carcinomas are also more likely to evade detection on conventional imaging and may persist as disseminated tumor cells in a quiescent state, contributing to delayed clinical presentation decades after initial treatment (11).
Given the unprecedented latency observed in this case, it is important to consider whether this presentation represents a true recurrence or a new primary malignancy. Although the exceptionally long disease-free interval raises the possibility of a new primary breast malignancy, several clinical and pathologic features support this lesion representing a true recurrence. These include ipsilateral chest wall location along the prior mastectomy field and histopathologic confirmation of breast origin.
Late recurrence is thought to arise from the persistence of disseminated tumor cells in a dormant state for extended periods. These cells may exhibit minimal proliferative activity for years (12). Two principal mechanisms of tumor dormancy have been proposed: cellular dormancy, in which tumor cells arrest in the G0 phase of the cell cycle, and tumor mass dormancy, characterized by a balance between cellular proliferation and apoptosis (13). Reactivation of dormant cells may be triggered by alterations in the tumor microenvironment, immune evasion, or stress-related metabolic changes (14). Changes in cytokine signaling, extracellular matrix remodeling, and interactions with stromal and immune cells have all been implicated in promoting tumor reawakening. Tumor-associated macrophages and other immune cells may also secrete regulatory factors, such as transforming growth factor-β (TGF-β), which can facilitate the transition from dormancy to proliferation (15). Furthermore, stress-related metabolic changes, such as hypoxia, nutrient deprivation, and stress-activated neutrophils, may upregulate growth factor pathways promoting escape from dormancy (14, 16).
ER+ tumors appear particularly prone to cellular dormancy-mediated relapse due to their dependence on hormonal signaling pathways (17). Estrogen receptor signaling influences downstream modulation of cyclin-dependent kinases and anti-apoptotic pathways, enabling tumor cell survival and prolonged cell-cycle arrest. This biologic dependence may permit tumor persistence for extended periods, followed by delayed reactivation years after initial treatment (18).
Long-term population-based data further support the clinical relevance of late recurrence in ER+ breast cancer. A Danish registry cohort study reported a cumulative recurrence rate of approximately 17% between 10 to 32 years after diagnosis among patients who had remained disease-free for at least 10 years after initial treatment and diagnosis. Recurrence risk was particularly elevated in ER+/PR− tumors. Overall, cumulative recurrence rates approached 16.6% by 22 years, and up to 34% in higher-risk subgroups. In contrast, ER-negative tumors demonstrated a lower, though still measurable, late recurrence risk of approximately 8% over 10-25 years (5).
Current American Society of Clinical Oncology (ASCO) Guidelines recommend history and physical examinations every 3 to 6 months for the first four years, every 6-12 months during years four to five, and annually thereafter, with annual mammography (19). However, these guidelines do not specifically tailor surveillance strategies based on hormone receptor status or the potential for very late recurrence. In older patients, surveillance decisions must be individualized and balanced against life expectancy. ASCO Task Force Guidance recommends discontinuing routine mammography in breast cancer survivors older than 75 years old with a life expectancy of less than five years (20). For those with an estimated life expectancy of 5-10 years, screening may be considered, while annual screening is advised for those expected to live longer than 10 years.
In 2024, The United States Preventive Services Task Force (USPSTF) updated its breast cancer screening recommendations to advise biennial mammography beginning at age 40 rather than 50, aiming to facilitate earlier detection and potentially less aggressive treatment (21). While expanded screening carries risks, including false-positive results, unnecessary biopsies, and increased patient anxiety, the USPSTF concluded that the benefits outweighed the harms, especially given the rising breast cancer incidence among women aged 40-49 in the United States. The American Cancer Society endorsed similar recommendations and further advised earlier screening initiation for high-risk individuals, such as those with BRCA mutations (22).
Beyond imaging, advances in molecular surveillance offer promising avenues for earlier detection of recurrence. Circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) have emerged as potential biomarkers of residual disease (23). In a study of 61 high-risk patients with breast cancer treated with neoadjuvant chemotherapy, ctDNA was detected in 10 patients using personalized circulating markers (PCM), conferring a hazard ratio of 37.2 for relapse and a median lead time of 11.7 months before clinical recurrence (23). Both specificity and positive predictive value for ctDNA detection were nearly 100% in this study, highlighting its potential as an early indicator of relapse.
Extended endocrine therapy, including selective estrogen receptor modulators (SERMs) and aromatase inhibitors, has been shown to significantly reduce the risk of late recurrence in ER+ breast cancer. The ATLAS trial demonstrated that extending tamoxifen therapy to 10 years, compared with stopping at five years, reduced recurrence rates (21.4% vs. 25.1%, p=0.0002) and breast cancer-specific mortality (12.2% vs. 15.0%, p=0.01) among ER-positive patients. However, extended therapy is associated with increased risks, including thromboembolism, vasomotor symptoms, osteoporosis, and in postmenopausal women without hysterectomy, endometrial cancer (24).
Emerging therapeutic strategies aim to directly target dormant tumor cells. One promising strategy involves inhibition of autophagy, a key survival mechanism in dormant cells. A recent study by Elkholi et al. suggested that hydroxychloroquine, an autophagy inhibitor, may suppress progression of dormant D2A1 and D2OR breast cancer cells (25). Other investigational strategies include modulation of the tumor microenvironment, such as targeting TGF-β and other proliferative cytokine pathways that promote the switch from dormancy to proliferation, or enhancing immune-mediated clearance of residual disease, though these remain investigational (26).
Table I summarizes several reported cases of breast cancer recurrence in the literature, including patient age at presentation, tumor subtype, relapse interval, and subsequent management strategies. Patient ages at recurrence ranged from 33 to 73 years, and all cases involved ER-positive tumors. Subtypes included ER+ alone (2/9), ER+/PR+ (4/9), and ER+/PR+/HER2+ (2/9) disease. The recurrence interval varied significantly across cases, spanning from 10 to 39 years after initial treatment. Most patients initially underwent mastectomy with axillary lymph node dissection, followed by systemic therapy. Following recurrence, management strategies varied widely. Three patients were initiated on aromatase inhibitor therapy, while others received monoclonal antibody therapy, hormone therapy, chemotherapy, or surgical intervention. These cases underscore both the diversity of therapeutic responses and the long-term vigilance required in the surveillance of ER-positive breast cancer survivors.
Summary of reported cases of recurrent breast cancer in the literature.
The presented case of a 96-year-old female with ER-positive breast cancer recurrence occurring 46 years after initial treatment represents a significant outlier in both latency to recurrence and patient age compared to previously reported cases. Given the patient’s advanced age and extensive prior radiation exposure, the treatment approach was constrained by concerns regarding treatment-related toxicity and comorbidities. These factors informed the decision to initiate primary endocrine therapy with tamoxifen. The exceptional delay in recurrence highlights the complex biology of ER-positive breast cancer and the need for individualized, age-appropriate management strategies for elderly breast cancer survivors.
Conclusion
This case documents an exceptionally late recurrence of estrogen receptor-positive breast cancer occurring 46 years after initial treatment, representing one of the longest latency periods reported in the literature. It highlights the enduring biologic potential of dormant tumor cells and highlights the unique propensity of hormone receptor-positive disease for relapse, even decades after remission. The patient’s advanced age, prior radiation exposure, and comorbidities necessitated an individualized management approach that prioritized disease control whilst minimizing treatment-related toxicity and morbidity. Primary endocrine therapy with tamoxifen provided effective clinical response and was well-tolerated, demonstrating its utility as a reasonable therapeutic option in selected patients who are poor candidates for surgery, chemotherapy, or re-irradiation.
This case also raises important considerations regarding long-term survivorship care. Current surveillance guidelines do not fully account for subtype-specific risks of very late recurrence, particularly in ER-positive breast cancer. Maintaining clinical vigilance in patients with even a remote history of malignancy remains essential. As advances in molecular monitoring and therapies evolve, future strategies may better identify and manage patients at risk for later relapse. Ultimately, this case reinforces the importance of individualized, age-appropriate decision-making and long-term awareness of recurrence risk in breast cancer survivors.
Footnotes
Authors’ Contributions
H.P., A.B., S.R., and A.K. drafted the manuscript. Y.P., Z.M., M.A., and H.R. made substantial contributions to the conception of the work, as they reviewed and edited the manuscript for content.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
Artificial Intelligence (AI) Disclosure
No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.
- Received December 26, 2025.
- Revision received February 8, 2026.
- Accepted February 11, 2026.
- Copyright © 2026 The Author(s). Published by the International Institute of Anticancer Research.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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