Distant Breast Cancer Recurrence Research Articles

Abstract PO5-20-07: A Case of Metastatic Breast Cancer to Soft Tissue of the Thigh

Abstract Breast cancer is the most diagnosed cancer in women worldwide. The predominant cause of breast cancer mortality is metastatic disease with bone, lung, liver and brain being most common sites of metastasis. After melanoma, breast cancer is the most common cancer to have cutaneous metastatic disease and this presentation represents half of all cutaneous metastases. We are presenting a case of a 70-year-old female with distant recurrence of breast cancer to the left thigh. A 70-year-old female presented to clinic with a palpable left breast mass noted July 2022. Her medical history was notable for right sided upper lobe stage IIIB squamous cell lung cancer diagnosed in 2013 treated with chemotherapy and chest radiation (RT), menopause at 25 years old following TAH/BSO for fibroids. Family history included prostate cancer and genetic testing was negative for pathogenic mutation. Diagnostic mammogram showed a lesion in the left breast at 9:00 of 1.4 cm x 1.2 cm x1.4 cm, and biopsy showed grade 3 triple negative invasive ductal carcinoma (IDC). Her nodes were clinically and radiologically negative. She opted for breast conservation. In September of 2020 the patient had a left lumpectomy with sentinel lymph node biopsy. Final pathology (path) was pT1cN0 with two foci of IDC, grade 3, measuring 1.9 × 1.9 × 1.1 cm and 0.4 × 0.2 × 0.2 cm with negative margins. Two sentinel lymph nodes were negative for carcinoma. She received 4 cycles of doxorubicin and cyclophosphamide and started paclitaxel, but only completed 5/12 planned cycles. During these treatment cycles she was admitted twice for shortness of breath and found to have an exudative pleural effusion, repeat cytology was negative for malignancy at which point fluid did not recur. There was no CT evidence of lung nodules or plural thickening. Echocardiogram showed normal ejection fraction of 45%. PET scan was negative. Chemotherapy was stopped in February of 2021. Initial pre-operative discussion with radiation oncology indicated no contraindication to adjuvant RT. However, after simulation, it was deemed by radiation oncology that the patient was no longer a candidate for RT as during her lung cancer treatment, she had received RT of 69.4 Gy including the area of the current lumpectomy cavity. She then opted for bilateral mastectomy with immediate reconstruction in June 2021. Final path from both breasts showed no carcinoma. In November of 2021 she was admitted for shortness of breath and on CT scan was noted to have a left sided lung nodule. The patient declined biopsy and underwent a left wedge resection in January of 2022. Final path showed a 2.2. cm carcinoma consistent with breast primary that was ER 0, PR 0, and Her 2 neu 1+. She was started on capecitabine with plan for 6 months of treatment but stopped taking this after one month due to severe pain in her hands and feet. In November 2022 the patient noted a left thigh mass. Exam showed a firm, palpable thigh mass without overlying skin changes and core needle biopsy showed adenocarcinoma, favoring breast primary, ER 0, PR 0, HER 2 neu 2+ and FISH negative. PET scan showed no uptake in the chest abdomen or pelvis, however a 2.6 × 2.3 × 3.1 cm round mass in the left thigh was seen with SUV max of 8.6. She was started on traztuzumab-deruxtecan by medical oncology in December of 2022. The thigh tumor shrank significantly, however, patient discontinued after two infusions, citing intolerable hand weakness. She then received RT to the thigh. She was treated using 3D technique and 6 MV photons for a total dose of 5400 cGY, from February to March of 2023. Repeat PET June 2023 showed no avid uptake in the thigh. She has declined any additional systemic therapy. Soft tissue metastasis in distant recurrent breast cancer is uncommon and little guidance exists on clinical management. In cases of metastatic disease to the skin, hormone positive lesions can be managed with hormonal therapy. Early detection and biopsy for receptor studies may help guide therapy in cases of distant soft tissue recurrence. Citation Format: Rangel Melissa, Julia Alexieva, Alison Coogan, Lily Hussein, Elizabeth Marcus, Julie Wecsler. A Case of Metastatic Breast Cancer to Soft Tissue of the Thigh [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-20-07.

Abstract PO2-11-03: A long-term follow-up of patients who interrupted endocrine therapy to become pregnant following breast cancer surgery

Abstract Introduction: Regarding discontinue adjuvant endocrine therapy to attempt pregnancy, Pregnancy Outcome and Safety of Interrupting Therapy for Women with Endocrine Responsive Breast Cancer (POSITIVE) clinical trials have revealed temporary interruption of endocrine therapy to attempt pregnancy did not confer short-term risk of breast cancer events. However, that report involved a short observation period, longer-term follow-up is required. This study was aimed to evaluate the safety of endocrine therapy interruption with long-term followed-up data base. Methods: This was a retrospective study using surveying of medical chart data between June 2007 and November 2015 at St. Luke’s International Hospital. The subjects were 65 patients with estrogen-receptor positive primary breast cancer (clinical stage I-III) who had been performed fertility preservation prior to starting breast cancer treatment. Adjuvant endocrine therapy completion was defined as 120 months (10 years) and discontinuation was defined as < 120 months. Using the definition, we classified the patients into an endocrine therapy interruption-group and a continuation-group. The primary outcome was the breast cancer free interval (BCFI). We defined breast cancer events as local, regional, or distant recurrence of invasive breast cancer or new contralateral invasive breast cancer during follow-up. Results: Median follow-up period was 110 (range, 36–181) months. The number of adjuvant endocrine therapy interruption-group was 30 and continuation-group was 35. Among 65 patient, the mean patient age in the interruption vs. continuation groups were as follows: 38(range, 26-48) years vs. 36.5 (range, 26–45) years at breast cancer diagnosis and HER2 positive breast cancer was identified in 4 (11.4%) vs 4 (13.3%) patients. Clinical stages were Stage I, 9 (30%) vs. 11 (31.4%) patients; Stage II, 18 (60%) vs. 18 (51.4%) patients; and Stage III, 3 (10%) vs. 6 (17.1%) patients. Chemotherapy was administered in 17 (56.7%) and 23 (65.7%) patients, respectively. The median duration of endocrine therapy before interruption was 25.5 months: 3 (10%) patients received endocrine therapy for 0–18 months, 16 (53.3%) for 18–30 months, and 11 (36.7%) for >30 months. The BCFI was 124 and 119 months in the interruption and continuation groups, respectively (p = 0.16). There were 6 (20%) and 9 (25.7%) breast cancer events in the interruption-group and continuation-group, respectively (p = 0.4). All the pregnancies were in the endocrine therapy interruption group (17 pregnancies, 16 deliveries), with one pregnancy involving the delivery of twins. Three pregnancies were spontaneous. Endocrine therapy was resumed in 16 (59.3%) patients in the interruption-group (median time to resumption, 20.5 months). One patient developed distant metastasis during endocrine therapy interruption period. Conclusion: Among patients who performed fertility preservation prior to starting breast cancer treatment, our long-term follow-up data, almost 9 years, suggested that the BCFI was not statistically different between endocrine therapy interruption-group and continuation-group. A limitation of this study is that only three cases of Stage III breast cancer were included in the interruption group. Therefore, we consider that careful decisions should be made regarding interruption of endocrine therapy. Citation Format: Risa Kasahara, Atsuko Kitano, Fumi Akitani, Kyoko Shiota, Kumiko Kida, Junko Takei, Atsushi Yoshida. A long-term follow-up of patients who interrupted endocrine therapy to become pregnant following breast cancer surgery [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-11-03.

Association of androgen receptor and tumour-infiltrating lymphocytes with bone recurrence in triple-negative breast cancer

BackgroundAs compared to endocrine responsive breast cancer bone is less frequent site of distant recurrence in triple-negative breast cancer (TNBC). A biomarker which predicts bone recurrence would allow a more personalized treatment approach with adjuvant bisphosphonates in TNBC. Here we hypothesised that tumour expression of androgen receptor (AR) is associated with bone recurrence in TNBC. Materials and methodsPatients with operable TNBC who were treated at the Institute of Oncology Ljubljana between 2005 and 2015 and developed distant recurrence were included into our study. Nuclear expression of AR in the tissue of primary tumours was determined immunohistochemically by using the Androgen Receptor (SP107) Rabbit Monoclonal Antibody. We applied a logistic regression model to test the association between expression of AR and development of bone metastases. The model was adjusted for selected known prognostic factors and possible confounders in TNBC, including the level of the stromal tumour-infiltrating lymphocytes (sTILs). ResultsAt recurrence 45 (45 %) out of 100 patients presented with bone metastases. Additionally, seven (7 %) developed bone metastases metachronously. AR was expressed in primary tumours of 35 (35 %) women and 19 (54.3 %) developed bone recurrence. In 25 (25 %) patients sTILs were absent. Neither the proportion of AR positive cancer cells (OR = 1.00; 95 % CI 0.96–1.03; p = 1.00) nor the intensity of AR positive reaction (OR = 0.71; 95 % CI 0.02–21.4; p = 1.00) were significantly associated with bone recurrence. However, women with at least mild level of the sTILs were at significantly lower risk for bone recurrence as compared to those without any sTILs (OR = 0.01; 95 % CI < 0.01–0.08; p = 0.01). ConclusionsExpression of AR is not significantly associated with the development of bone metastases in TNBC. However, patients with absent sTILs in their primary tumours are highly susceptible for recurrence in the bone and might particularly benefit from adjuvant bisphosphonates.

Decline in the Incidence of Distant Recurrence of Breast Cancer: A Population-Based Health Record Linkage Study, Australia 2001-2016.

We investigated differences in cumulative incidence of first distant recurrence (DR) following non-metastatic breast cancer over a time period when new adjuvant therapies became available in Australia. We conducted a health record linkage study of females with localized (T1-3N0) or regional (T4 or N+) breast cancer in the New South Wales Cancer Registry in 2001 to 2002 and 2006 to 2007. We linked cancer registry records with administrative records from hospitals, dispensed medicines, radiotherapy services, and death registrations to estimate the 9-year cumulative incidence of DR and describe use of adjuvant treatment. The study included 13,170 women (2001-2002 n = 6,338, 2006-2007 n = 6,832). The 9-year cumulative incidence of DR was 3.6% [95% confidence interval (CI), 2.3%-4.9%] lower for 2006-2007 diagnoses (15.0%) than 2001-2002 (18.6%). Differences in the annual hazard of DR between cohorts were largest in year two. DR incidence declined for localized and regional disease. Decline was largest for ages <40 years (absolute difference, 14.4%; 95% CI, 8.3%-20.6%), whereas their use of adjuvant chemotherapy (2001-2002 49%, 2006-2007 75%) and HER2-targeted therapy (2001-2002 0%, 2006-2007 16%) increased. DR did not decline for ages ≥70 years (absolute difference, 0.9%; 95% CI, -3.6%-1.8%) who had low use of adjuvant chemotherapy and HER2-targeted therapy. This whole-of-population study suggests that DR incidence declined over time. Decline was largest for younger ages, coinciding with changes to adjuvant breast cancer therapy. Study findings support the need for trials addressing questions relevant to older people and cancer registry surveillance of DR to inform cancer control programs.

Impact of cost of Oncotype DX versus CanAssist Breast, an Indian prognostic test, in the management of node-negative early breast cancer in a single centre in India.

14 Background: It is well known that prognostication is important as not all women benefit equally from adjuvant chemotherapy, especially in HR+/HER2- early breast cancer (BC). Multiple publications have showcased the cost-effectiveness of Oncotype DX (ODX) in various countries. However, ODX remains out of reach for many patients in under-resourced geographies like Asia, Africa etc where healthcare insurance is not a norm. CanAssist Breast (CAB) is an affordable prognostic test developed on Indian patients. CAB couples the immunohistochemistry technique with an AI/ML-based prediction model to segregate patients as either low-risk or high-risk for distant breast cancer recurrence. CAB has been validated in the USA, Spain, Germany, Austria, Italy, and The Netherlands for predicting 5–10-year distant recurrences and has comparable low-risk accuracy with that of ODX/MammaPrint. In this abstract, we present real-world data about cost-analysis of the use of CanAssist Breast versus ODX in a single cancer care centre in Rajasthan, a state in Western India that has a per capita income of $ 1504 as against $ 68,400 in the USA. Methods: 124 patients with node-negative early BC were treated at a trust hospital in Jaipur, Rajasthan from 2020-2022. All the high-risk patients received chemotherapy at the treating clinician’s discretion. For the cost analysis model, the cost of chemotherapy drugs, hospitalization charges, and costs involved in managing short-term adverse events was compared for CAB and ODX. Treatment is provided at subsidized costs to the patients in this trust hospital. Results: The median age of this cohort was 55 years (35-78), with primarily T2 and G2 diseases. High-risk proportions were 27% and 17% (as per TAILORx) and by CAB and ODX respectively. The cost of ODX is 5.8 times higher than the cost of CAB. The cost savings per patient with CAB over ODX were US $ 3477 (Rs. 278161) in this trust hospital. Conclusions: This economic model shows that the use of ODX could impose an economic burden due to its cost. Use of CAB would lead to savings without comprising the patient’s health, as both tests have comparable performance.

Racial disparity in tumor microenvironment and distant recurrence in residual breast cancer after neoadjuvant chemotherapy

Black, compared to white, women with residual estrogen receptor-positive (ER+) breast cancer after neoadjuvant chemotherapy (NAC) have worse distant recurrence-free survival (DRFS). Such racial disparity may be due to difference in density of portals for systemic cancer cell dissemination, called TMEM doorways, and pro-metastatic tumor microenvironment (TME). Here, we evaluate residual cancer specimens after NAC from 96 Black and 87 white women. TMEM doorways are visualized by triple immunohistochemistry, and cancer stem cells by immunofluorescence for SOX9. The correlation between TMEM doorway score and pro-metastatic TME parameters with DRFS is examined using log-rank and multivariate Cox regression. Black, compared to white, patients are more likely to develop distant recurrence (49% vs 34.5%, p = 0.07), receive mastectomy (69.8% vs 54%, p = 0.04), and have higher grade tumors (p = 0.002). Tumors from Black patients have higher TMEM doorway and macrophages density overall (p = 0.002; p = 0.002, respectively) and in the ER+/HER2- (p = 0.02; p = 0.02, respectively), but not in the triple negative disease. Furthermore, high TMEM doorway score is associated with worse DRFS. TMEM doorway score is an independent prognostic factor in the entire study population (HR, 2.02; 95%CI, 1.18–3.46; p = 0.01), with a strong trend in ER+/HER2- disease (HR, 2.38; 95%CI, 0.96–5.95; p = 0.06). SOX9 expression is not associated with racial disparity in TME or outcome. In conclusion, higher TMEM doorway density in residual breast cancer after NAC is associated with higher distant recurrence risk, and Black patients are associated with higher TMEM doorway density, suggesting that TMEM doorway density may contribute to racial disparities in breast cancer.

Reviewing the risk of breast cancer recurrence following breast reconstruction.

It is widely accepted that both autologous and alloplastic reconstruction are safe. A recent publication reported a significant association between textured implants and metastatic recurrence of breast cancer. This study aims to assess if the published results are reproducible in our cohort and to review the safety of breast reconstruction. This is a retrospective cohort study of adult patients undergoing mastectomy and either alloplastic or autologous breast reconstruction at a single quaternary hospital. Outcomes include disease free survival (DFS), local and recurrence free survival (LRRFS) and BIA-ALCL. For time to event endpoints, unadjusted and multivariate adjusted hazard ratios (HRs) were estimated using Cox regression, and penalized Cox regression respectively. Four hundred and twenty-six patients of whom 187 underwent autologous reconstruction and 239 underwent alloplastic. There were 43 cancer recurrences (24 alloplastic and 19 autologous) and 14 local regional recurrences (8 alloplastic and 4 autologous). There were 26 deaths and no instances of BIA-ALCL. Median follow-up time was 4.7 years. No evidence of association was found between breast reconstruction method and DFS (HR 0.87 CI: 0.47-1.58). It is uncertain whether implant texture grade was associated with increased breast cancer recurrence (HR 2.17 CI: 0.65-7.52). Both autologous and alloplastic breast reconstruction have been carried out in our cohort and reconstructive modality was not associated with either reduced DFS or LRRFS. The results in this cohort show there is uncertainty between the use of textured breast implants and either local or distant breast cancer recurrence.

Interrupting Endocrine Therapy to Attempt Pregnancy after Breast Cancer

BackgroundProspective data on the risk of recurrence among women with hormone receptor–positive early breast cancer who temporarily discontinue endocrine therapy to attempt pregnancy are lacking.MethodsWe conducted a single-group trial in which we evaluated the temporary interruption of adjuvant endocrine therapy to attempt pregnancy in young women with previous breast cancer. Eligible women were 42 years of age or younger; had had stage I, II, or III disease; had received adjuvant endocrine therapy for 18 to 30 months; and desired pregnancy. The primary end point was the number of breast cancer events (defined as local, regional, or distant recurrence of invasive breast cancer or new contralateral invasive breast cancer) during follow-up. The primary analysis was planned to be performed after 1600 patient-years of follow-up. The prespecified safety threshold was the occurrence of 46 breast cancer events during this period. Breast cancer outcomes in this treatment-interruption group were compared with those in an external control cohort consisting of women who would have met the entry criteria for the current trial.ResultsAmong 516 women, the median age was 37 years, the median time from breast cancer diagnosis to enrollment was 29 months, and 93.4% had stage I or II disease. Among 497 women who were followed for pregnancy status, 368 (74.0%) had at least one pregnancy and 317 (63.8%) had at least one live birth. In total, 365 babies were born. At 1638 patient-years of follow-up (median follow-up, 41 months), 44 patients had a breast cancer event, a result that did not exceed the safety threshold. The 3-year incidence of breast cancer events was 8.9% (95% confidence interval [CI], 6.3 to 11.6) in the treatment-interruption group and 9.2% (95% CI, 7.6 to 10.8) in the control cohort.ConclusionsAmong select women with previous hormone receptor–positive early breast cancer, temporary interruption of endocrine therapy to attempt pregnancy did not confer a greater short-term risk of breast cancer events, including distant recurrence, than that in the external control cohort. Further follow-up is critical to inform longer-term safety. (Funded by ETOP IBCSG Partners Foundation and others; POSITIVE ClinicalTrials.gov number, NCT02308085.)

Machine Learning Algorithm to Estimate Distant Breast Cancer Recurrence at the Population Level with Administrative Data.

High-quality population-based cancer recurrence data are scarcely available, mainly due to complexity and cost of registration. For the first time in Belgium, we developed a tool to estimate distant recurrence after a breast cancer diagnosis at the population level, based on real-world cancer registration and administrative data. Data on distant cancer recurrence (including progression) from patients diagnosed with breast cancer between 2009-2014 were collected from medical files at 9 Belgian centers to train, test and externally validate an algorithm (i.e., gold standard). Distant recurrence was defined as the occurrence of distant metastases between 120 days and within 10 years after the primary diagnosis, with follow-up until December 31, 2018. Data from the gold standard were linked to population-based data from the Belgian Cancer Registry (BCR) and administrative data sources. Potential features to detect recurrences in administrative data were defined based on expert opinion from breast oncologists, and subsequently selected using bootstrap aggregation. Based on the selected features, classification and regression tree (CART) analysis was performed to construct an algorithm for classifying patients as having a distant recurrence or not. A total of 2507 patients were included of whom 216 had a distant recurrence in the clinical data set. The performance of the algorithm showed sensitivity of 79.5% (95% CI 68.8-87.8%), positive predictive value (PPV) of 79.5% (95% CI 68.8-87.8%), and accuracy of 96.7% (95% CI 95.4-97.7%). The external validation resulted in a sensitivity of 84.1% (95% CI 74.4-91.3%), PPV of 84.1% (95% CI 74.4-91.3%), and an accuracy of 96.8% (95% CI 95.4-97.9%). Our algorithm detected distant breast cancer recurrences with an overall good accuracy of 96.8% for patients with breast cancer, as observed in the first multi-centric external validation exercise.

The association between perioperative opioids and breast cancer recurrence: a narrative review of the literature.

Opioid use disorder is an evolving crisis, and 17.2% of postsurgical patients continue to fill an opioid prescription one year after surgery. Preclinical studies suggest perioperative opioid use, defined here as opioids used in the setting of operative pain, may be linked to inferior oncologic outcomes. If this were true, opioid minimization strategies for surgical patients may reduce opioid-related deaths in more than one way. This review aims to describe the association between perioperative opioid use and breast cancer recurrence. On November 1, 2021, we searched the Ovid and EMBASE databases for the terms "breast neoplasm", "opioid analgesics", "neoplasm recurrence", and "neoplasm metastasis". Of the 350 articles retrieved, 11 met our inclusion criteria. The review was undertaken using the enhancing transparency in reporting the synthesis of qualitative research (ENTREQ) checklist for quality. Clinical studies report no clear association between perioperative opioid use and local or distant breast cancer recurrence. Mixed results were found when assessing perioperative opioid use and overall survival. Multiple studies paradoxically found opioid use to be associated with lower recurrence rates, despite higher mortality rates. Most studies showed no difference in recurrence or survival in breast cancer surgery patients who did or did not receive opioid-containing analgesia, although most findings were limited by study design and low event rates in patients with breast cancer. The lack of a clear connection between perioperative opioid use and breast cancer recurrence contradicts some preclinical data, which describes mechanisms through which opioids upregulate tumor proliferation which might worsen oncologic outcomes. Existing clinical literature is limited to mostly retrospective studies in patients with predominantly early-stage breast cancers, with low event rates. Given the worsening opioid epidemic and preclinical study findings, opioid minimization strategies should still be explored. Future work should be prospective and examine cancer recurrence in high-risk patients with more advanced tumor pathologies.

Abstract P3-03-08: Depression and breast cancer recurrence among female veterans in the United States: a retrospective cohort study

Abstract Background: The importance of mental health to improve the quality of cancer survivorship and outcomes is gaining increased attention. Major depressive disorder (MDD) has been associated with higher breast cancer (BC) incidence, BC-specific and all-cause mortality. The effect of MDD on BC recurrence remains under-studied. The Veterans Health Administration (VHA) provides a unique opportunity to examine this relationship as it mandates annual MDD screening in the primary care setting and reports national screening rates of 96%. Objective: To examine the relationship between pre-existing MDD and BC recurrence among a diverse cohort of women in the United States. Methods: We established a retrospective cohort of women (age ≥ 18 years) diagnosed with early-stage incident BC from 2010 through 2019 using the VHA’s electronic medical record database. We used a two-year window to identify women with clinically diagnosed MDD prior to their BC diagnosis. Our outcome of interest was BC recurrence (local recurrence/second primary and distant recurrence). We used multivariable proportional hazards regression to examine the association between MDD and BC recurrence, accounting for competing risk of death. Our analyses were adjusted for age, race, ethnicity, marital status, priority group rating (proxy for socioeconomic status), rurality of primary residence, geographical region, cancer stage, year of BC diagnosis, and comorbidity burden. Priority group rating is a metric that incorporates patients’ income, receipt of VHA assistance benefits, capacity for gainful employment, and severity of service-connected conditions. We conducted subgroup analyses by tumor subtype. RESULTS: Our cohort consists of 6,045 women with BC, of whom 1,750 (29.0%) had a pre-existing MDD diagnosis. The median length of follow-up from BC diagnosis was 4.5 years (IQR=4.8 years). The average age at BC diagnosis was 57 years (SD=11 years) overall and 56 years (SD=10 years) among women with MDD. Sixty-one percent of women were white, 29% were black, 27% were married, and 28% were rural dwelling. Forty-four percent of invasive carcinomas were localized and 21% were regional. Thirty-five percent of patients had ductal carcinoma in situ. Women with MDD had a higher average Charlson Comorbidity Index score (mean=0.75, SD=1.13 vs. mean=0.58, SD=1.03) and proportion with a priority group rating between 1-4 (40% vs. 32%). The distribution of other described patient characteristics among women with MDD were similar to the overall cohort. On multivariable analysis, women with MDD had a 31% (95% CI: 1.11, 1.56) higher risk of BC recurrence compared to women without MDD. MDD was associated with a 29% (95% CI: 1.01, 1.66) and 33% (95% CI: 1.05, 1.67) higher risk of local recurrence/second primary and distant recurrence, respectively. The relationship between MDD and BC recurrence remained significant after adjusting for tumor subtype (HR=1.40, 95% CI: 1.07, 1.83). In subgroup analyses stratified by tumor subtype, MDD was associated with a higher risk of BC recurrence among women with estrogen receptor positive versus negative tumors (HR=1.65, 95% CI: 1.27, 2.14 vs. HR=0.71, 95% CI: 0.34, 1.46) and HER2/neu negative versus positive tumors (HR=1.53, 95% CI: 1.16, 2.00 vs. HR=1.24, 95% CI: 0.51, 2.96). The interaction between estrogen receptor status and MDD was statistically significant (p-interaction=0.02). CONCLUSION: Women with incident BC should be screened for MDD early in the cancer care continuum given the prevalence of MDD and association with increased risk of local recurrence/second primary and distant BC recurrence. Further research is needed to understand the interplay between these two diseases and their treatments. Citation Format: Maya Aboumrad, Brian Shiner, Avonne Connor, Bradley V. Watts, Kala Visvanathan. Depression and breast cancer recurrence among female veterans in the United States: a retrospective cohort study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-03-08.

Abstract P2-11-09: Association of 21-gene recurrence score with overall survival in phase 3 TAILORx trial

Abstract Background: The 21-gene recurrence score (RS) assay is a prognostic measurement originally established for distant recurrence in estrogen receptor-positive and node-negative breast cancer. Retrospective studies and the Trial Assigning Individualized Options for Treatment (TAILORx; ClinicalTrials.gov NCT00310180) validated its significance besides testing chemotherapy benefit in patients with midrange RS (11-25). However, unclarity remains as to whether RS has comparable prognostic value for overall survival (OS) in the TAILORx trial population. Methods: Association between the recurrence scores (midrange or high-range 26-100 vs. low-range 0-10) and OS was evaluated in all eligible patients with clinicopathological and treatment information by multivariable Cox proportional hazards regression model including RS, tumor size, tumor grades, chemotherapy, endocrine regimens, surgery type, progesterone receptor and demographics. We also evaluated the association between RS and invasive disease-free survival (DFS), recurrence-free interval (RFI) or distant recurrence-free interval (dRFI) by multivariable Cox analysis. Results: Median follow-up was 95.5 (range 0.1 to 138.6) months for OS, 89.6 months (range 0 to 134.8) for DFS, 87.7 (range 0 to 134.8) months for RFI or 87.6 (range 0-134.8) months for dRFI. Compared with low score group, midrange and high-range scores were associated with RFI and dRFI, respectively (P≤0.01 each). However, midrange score was neither associated with OS (adjusted HR 1.15; 95% CI 0.87-1.52; P=0.33) nor associated with DFS (HR 1.16; 95% CI 0.97-1.38; P=0.11). High-range score was associated with DFS (HR 1.58; 95% CI 1.21-2.06; P&amp;lt; 0.01) and had a trend towards association with OS (HR 1.44; 95% CI 0.95-2.19; P=0.08). Conclusions: The data indicate that the recurrence scores provide independent prognosis for breast cancer recurrence at both distant and locoregional sites and for distant recurrence, respectively. High-range score is prognostic of disease-free survival, with the midrange score showing marginal association. Midrange and high-range recurrence scores do not provide independent prognostic information for overall survival in hormone receptor-positive, HER2-negative, node-negative breast cancer in the TAILORx trial population. Citation Format: Sherry X. Yang, John Yu, Molin Wang. Association of 21-gene recurrence score with overall survival in phase 3 TAILORx trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-09.

Abstract P2-03-23: Retrospective evaluation of outcomes in a real-world, prospective cohort using EndoPredict: Results from the Charité registry

Abstract Background: EndoPredict is a prognostic and predictive gene expression assay that provides an EPclin risk score, which can be used to identify individuals with low enough risk of distant breast cancer recurrence that they may forgo chemotherapy. In clinical studies, EndoPredict has been validated to predict risk of distant recurrence up to 15 years and chemotherapy benefit. To date, real-world studies evaluating patient outcomes after prospective EndoPredict testing have been limited. Here, we report on outcomes collected via survey from patients enrolled in a registry created to generate real-world evidence from over 800 patients routinely tested with EndoPredict at Charité University Hospital Berlin. Methods: Female patients with hormone receptor positive, HER2 negative primary breast cancer with up to three positive lymph nodes who received prospective EndoPredict testing at Charité University Hospital Institute of Pathology between 2011 and 2016 were contacted to complete a survey for participation in this study. Surveys included questions on treatment and recurrence history. Patient demographics, clinical characteristics of the cancer, and EndoPredict results were retrieved from Charité records. All patients received EndoPredict test results before decision making on systemic treatment. After testing, treatment included either adjuvant endocrine therapy or adjuvant endocrine therapy plus adjuvant chemotherapy, and may have included radiotherapy. Cox proportional hazards models were fit with binary EPclin risk category (high, low) or continuous EPclin risk score predicting 5-year distant recurrence or recurrence of any kind. Analyses were performed across all survey responses, and in subsets of patients stratified by adjuvant chemotherapy treatment. Kaplan-Meier estimates of 5-year risk of recurrence were also calculated. Results: 842 patient survey responses were returned with informed consent and met study inclusion criteria. The median age at diagnosis was 54 years (IQR 49, 63), and across survey responses, 63.5% (N=535/842) of patients were lymph node negative, 60.9% (N=513/842) were T1, and 43.9% (N=370/842) were treated with adjuvant chemotherapy. Among included patients, 49.5% (N=417/842) were classified as EPclin low-risk and 50.5% (N=425/842) were high-risk. The concordance between EPclin risk category and chemotherapy status was 0.89 with 5.5% (N=23/417) of EPclin low-risk and 81.6% (N=347/425) of EPclin high-risk patients receiving treatment with chemotherapy. In the subset of patients not treated with adjuvant chemotherapy (N=472/842, 55.7%), continuous EPclin score was a significant predictor of distant recurrence (N=469; HR: 4.34, 95% CI 1.75-9.58); p = 2.4 × 10-3), and recurrence of any kind (N=468; HR: 3.39, 95% CI 1.61-6.58); p = 1.9 × 10-3). In EPclin low-risk patients treated with endocrine therapy alone, there was a low risk of 5-year distant recurrence (1.6%, 95% CI 0.7%-3.4%). In EPclin high-risk patients the risk of distant recurrence at 5 years was 6.8% (95% CI 2.6%-17.4%) in patients without chemotherapy and 3.6% (95% CI 2.1%-6.3%) in patients treated with chemotherapy. In an exploratory subgroup analysis in patients with node negative and node positive disease, risk of 5-year distant recurrence in EPclin low-risk patients without chemotherapy was 1.3% (95% CI 0.5%-3.5%) and 2.4% (95% CI 0.6%-9.2%), respectively. Conclusion: In this real-world cohort of patients with prospective routine testing with EndoPredict, EPclin scores were a significant predictor for patient-reported outcomes. Patients with EPclin low-risk scores had a low risk of 5-year distant recurrence even in the absence of chemotherapy treatment. This real-world result supports previous clinical studies demonstrating that patients with EPclin low-risk scores can safely forgo chemotherapy. Citation Format: Wolfgang D. Schmitt, Paul Jank, Inga Hoffmann, Berit M. Pfitzner, Lauren Lenz, Wyatt Clegg, Elke Keil, Sarah Ratzel, Elizabeth S. Cogan, Jens-Uwe Blohmer, Pauline Wimberger, Ralf Kronenwett, David Horst, Carsten Denkert. Retrospective evaluation of outcomes in a real-world, prospective cohort using EndoPredict: Results from the Charité registry [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-03-23.

138MO Prognostic performance of Breast Cancer Index (BCI) in postmenopausal women with early-stage HR+ breast cancer in the TEAM trial

Early-stage HR+ breast cancer patients face a prolonged risk of recurrence even after adjuvant endocrine therapy. The Breast Cancer Index (BCI) and BCIN+ prognostic models are significantly prognostic for risk of overall (0-10y) and late (5-10y) distant recurrence (DR) in N0 and N1 breast cancer, respectively. Here, the prognostic performance of BCI and BCIN+ was evaluated in a cohort of HR+ postmenopausal women from the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial.

Abstract 3403: Multiomic, plasma-only circulating tumor DNA (ctDNA) assay identifies breast cancer patients with minimal residual disease (MRD) and predicts distant recurrence

Abstract Background: Detection of MRD after curative intent treatment may identify patients at high risk for recurrence. Most ctDNA-based MRD assays require a priori knowledge of genomic alterations from tumor tissue to achieve acceptable sensitivity and specificity. However, tissue availability may be limited in some patients with breast cancer, particularly following neoadjuvant therapy. Here we report results of a pilot study evaluating a plasma-only multiomic ctDNA MRD assay and its association with breast cancer recurrence. Methods: 47 plasma samples from 38 patients with early-stage breast cancer were collected through the BRandO BiO Registry at 12- or 36-months post-diagnosis and/or at the time of clinical recurrence. BRandO BiO is a multi-center regional registry with longitudinal biobanking from patients with newly diagnosed breast cancer at 20 affiliated network hospitals in Germany. The presence of ctDNA was evaluated using the Guardant Reveal multi-cancer assay, a next generation sequencing panel covering ~500 genes and ~4Mb of epigenomic regions that undergo differential methylation in multiple solid tumor types. The presence/absence of ctDNA is determined by a custom bioinformatics classifier that identifies tumor-derived somatic variants and methylation profiles specific to individual cancer types without the need for tumor tissue or peripheral blood mononuclear cell analysis. Samples were analyzed blinded to recurrence status.Results: 20 patients were confirmed to have clinical recurrence (7 local, 13 distant). ctDNA was detected at or prior to distant recurrence in 11/13 (85%) patients and in 1/7 (14%) patients with local recurrence. Five patients with distant recurrence had a sample available that was collected prior to distant recurrence; ctDNA was detected in 4/5 with a 3.8-18.6 month lead time. Among 15 ctDNA+ samples, 5 were positive for both methylation and somatic variant calls, 1 by somatic variants only, and 9 by methylation only. Somatic mutations were identified in AKT, RB1, KRAS, PIK3CA, ERBB2, MAP3K1, GATA3, and ESR1. The ESR1 mutation occurred in a patient with endocrine therapy resistance, confirming the ability of the assay to identify acquired treatment resistance mutations. ctDNA was not detected in samples from the 14 patients who had no confirmed clinical recurrence (100% specificity). Conclusions: This is the first study to demonstrate the feasibility of MRD detection in breast cancer using a plasma-only multiomic ctDNA-based approach. The Guardant Reveal assay demonstrated high sensitivity and specificity to detect distant breast cancer recurrence. Larger studies in this population are ongoing to further validate the clinical performance of the assay and demonstrate its applications in the management of early-stage breast cancer. Citation Format: Wolfgang Janni, Jens Huober, Tatjana Braun, Volkmar Müller, Angelina Fink, Amelie de Gregorio, Brigitte Rack, Thomas W. Friedl, Lisa Wiesmüller, Klaus Pantel, Thereasa Rich, Princy Parsana, Elena Zotenko, Shile Zhang, Sophia Huesmann. Multiomic, plasma-only circulating tumor DNA (ctDNA) assay identifies breast cancer patients with minimal residual disease (MRD) and predicts distant recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3403.

Comparison of predicted benefit using RS clin versus observed benefit in a U.S. registry of stage I ER-positive HER2-negative high oncotype DX RS breast cancer.

544 Background: The 21-gene recurrence score assesses the risk of distant breast cancer recurrence and predicts the benefit of adjuvant chemotherapy in ER positive early-stage breast cancer. However, clinicopathologic risk factors continue to impact absolute benefit of adjuvant chemotherapy. Absolute benefit of adjuvant chemotherapy in low clinicopathologic risk Stage I ER positive breast cancer with high Oncotype RS is an important clinical component of shared decision making. The RSClin clinical tool, which integrates the 21-gene recurrence score (RS) and clinicopathologic features, was found to be more prognostic than RS result alone. We assessed RS Clin predicted benefit and compared to absolute benefit in low clinicopathologic risk Stage I ER positive breast cancer with high Oncotype RS as observed in the NCDB. Methods: Using the National Cancer Data Base (NCDB), we identified female patients age 18-75, ER positive and Her 2 negative, 21 gene signature high risk &gt; 25 with negatives surgical margins, &lt;2cm, lymph node negative breast cancers, who had received endocrine therapy with either Tam or AI diagnosed during 2010 - 2017. Clinicopathologic factors and RS were entered into the RSClin calculator, and a predicted benefit of chemotherapy was calculated for each patient. Using NCDB data, Cox proportional hazards regression models were used to project absolute survival benefit at 10 years from diagnosis for those who did vs those who did not receive chemotherapy. NCDB-derived absolute benefit of chemotherapy was compared to estimated absolute benefit as predicted by the RSClin tool. Results: 18,226 patients were identified. Stages T1a = 670(4%), T1b = 4,289(23%), and T1c = 13,267(73%). Median age 59 years (21-75). Race white 84% (15,365), black 10% (1840), and other 1021(6%). AI use 80% (14,711) was greater than Tam use 20% (3515). Chemotherapy was administered in 75% (13,827) of patients. Most patients had high or intermediate grade disease, G3 45% (8225), G2 46% (8328), and G1 9% (1672). Median duration of follow up was 57 months (2-160). Probability of death T1b at 10yrs with chemotherapy was 8.5%, and without chemotherapy was 15.1% with an absolute benefit of 6.6%. Predicted benefit in T1b using RS Clin at 10yrs was 10.8%. Probability of death for T1c at 10yrs with chemotherapy was 15.1%, and without chemotherapy was 23.5% with an absolute benefit of 8.4%. Predicted benefit in T1c using RS Clin at 10yrs was 14%. Conclusions: Patients with stage IB and IC hormone receptor positive HER2 negative breast cancers with high RS had a lower absolute benefit than predicted by RS Clin. The RSClin tool overestimated benefit of therapy in both IB and IC stages requiring caution when using this tool in patients with the lowest clinicopathologic risks.

Cost-effectiveness analysis of the Oncotype DX Breast Recurrence Score test in node-positive early breast cancer

Aims Given the high rate of adverse events and high cost of adjuvant chemotherapy, it is optimal to avoid its use when endocrine therapy is equally effective at preventing distant recurrence of early breast cancer. The Oncotype DX test is a predictive and prognostic multigene assay used to guide adjuvant chemotherapy decisions in early breast cancer based on a Recurrence Score (RS) result. A model-based cost-effectiveness analysis compared the Oncotype DX test to clinical risk tools alone for HR+/HER2– node-positive (1–3 axillary lymph nodes) early breast cancer patients based on results from the RxPONDER trial. Materials and methods A decision-tree and Markov model was developed in Microsoft Excel. Distributions of patients and distant recurrence probabilities with endocrine and chemo-endocrine therapy were derived from the RxPONDER trial, TransATAC and SWOG-8814. Chemotherapy assignment data were obtained from the Clalit registry. The cost of adjuvant chemotherapy was based on the distribution of treatments used in the UK combined with published drug unit costs in the UK. The cost of distant recurrence and health state utility values were obtained from literature. Results The Oncotype DX test was found to be more effective (with an estimated 0.02 additional QALYs) at a lower estimated cost (–£989) compared to clinical risk tools alone. The results did not substantially change with more conservative clinical and cost scenarios. The RxPONDER trial was restricted to RS 0–25, and data synthesis with other studies was required to inform the analysis, which increased uncertainty. Conclusions The Oncotype DX test is highly likely to be cost-effective in node-positive early breast cancer. The results were driven by reduction in the use of chemotherapy with consequence avoidance of the costs and harmful effects of chemotherapy. Targeted treatment of a minority (11%) of women with RS 26–100 who benefit from chemotherapy reduced cost and improved survival.

Incidence and impact of brain metastasis in patients with hereditary BRCA1 or BRCA2 mutated invasive breast cancer

Patients with hereditary mutations in BRCA1 or BRCA2 (gBRCA1/2) and breast cancer have distinct tumor biology, and encompass a predilection for brain metastasis (BM). We looked into baseline risk of BMs among gBRCA1/2 patients. Patients with gBRCA1/2, stage I-III invasive breast cancer seen between 2000–2017 with parenchymal BMs. Among gBRCA1 with distant breast cancer recurrence, 34 of 76 (44.7%) were diagnosed with brain metastases compared to 7 of 42 (16.7%) patients with gBRCA2. In the comparator group, 65 of 182 (35.7%) noncarrier triple-negative breast cancer (TNBC) and a distant recurrence experienced BM’s. In a competitive risk analysis using death as a competing factor, the cumulative incidence of BMs was similar between gBRCA1 and noncarrier TNBC patients. The time from primary breast cancer diagnosis to detection of BMs was similar between gBRCA1 and noncarrier TNBC patients (2.4 vs 2.2 years). Survival was poor after BMs (7.8 months for gBRCA1 patients vs. 6.2 months for TNBC noncarriers). Brain was a more common site of initial distant recurrence in gBRCA1 patients versus TNBC noncarriers (26.3% vs. 12.1%). Importantly, the presence of BMs, adversely impacted overall survival across groups (HR 1.68 (95% CI 1.12–2.53), hazard ratio for death if a patient had BMs at the time of initial breast cancer recurrence vs. not). In conclusion, breast cancer BMs is common and is similarly frequent among gBRCA1 and noncarrier patients with recurrent TNBC. Our study highlights the importance of improving the prevention and treatment of BMs in patients with TNBC, gBRCA1 carriers, and noncarriers.

Incidence of brain metastases in patients with early HER2-positive breast cancer receiving neoadjuvant chemotherapy with trastuzumab and pertuzumab

The addition of pertuzumab (P) to trastuzumab (H) and neoadjuvant chemotherapy (NAC) has decreased the risk of distant recurrence in early stage HER2-positive breast cancer. The incidence of brain metastases (BM) in patients who achieved pathological complete response (pCR) versus those who do not is unknown. In this study, we sought the incidence of BM in patients receiving HP-containing NAC as well as survival outcome. We reviewed the medical records of 526 early stage HER2-positive patients treated with an HP-based regimen at Memorial Sloan Kettering Cancer Center (MSKCC), between September 1, 2013 to November 1, 2019. The primary endpoint was to estimate the cumulative incidence of BM in pCR versus non-pCR patients; secondary endpoints included disease free-survival (DFS) and overall survival (OS). After a median follow-up of 3.2 years, 7 out of 286 patients with pCR had a BM while 5 out of 240 non-pCR patients had a BM. The 3-year DFS was significantly higher in the pCR group compared to non-pCR group (95% vs 91 %, p = 0.03) and the same trend was observed for overall survival. In our cohort, despite the better survival outcomes of patients who achieved pCR, we did not observe appreciable differences in the incidence of BM by pCR/non-pCR status. This finding suggests that the BM incidence could not be associated with pCR. Future trials with new small molecules able to cross the blood brain barrier should use more specific biomarkers rather than pCR for patients’ selection.

Clinical Treatment Score post-5 years as a predictor of late distant recurrence in hormone receptor-positive breast cancer: systematic review and meta-analysis.

The Clinical Treatment Score post-5 years (CTS5) integrates four clinicopathological variables to estimate the residual disease recurrence risk in hormone receptor-positive breast cancer patients who have been treated with five years of adjuvant endocrine therapy. This study aimed to determine the accuracy of the CTS5. A systematic review was performed in accordance with the PRISMA statement. Studies relevant for inclusion in the current review were identified from The Cochrane Library, EBSCO, Ovid, PubMed, and Embase. Six papers reported on 30 354 postmenopausal patients (age range 42 to 91 years). The pooled hazard ratio (HR) of distant recurrence relative to the low-risk CTS5 category was 5.41 (95% c.i. 4.50 to 6.51; P < 0.05) for the high-risk CTS5 category and 2.32 (95% c.i. 1.90-2.84; P < 0.05) for the intermediate CTS5 category. Three papers reported on 10 425 premenopausal patients (age range 18 to 54 years). The pooled HR of distant recurrence relative to the low-risk CTS5 category was 5.42 (95% c.i. 2.26 to 13.01; P < 0.05) for the high-risk CTS5 category and 2.82 (95% c.i. 1.35 to 5.88; P < 0.05) for the intermediate CTS5 category. Relative to high-risk postmenopausal patients, the mean observed 10-year distant recurrence risk for the high CTS5 category was 13.83 per cent, which differs significantly from the CTS5 estimation of 10-year distant recurrence risk (20.3 per cent, 95% c.i. 17.2 to 24; P = 0.000). The CTS5 can predict late distant recurrence risk in pre- and postmenopausal hormone receptor-positive breast cancer patients. CTS5 overestimates the risk for high-risk patients and thus, its use in these patients warrants caution.