Advancements in oligometastatic breast cancer: a comprehensive review of current strategies and the role of artificial intelligence.

In the dynamic landscape of Breast Cancer (BC), Oligo- Metastatic Breast Cancer (OMBC) presents unique challenges and opportunities. This comprehensive review delves into current strategies for addressing OMBC, covering locoregional and site-specific metastasis management, and addressing both surgical and minimally invasive therapies as essential components. Moreover, the transformative role of Artificial Intelligence (AI) is spotlighted. However, while the future looks promising, several limitations need addressing, including the need for further research, especially in diverse patient populations and resource-challenged settings. AI implementation may require overcoming the lack of Electronic Health Records acceptance in resource-challenged countries, which contributes to a scarcity of large datasets for AI training. As AI continues to evolve, validation and regulatory aspects must be continually addressed for seamless integration into clinical practice. In summary, this review outlines the evolving landscape of OMBC management, emphasizing the need for comprehensive research, global collaboration, and innovative AI solutions to enhance patient care and outcomes.

Detecting Metastatic Patterns of Oligometastatic Breast Cancer: A Comparative Analysis of 18F-FDG PET/CT and Conventional CT Imaging.

Metastasis-directed therapy has the potential to improve progression-free and overall survival in oligometastatic disease (OMD). For breast cancer, however, randomized trials have failed so far to confirm this finding. Because the concept of metastasis-directed therapy in OMD is highly dependent on the accuracy of the imaging modality, we aimed to assess the impact of 18F-FDG PET/CT on the definition of OMD in breast cancer patients. Methods: Eighty patients with a total of 150 18F-FDG PET/CT images (between October 2006 and January 2022) were enrolled in this retrospective study at the Technical University of Munich. The inclusion criteria were OMD, defined as 1-5 distant metastases, at the time of 18F-FDG PET/CT. For the current study, we systemically compared the metastatic pattern on 18F-FDG PET/CT with conventional CT. Results: At the time of 18F-FDG PET/CT, 21.3% of patients (n = 32) had a first-time diagnosis of metastatic disease, 40.7% (n = 61) had a previous history of OMD, and 38% (n = 57) had a previous history of polymetastatic disease. In 45.3% of cases, the imaging modality (18F-FDG PET/CT vs. conventional CT) had an impact on the assessment of whether OMD was present. An identical metastatic pattern was observed in only 32% of cases.18F-FDG PET/CT detected additional metastases in 33.3% of cases, mostly in the nonregional lymph node system. Conclusion: The use of 18F-FDG PET/CT had a substantial impact on the definition of OMD and detection of metastatic pattern in breast cancer. Our results emphasize the importance of establishing a standardized definition for imaging modalities in future trials and clinical practices related to metastasis-directed therapy in breast cancer patients.

Mind the Gap: Recurrence of Oligometastatic Breast Invasive Ductal Carcinoma in the Sternal Gap of Two Tangential Photon Fields of Bilateral Whole Breast Irradiation a Decade Later.

Despite bilateral breast cancer being a rare clinical entity compared to unilateral breast cancer, both share a treatment paradigm of breast-conserving therapy for limited disease and metastasis direct therapy for oligometastatic disease. We present a case of left breast invasive ductal carcinoma in the setting of original bilateral breast cancer, now with oligometastatic recurrence to the soft tissue of the sternum, notably in an area not previously irradiated, over a decade later.

The Role of Cyclin-Dependent Kinase 4/6 Inhibitors Treatment in Oligometastatic Breast Cancer: A Case Report on a Possible Curative Intent Strategy.

A small but important subset of patients with metastatic breast cancer has an oligometastatic disease. Some of these patients are highly responsive to systemic therapy and have the potential to achieve complete remission with treatment. However, it remains to be clarified the best locoregional and systemic treatment strategy for such patients and what features can determine whose patients are the best candidates. We also don't know what will be the role of cyclin-dependent kinase 4/6 inhibitors in those cases. We report the case of a 41-year-old woman with HR-positive/HER2-negative oligometastatic breast cancer who, after an excellent response to systemic treatment with palbociclib, anastrozole, and goserelin, underwent breast surgery and liver metastasectomy. After completing three years of systemic treatment, the CDK inhibitor was discontinued, maintaining the hormone therapy. The patient remained under regular follow-up with no evidence of disease after eight months.

Clinical and pathological characterization of 158 consecutive and unselected oligometastatic breast cancers in a single institution.

PURPOSE: Data about incidence, biological, and clinical characteristics of oligometastatic breast cancer (OMBC) are scarce. However, these data are essential in determining optimal treatment strategy. Gaining knowledge of these elements means observing and describing large, recent, and consecutive series of OMBC in their natural history. METHODS: We collected data retrospectively at our institution from 998 consecutive patients diagnosed and treated with synchronous or metachronous metastatic breast cancer (MBC) between January 2014 and December 2018. The only criterion used to define OMBC was the presence of one to five metastases at diagnosis. RESULTS: Of 998 MBC, 15.8% were classified OMBC. Among these, 88% had one to three metastases, and 86.7% had only one organ involved. Bone metastases were present in 52.5% of cases, 20.9% had progression to lymph nodes, 14.6% to the liver, 13.3% to the brain, 8.2% to the lungs, and 3.8% had other metastases. 55.7% had HR+/HER2- OMBC, 25.3% had HER2+OMBC, and 19% had HR-/HER2- OMBC. The HR+/HER2- subtype statistically correlated with bone metastases (p = 0.001), the HER2+subtype with brain lesions (p = 0.001), and the HR-/HER2- subtype with lymph node metastases (p = 0.008). Visceral metastases were not statistically associated with any OMBC subtypes (p = 0.186). OMBC-SBR grade III was proportionally higher than in the ESME series of 22,109 MBC (49.4% vs. 35.1%, p < 0.001). CONCLUSION: OMBC is a heterogeneous entity whose incidence is higher than has commonly been published. Not an indolent disease, each subgroup, with its biological and anatomical characteristics, merits specific management.

Oligometastatic breast cancer: Dissecting the clinical and biological uniqueness of this emerging entity. Can we pursue curability?

Metastatic breast cancer represents an incurable condition, however, the increasing interest towards the oligometastatic entity is now challenging this assumption. Up to 20% of patients with metastatic breast cancer present with oligometastatic disease, which refers to metastatic breast cancer presenting or recurring with limited metastatic burden. In the last years, progressive advancements in imaging techniques, the growing availability of minimally invasive locoregional treatments, alongside the increasing expectations from a patient perspective, have contributed to rising the awareness towards this emerging entity. In the present work we comprehensively reviewed available evidence regarding oligometastatic breast cancer, focusing on clinical and biological notions virtually supporting the adoption of a curative approach when treating this condition. We also discussed main areas of uncertainties, providing a research agenda that may guide and fine-tune the future investigation in this field.

Clinical significance of the neutrophil-to-lymphocyte ratio in oligometastatic breast cancer.

PURPOSE: This study investigated the clinical impact of pretreatment neutrophil-to-lymphocyte ratio (NLR) on survival in patients with oligometastatic breast cancer. PATIENTS AND METHODS: We collected data from 397 patients who underwent primary breast surgery from 2004 to 2015 and developed recurrence during the follow-up. We reviewed the images and clinical information and defined OMD according to the European Society for Medical Oncology advanced breast cancer guidelines. The NLR was calculated using pretreatment data of primary breast cancer. The cutoff value of the NLR was determined by receiver operating characteristic curve with Youden Index. RESULTS: Among 397 patients, 131 had OMD at recurrence. The low-NLR group included patients of significantly older age at primary cancer than those in the high-NLR group. A low NLR indicated a better overall survival (p = 0.023) after adjusting for relevant factors, including estrogen receptor status, surgical resection of metastatic disease, metastatic organ number, disease-free interval, and liver metastasis than did the high-NLR group. We developed prognostic models for OMD using six independent prognostic factors, including the NLR. The number of factors was associated with overall survival; patients with all six favorable factors showed a good overall survival of 90.9% at 8 years and those with four or more factors showed 70.4%. CONCLUSIONS: The NLR was an independent prognostic factor for overall survival in OMD. The number of favorable prognostic factors was associated with overall survival. A prognostic model, including the NLR, will help identify patients with a favorable prognosis.

Oligometastatic breast cancer: An institutional analysis.

Introduction: Oligometastatic represents a distinctive subset of metastatic breast cancer (MBC). Incidence has been reported, in 1-5% of all newly diagnosed MBC. Literature is very sparse, especially from India. Material and Methods: We have ambispectively screened 500 patients of upfront female MBC between the period of January 2013 and August 2018 at Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi and 120 patients of oligometastatic breast cancer (OMBC) were included for analysis. Clinical, pathological, receptor status (ER estrogen receptor, PR progesterone receptor, and HER2/neu human epidermal growth factor), radiological, treatment, and survival details were recorded. Results: The median age of presentation was 50 (range 22-78) years. One organ was involved in 96 (80%) patients, and two organs were involved in 36 (20%) patients. ER and/or PR was positive in 48 (40.0%), ER/PR, and HER2/neu were positive in 28 (23.3%) cases. Only HER2/neu was positive in 21 (17.5%), and triple negativity was seen in 23 (19.2%) patients. Ninety-four (78.3%) patients received neoadjuvant therapy, and 12 (10%) patients underwent conservative breast surgery. The overall response rate at the metastatic site was 74.1%, and a complete response was seen in 42.5% of patients. Median progression-free survival (PFS) for the cohort was 25.43 months. The estimated PFS at 2 years and, at 5 years, was 54.6% and 21.6%, respectively. The hormone receptor positivity, bone metastasis, and patients with surgery after neoadjuvant chemotherapy (NACT) had a statistically significant better PFS on multivariate analysis. In a subset analysis of HER2/neu receptor-positive patients, who received targeted therapy showed better PFS compared to those who did not receive. Conclusion: The incidence of OMBC is 24% of the total MBC. The patients with OMBC who have hormone receptor-positive, bone-only metastasis, and surgery after NACT show a better outcome.

Proton Radiotherapy for Patients With Oligometastatic Breast Cancer Involving the Sternum.

INTRODUCTION: A subset of metastatic breast cancer patients present with oligometastatic disease involving the sternum. Given the proximity to traditional target structures, a proton radiation field can be expanded to include this region, providing definitive therapy for patients who are otherwise metastatic. We evaluated the feasibility and outcomes of a small series of patients who received comprehensive nodal irradiation inclusive of an isolated sternal metastasis using proton pencil beam scanning. MATERIALS AND METHODS: Four patients with a diagnosis of metastatic breast cancer with an isolated metastasis to the sternum received multimodality therapy with curative intent and then underwent adjuvant pencil beam scanning with definitive treatment to the sternum. Dosimetric parameters and treatment outcomes were evaluated. RESULTS: With respect to treatment coverage, proton therapy was able to deliver comprehensive target structure coverage while maintaining modest doses to the organs at risk compared with photon techniques. At a median follow-up of 28 months from diagnosis, none of the patients have experienced relapse within the radiation portal or developed additional sites of metastatic disease. CONCLUSION: Pencil beam scanning for oligometastatic breast cancer with isolated sternal lesions appears feasible without undue normal tissue exposure. Current treatment outcomes appear promising.

Distribution Characteristics and Prognostic Value of Immune Infiltration in Oligometastatic Breast Cancer.

BACKGROUND: To assess the distribution characteristics and the prognostic value of immune infiltration in female oligometastatic breast cancer patients. METHODS: We retrospectively analyzed the clinicopathological data of oligometastatic breast cancer (OMBC) patients diagnosed between June 2000 and January 2020. Immune markers were quantified by immunohistochemistry on FFPE tissues in paired normal breast tissues, primary breast cancers and oligometastatic lesions. Survival analyses were performed using the Kaplan-Meier curves and Cox-proportional hazards model. RESULTS: A total of 95 female OMBC patients visited Sun Yat-sen University Cancer Center between June 2000 and January 2020, and 33 of them had matched normal breast tissues, primary cancers and oligometastatic lesions and were reviewed in immune infiltration analysis. CD8 of primary tumors had a higher expression than that in matched normal tissues. The expressions of CD8 and FOXP3 were higher in the primary sites than that in the oligometastatic lesions. CD3, CD4 and CD8 were significantly lower in the intratumoral regions than that in the peritumoral regions both in primary and oligometastatic lesions. Notably, the high percentage of CD3 in the intratumoral oligometastatic lesions predicted the longer PFS and OS, and higher CD4 in the same lesions also predicted a better OS. There was obviously positive correlation between CD4/CD3 and Ki-67 in primary cancers and negative correlation between CD4/CD3 and ER in oligometastatic sites. CONCLUSION: We explored immune distribution and evolution in time and space in OMBC to provide new understandings for biological behaviors of this disease and further divided patients in different prognosis.

Oligometastatic Breast Cancer: How to Manage It?

Breast cancer (BC) is the most frequent cancer among women and represents the second leading cause of cancer-specific death. A subset of patients with metastatic breast cancer (MBC) presents limited disease, termed 'oligometastatic' breast cancer (OMBC). The oligometastatic disease can be managed with different treatment strategies to achieve long-term remission and eventually cure. Several approaches are possible to cure the oligometastatic disease: locoregional treatments of the primary tumor and of all the metastatic sites, such as surgery and radiotherapy; systemic treatment, including target-therapy or immunotherapy, according to the biological status of the primary tumor and/or of the metastases; or the combination of these approaches. Encouraging results involve local ablative options, but these trials are limited by being retrospective and affected by selection bias. Systemic therapy, e.g., the use of CDK4/6 inhibitors for hormone receptor-positive (HR+)/HER-2 negative BC, leads to an increase of progression-free survival (PFS) and overall survival (OS) in all the subgroups, with favorable toxicity. Regardless of the lack of substantial data, this subset of patients could be treated with curative intent; the appropriate candidates could be mostly young women, for whom a multidisciplinary aggressive approach appears suitable. We provide a global perspective on the current treatment paradigms of OMBC.

Diagnosis, biology and epidemiology of oligometastatic breast cancer.

Does oligometastatic breast cancer (OMBC) deserve a dedicated treatment? Although some authors recommend multidisciplinary management of OMBC with a curative intent, there is no evidence proving this strategy beneficial in the absence of a randomized trial. The existing literature sheds little light on OMBC. Incidence is unknown; data available are either obsolete or biased; there is no consensus on the definition of OMBC and metastatic sites, nor on necessary imaging techniques. However, certain proposals merit consideration. Knowledge of eventual specific OMBC biological characteristics is limited to circulating tumor cell (CTC) counts. Given the data available for other cancers, studies on microRNAs (miRNAs), circulating tumor DNA (ctDNA) and genomic alterations should be developed Finally, safe and effective therapies do exist, but results of randomized trials will not be available for many years. Prospective observational cohort studies need to be implemented.

Oligometastatic breast cancer: Are we there yet?

Patients with metastatic breast cancer are usually considered incurable. Recent advances have resulted in significant improvements in survival for patients with metastatic breast cancer. Due to the lack of randomised trials and heterogeneous disease biology, treatment decisions for patients with oligometastatic breast cancer vary widely. Some patients are treated similar to those with widespread disease while others are treated more aggressively. We conducted a review of the evidence for treatment options in oligometastatic breast cancer and consulted ClinicalTrials.gov to explore currently accruing or studies in development aimed at investigating oligometastatic disease in breast cancer. Surgery to the primary tumour in patients with metastatic breast cancer has failed to show any advantage over systemic therapy. However, there may be a benefit in women with controlled systemic disease who are hormone receptor positive with bone-predominant metastasis. Stereotactic radiotherapy has gained increased interest in this setting due to its excellent efficacy and lower rates of associated toxicity. A significant challenge remains in identifying the patient population who would benefit from such an approach, and to do so, we need to understand the distinct biology of oligometastatic breast cancer. Unique miRNA expression and low levels of tumour infiltrating lymphocytes in the immune micro-environment have been described in tumour tissues in patients with oligometastatic breast cancer. There is ongoing research aimed to better characterise these tumours, thus, allowing the selection of patients who would truly benefit from multi-modality treatment in an attempt for long-term survival and cure.

Long-term outcomes of oligometastatic breast cancer patients treated with curative intent: an updated report.

BACKGROUND: Oligometastatic breast cancer (OMBC) is characterized by limited metastatic tumor numbers and sites. We have reported a 20-year overall survival (OS) rate and relapse-free rate (RFR) of 34.1% and 27.4%, respectively, in a retrospective analysis of OMBC patients treated with curative intent including a multidisciplinary approach. Metastatic breast cancer (MBC) is generally incurable; however, OMBC might be a potentially curable subset. The previous analysis included isolated locoregional recurrence (ILRR) cases, which differs from distant metastasis in treatment strategies. Therefore, in this study, we excluded ILRR cases and provided an update on clinical outcomes. We also performed a detailed subgroup analysis of OMBC patients by introducing new prognostic variables. METHODS: Data of 73 OMBC patients, including 10 ILRR cases, treated in our institution between 1980 and 2010 were retrospectively analyzed. OMBC was defined as the presence of metastatic lesions in 1-2 organs, < 5 lesions per metastasized organ, and lesion diameter < 5 cm. RESULTS: The median follow-up duration was 151 (range 12-350) months. Twenty-eight (44%) patients received local therapy. Excluding ILRR cases, the OS rates were 28.3% and 18.9% and RFRs were 26.7% at 20 and 25 years, respectively. In multivariate analysis, single-organ involvement and three or fewer metastatic lesions per organ were associated with a longer progression-free and relapse-free interval (RFI). CONCLUSIONS: Relapse-free interval reached a plateau after 20 years at approximately 25% probability. Patients with long-term survival without disease relapse are considered cured. Curative-intent therapy should be considered for OMBC patients, especially those with low tumor volume.

Prognostic factors in patients with oligometastatic breast cancer - A systematic review.

AIM: Oligometastatic breast cancer (OMBC) is a disease-entity with potential for long-term remission in selected patients. Those with truly limited metastatic load (rather than occult widespread metastatic disease) may benefit from multimodality treatment including local ablative therapy of distant metastases. In this systematic review, we studied factors associated with long-term survival in patients with OMBC. METHODS: Eligible studies included patients with OMBC who received a combination of local and systemic therapy as multimodal approach and reported overall survival (OS) or progression-free survival (PFS), or both. The Quality in Prognosis Studies (QUIPS) tool was used to assess the quality of each included study. Independent prognostic factors for OS and/or PFS are summarized. RESULTS: Of 1271 screened abstracts, 317 papers were full-text screened and twenty studies were included. Eleven of twenty studies were classified as acceptable quality. Definition of OMBC varied between studies and mostly incorporated the number and/or location of metastases. The 5-year OS ranged between 30 and 79% and 5-year PFS ranged between 25 and 57%. Twelve studies evaluated prognostic factors for OS and/or PFS in multivariable models. A solitary metastasis, >24 months interval between primary tumor and OMBC, no or limited involved axillary lymph nodes at primary diagnosis, and hormone-receptor positivity were associated with better outcome. HER2-positivity was associated with worse outcome, but only few patients received anti-HER2 therapy. CONCLUSIONS: OMBC patients with a solitary distant metastasis and >24 months disease-free interval have the best OS and may be optimal candidates to consider a multidisciplinary approach.

Oligometastatic Breast Cancer: Is This a Curable Entity? A Contemporary Review of the Literature.

PURPOSE OF REVIEW: Oligometastatic breast cancer (OMBC) remains a poorly understood entity for which no standard of care exists at this time. This review will focus on our biologic understanding of OMBC and provide an update on current treatment strategies. RECENT FINDINGS: The introduction of micro RNA expression profiling has advanced our understanding of the biologic underpinnings of OMBC. Although most of the data regarding treatment have come from retrospective studies, there are now prospective randomized trials reporting progression-free survival and overall survival improvements with stereotactic ablative radiotherapy (SABR). Ongoing studies designed to evaluate addition of SABR as well as other novel agents will further develop this field and provide new treatment options. A "cure" for OMBC remains elusive. With further basic research coupled with novel prospective trials, patients will hopefully enjoy increased progression-free survival and overall survival, and ideally a delay to more toxic systemic therapy.

Local High-Dose Radiotherapy Induces Systemic Immunomodulating Effects of Potential Therapeutic Relevance in Oligometastatic Breast Cancer.

Local irradiation of cancer through radiotherapy can induce spontaneous regression of non-directly irradiated lesions, suggesting the involvement of systemic antitumor immune responses. In oligometastatic breast cancer (BC) patients, the use of stereotactic body radiotherapy (SBRT) favors the local control of treated lesions and may contribute to break local tolerance and release tumor-associated antigens (TAAs), improving host antitumor immunity. We performed a detailed immunomonitoring of BC patients undergoing SBRT to verify its ability to "switch on" the anti-tumor immunity both systemically, in peripheral blood, and locally, employing in vitro BC models. Twenty-one BC patients with ≤6 metastases were treated with 3 daily doses of 10 Gy with SBRT. Blood samples for immune profiling were collected before and after treatment. One month after treatment a third of patients displayed the boosting or even the de novo appearance of polyfunctional CD4+ and CD8+ T cell responses against known BC TAAs (survivin, mammaglobin-A, HER2), through intracellular staining in flow cytometry. Half of patients showed increased numbers of activated natural killer (NK) cells, measured with multispectral flow cytometry, immediately after the first dose of SBRT. Interestingly, high levels of activated NK cells at diagnosis correlated with a longer progression-free survival. BC in vitro models, treated with the same SBRT modality, showed enhanced expression of MHC class-I and class-II, major histocompatibility complex class I-related chain A/B, and Fas molecules, and increased release of pro-inflammatory cytokines, such as IL-1ß and TNF-α. Consistently, we noticed enhanced production of perforin by CD4+ T cells when patients' lymphocytes were cultured in the presence of irradiated BC cell line, compared to untreated targets. Besides immunogenic effects, SBRT also enhanced the percentages of circulating regulatory T cells, and increased indoleamine 2,3 dioxygenase and PD-L1 expression in BC in vitro models. These results suggest that SBRT may boost host antitumor immune responses also in an advanced disease setting such as oligometastatic BC, by inducing immunomodulating effects both locally and systemically. However, the concomitant induction of immunosuppressive pathways suggests that a combination with immunotherapy could further enhance the in situ vaccination ability of radiotherapy, possibly further improving the curative potential of SBRT in this subset of patients.

Long-term survival after high-dose chemotherapy with autologous hematopoietic cell transplantation in metastatic breast cancer.

OBJECTIVE/BACKGROUND: The most common indication for high-dose chemotherapy (HDC) and autologous hematopoietic cell transplantation (AHCT) in the 1990s was breast cancer. Several randomized trials and a more recent meta-analysis failed to show a survival benefit for AHCT in metastatic breast cancer (MBC); however, they demonstrated a better-than-expected 10-year to 15-year survival in 5-15% of patients. We thus evaluated the long-term results of treatment with HDC and AHCT in MBC at our institution. METHODS: From 1984 to 2000, 285 patients underwent AHCT for MBC. The patient characteristics were collected through the Cleveland Clinic, United Transplant Database. A retrospective review of the medical records of the long-term surviving breast-cancer patients treated with HDC and AHCT was conducted. RESULTS: With a median follow-up of 169 months, 34 (12%) remain alive. Of the 251 patients who died, 218 (87%) died of metastatic disease. A comparison by age (<50 years and >50 years) and hormonal status did not demonstrate any differences in relapse (p=.33 and p=.32, respectively) or survival (p=.13 and p=.42). Of the 34 long-term survivors, sufficient data were available on 28 patients, and further evaluation revealed that the majority had a primary or locally recurrent oligometastatic disease. CONCLUSION: This retrospective evaluation of patients who underwent AHCT for MBC demonstrates long-term survival in a small subset of patients, primarily those with primary or recurrent oligometastatic disease. Oligometastatic breast cancer is a distinct entity within MBC, which may be curable with multimodality therapy. We thus conclude there remains no overall-survival benefit to HDC in MBC.