Primary Non-metastatic Breast Cancer Research Articles

Survival and toxicity after breast-conserving surgery and external beam reirradiation for localized ipsilateral breast tumour recurrence: A population-based study

Breast-conserving surgery followed by reirradiation for a localized ipsilateral breast tumour relapse may increase the radiation dose delivered to the heart and result in a greater risk of cardiac adverse events. This study aimed to compare the incidence of cardiac mortality in patients treated for a localized ipsilateral breast tumour relapse, either with breast-conserving surgery followed by reirradiation or with total mastectomy between 2000 and 2020. All patients treated for a primary non-metastatic breast cancer with breast-conserving surgery and adjuvant radiotherapy were identified in the Surveillance, Epidemiology, and End Results (SEER) program database, and those who subsequently experienced a localized ipsilateral breast tumour relapse treated with breast-conserving surgery and reirradiation ("BCS+ReRT" group, n=239) or with total mastectomy ("TM" group, n=3127) were included. The primary objective was to compare the cardiac mortality rate between the patients who underwent breast-conserving surgery followed by reirradiation and total mastectomy. Secondary endpoints were overall survival and cancer specific survival. Cardiac mortality was significantly higher in patients treated with breast-conserving surgery followed by reirradiation (hazard ratio [HR]: 2.40, 95% confidence interval [95% CI]: 1.19-4.86, P=0.006) in univariate analysis; non-statistically significant differences were observed after adjusting for age, laterality and chemotherapy on multivariate analysis (HR: 1.96, 95% CI: 0.96-3.94, P=0.067), age being the only confounding factor. A non-statistically significant difference towards lower overall survival was observed in patients who had breast-conserving surgery followed by reirradiation compared with those who underwent total mastectomy (HR: 1.37, 95% CI: 0.98-1.90, P=0.066), and no differences were observed in terms of cancer specific survival (HR: 1.01, 95% CI: 0.56-1.82, P=0.965). In this study, the incidence of cardiac mortality was low, and breast-conserving surgery followed by reirradiation did not independently increased the risk of cardiac mortality for a localized ipsilateral breast tumour relapse.

Abstract PO3-02-13: Breast Cancer in Very Young Adult Women At or Under the Age of 35 Years: Characteristics and Outcomes

Abstract Background: Breast cancer (BC) is the most common malignancy among women in Saudi Arabia. Noticeably, it shows a higher incidence in younger age groups than what is reported from Western countries. Age 35 years and less is an applied cut-off age for clinically defining BC in very young women (BCVY). This study describes characteristics, survival and risk of death associated factors in this rare subset of patients. Methods: A retrospective cohort study included females > 18 and < 35 years with histologically confirmed primary non-metastatic breast cancer from an academic hospital in Jeddah, Saudi Arabia between the years 2009-2019. Demographic data, tumor clinicopathological features, and outcomes were obtained. Survival and potential associated factors were examined. A p-value of less than 0.05 was regarded as statistically significant. Results: 204 female patients with a confirmed breast cancer diagnosis were included. The mean age at diagnosis was 31.43 ± 2.94 years. Fifty-three percent of the patients had a left-sided tumor with the majority being IDC (92%) and one-third with positive axillary lymph nodes (N+) and multifocal disease in 17%. One-quarter of the tumors showed LVI, 45% revealed associated DCIS and 26% showed tumor necrosis on histopathology examination. The presence of tumor-infiltrating lymphocytes (TILs) was reported in 23% of TNBC cases. Tubular differentiation score 3 was reported in 79.4%, nuclear pleomorphism score 3 in 79% and mitosis activity score 3 in 19% while the most reported overall grade was II in 48.5% followed by grade III in 34%. HER2-positive in 33.8 %, HR-positive in 34.3 %, TNBC in 24% and unknown in 8% of the patients. Thirty percent had a distant recurrence and 15% were deceased. The mean survival time was 4.61 years with a maximum of 6.54 years and a minimum of 3.67 years. Table 1 shows the multivariate logistic regression analysis of factors influencing the risk of death in very young patients with breast cancer. Conclusions: The current study describes the clinicopathological characteristic, survival and related factors of breast cancer in very young patients < 35 years, which is considered an uncommon presentation. Large, high-grade tumors and a high frequency of HER2 and TNBC were observed in BCVY patients. Involvement of the regional lymph nodes and the development of distant recurrence were associated significantly with an increased risk of death. The presence or absence of TILs, LVI and tumor necrosis on histopathological examination did not influence the risk of recurrence or death in this cohort. Table 1. The multivariate logistic regression analysis of factors influencing the risk of death in very young patients with breast cancer. Citation Format: Atlal Abusanad, Rana Ajabnoor, Aydah Al-Awadhi, Omalkhair Abualkhair. Breast Cancer in Very Young Adult Women At or Under the Age of 35 Years: Characteristics and Outcomes [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 PO3-02-13.

Post-mastectomy reirradiation for ipsilateral T3N0M0 breast tumor relapse: apopulation-based study.

Post-mastectomy radiotherapy is commonly recommended for T3N0M0 breast cancer, particularly in the presence of adverse prognostic factors. However, for T3N0M0 ipsilateral recurrences following breast-conserving surgery and adjuvant radiotherapy, the situation is distinct. Recurrence alone signifies anegative prognostic factor. Moreover, tumor relapses within previously irradiated areas exhibit enhanced radioresistance, and reirradiation of the chest wall carries an escalated risk of radiation-induced toxicity. This study aimed to assess the impact of post-mastectomy reirradiation (PM-reRT) on patient outcomes in cases of ipsilateral T3N0M0 breast tumor recurrence, using data from the SEER database. We identified all patients who underwent treatment for primary non-metastatic breast cancer with breast-conserving surgery followed by adjuvant radiotherapy in the SEER database; among them, those who later experienced alocalized T3N0M0 breast tumor recurrence and underwent total mastectomy were included. The study's goal was to compare overall survival (OS) and cancer-specific survival (CSS) between patients who underwent only mastectomy versus those who had mastectomy followed by adjuvant PM-reRT for their ipsilateral T3N0M0 breast tumor relapse. From 2000 to 2020, the SEER database recorded 44patients with an ipsilateral T3N0M0 breast tumor recurrence after initial conservative treatment, managed with total mastectomy. No statistically significant differences in OS or CSS were observed between patients undergoing mastectomy (MT) alone versus those receiving MT combined with PM-reRT (p = 0.68 and p = 0.86, respectively). Five-year OS rates for the MT and MT + PM-reRT cohorts were 49.5% [95% CI: 29.9-81.8] and 41.7% [10.0-100.0], respectively, while 5‑year CSS rates were 51.6% [12.0-99.5] and 58.3% [15.2-100.0], respectively. For patients undergoing total mastectomy after an ipsilateral T3N0M0 breast tumor recurrence, subsequent to initial breast cancer treatment involving breast-conserving surgery and adjuvant radiotherapy, chest wall reirradiation does not enhance survival outcomes. As such, it should not be routinely performed.

Long-Term Outcomes and Predictors of Response in Breast Cancer Patients with Advanced Nodal Involvement.

Advanced nodal disease is associated with poor prognosis. However, modern neoadjuvant systemic therapy (NST) regimens have resulted in higher pathologic complete response (pCR) rates, which are associated with improved survival. We sought to assess contemporary outcomes in patients with advanced nodal involvement and response to NST. We conducted a single-institution, retrospective study of 521 patients with cN2-3 primary nonmetastatic breast cancer treated with NST followed by surgery and radiation from 2012 to 2018. Descriptive statistics, multivariate Cox regression, and Kaplan-Meier analyses were performed. The mean age was 50.5 years, and median follow-up was 61 (4.7 to 197) months. The majority of patients had hormone receptor-positive (HR+)/HER2-negative tumors (HER2-; n = 242, 47.8%). Most were cT2 (n = 243; 46.6%) or cT3 (n = 139; 26.7%) and 73.3% (n = 382) had cN3 disease. Rate of axillary pCR was 34.2%, and breast and axillary pCR was 19.4% (n = 101). Event-free survival (EFS) at 5 years was 75.1% (95% CI, 0.71 to 0.79). Rate of locoregional recurrence was 6.7%; distant metastatic rate was 29.4%. Axillary pCR with or without breast pCR was significantly associated with longer EFS (p = 0.001). Achieving breast/axillary pCR was an independent predictor of improved EFS (hazard ratio 0.22, p < 0.0001). Having triple-negative disease was associated with worse EFS (hazard ratio 1.74, p = 0.008). In a high-risk cohort of patients with cN2-3 disease, trimodality therapy was effective in achieving durable EFS. Approximately one-third of patients achieved axillary pCR, which was associated with improved survival. Further studies are needed to accurately determine axillary response in cN2-3 breast cancer after NST in order to develop de-escalation strategies to reduce morbidity associated with axillary surgery.

Oncoplastic breast conserving surgery versus standard breast conserving surgery for early and locally advanced breast cancer: a retrospective analysis from Sri Lanka

BackgroundBreast aesthetics is becoming increasingly important in breast cancer surgery due to changes in patient expectations and greater emphasis been placed on the psychosocial outcomes. Studies have shown no difference in local recurrence risk between mastectomy and breast conserving surgery (BCS) and also a higher overall survival rate after BCS. Breast preservation improves the quality of life substantially compared to mastectomy. Oncoplastic breast-conserving surgery (O-BCS) involves tumour excision whilst overcoming the limitations of standard breast conserving surgery (S-BCS) by allowing larger resection volumes, avoiding deformities with better aesthetic results. Our study aims to compare the oncosurgical and aesthetic outcomes of O-BCS versus S-BCS among women in Sri Lanka.MethodsWe conducted a retrospective study over a 4-year period including patients who underwent breast conservation surgery for primary non-metastatic breast cancer in two tertiary care units. We assessed outcomes in terms of re-excision rates, resection margin, complications and aesthetic outcomes using a Likert scale questionnaire to grade specific outcomes such as symmetry, volume, nipple position, scar visibility. Non-parametric tests were used for statistical analyses.ResultsFifty-four and seventy-three patients underwent S-BCS and O-BCS respectively. The median specimen volume and the maximum tumour diameter were significantly higher in O-BCS [160(range:65–220); 4.2(range: 1.2–5.2)] compared to S-BCS [65(range:45–86); 2.4(range: 1.0-2.6)]. The median closest tumour margin was 16 mm (range:4-25 mm) in O-BCS while 6 mm (range:<1 – 12 mm) in S-BCS (p = 0.01). Close (< 1 mm) and positive margins needing re-excision were seen mostly in S-BCS. Superior aesthetic outcomes with statistical significant difference were reported in the O-BCS compared to S-BCS group with better symmetry, volume, nipple position and scar visibility. The re-excision rates were significantly lower in O-BCS group. There was no significant difference in the operative time and complications while the aesthetic outcomes were significantly superior in OBCS.ConclusionsOverall, Level 2 perforator flap based reconstruction had superior aesthetic outcomes. O-BCS is safe and more aesthetically acceptable with no difference in oncological outcome and operative time. More consideration should be given to aesthetic parameters such as scar visibility, nipple position, breast volume and shape when considering the best surgical option for the patients.

Reirradiation with Photon Radiotherapy for Recurrent or New Primary Breast Cancer after Prior Breast Irradiation

<h3>Purpose/Objective(s)</h3> Recurrent or new primary breast cancer may benefit from the local and/or regional recurrence risk reduction provided by RT, but delivery of a repeat course of RT is challenging due to risks of potential serious toxicities to organs at risk. This has led to limited use and heterogeneous practice patterns of salvage RT delivery. We hypothesize that breast cancer reirradiation (reRT) may be feasible using modern photon treatment techniques, and we present clinical outcomes and toxicities from a large single institution cohort. <h3>Materials/Methods</h3> In an IRB-approved retrospective study, all consecutive patients with recurrent or new primary non-metastatic breast cancer treated with breast or chest wall (CW) RT and photon reRT from a single institution were identified. Patient and tumor characteristics, treatment parameters, clinical outcomes and toxicities were collected. Recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS) were defined from reRT start to date of any recurrence, distant recurrence, and death or last follow-up and estimated using Kaplan-Meier methodology. <h3>Results</h3> In total, 126 consecutive patients treated with reRT from 2013-2020 met criteria for analysis. Median age at reRT was 65 years (range 39-88). ReRT was delivered with 3DCRT in 47.6%, VMAT in 46.0%, and static IMRT in 6.4%. Median first, second, and cumulative prescription doses were 60.0 Gy, 46.4 Gy, and 105.0 Gy, respectively. Most received whole breast (WB) (80.2%) or partial breast (PB) (8.7%) initial RT. At reRT, 30.9% were treated to the PB, 11.1% WB/CW, 37.3% WB/CW with comprehensive regional lymph nodes (LN), and 12.8% WB/CW with partial regional LN. Median time between RT courses was 95 months (range 10-361). At a median follow-up of 26.5 months, 9 patients had died. Locoregional, distant, and any recurrence developed in 15 (11.9%), 22 (17.5%), and 28 (22.2%) patients, respectively. Estimated 3-year RFS was 80.7%, DMFS was 80.9%, and OS was 93.2%. Eleven (8.7%) patients developed grade 3 (G3) toxicities (dermatitis (n=8), acute (n=1) and late (n=1) CW pain, decreased joint range of motion (ROM) (n=1)); no G4 or G5 toxicities occurred. Five (4.0%) patients developed rib fracture. Of 23 patients retreated to a reconstructed CW, 30.4% and 34.8% developed Baker G1-2 or G3-4 implant contracture, respectively. Four patients had significant brachial plexus overlap, of whom 1 developed G2 decreased joint ROM and G2 soft tissue fibrosis and 1 developed G3 decreased joint ROM. <h3>Conclusion</h3> In the largest institutional experience to date on the use of photon reRT for recurrent or new primary breast cancer, reRT is associated with low rates of severe adverse events. In this high-risk population, locoregional and distant disease control rates are high. Further prospective study is needed to define the optimal treatment volume, prescription dose selection, and cumulative dose constraints with reRT to maximize the likelihood for successful and safe salvage therapy.

Is there a role for the oncotype DX breast recurrence score genomic assay in estrogen receptor-low positive breast cancer?

564 Background: The Oncotype DX Breast Recurrence Score assay is widely used in estrogen receptor (ER)-positive breast cancer patients to help determine the potential benefit of chemotherapy. However, little is known about the value of the test in breast cancer patients who have ER-low positive (1-10%) cancers. The purpose of this study was to determine the potential utility of the Oncotype test for these patients by describing the range of Recurrence Score (RS) results and patient outcomes. Methods: Patients treated between 8/2011-8/2020 for primary non-metastatic breast cancer that was ER-low positive (10%) and HER2-negative in whom tissue from their surgical excision specimen was available to perform the Oncotype DX assay were identified. Clinicopathologic characteristics were abstracted from patient charts, and the RS result was determined. Results: 38 women with ER-low positive breast cancer and available tissue were identified. The median age was 56.5 (range 36-94); 34 patients were Caucasian, 2 Black, 1 Asian and 1 Hispanic. Thirty-seven patients underwent surgery as their initial intervention and 1 received neoadjuvant chemotherapy. The final pathologic anatomic stage was IA in 26 (68.4%), IB in 10 (26.3%) and IIA in 2 (5.3%); the pathologic nodal status was pN0 in 24 (63.2%), pN0i+ in 3 (7.9%), pN1mi in 1 (2.6%), pN1 in 6 (15.8%) and pNx in 4 (10.5%). The average and median RS was 49 with a range of 23-72; only 2 patients had a RS 25. One patient with RS = 24 was a 64yo with pT1cN0 disease who received chemotherapy + endocrine therapy therefore could potentially have been spared chemotherapy based on the RS result and the TAILORx trial data. Six patients had previously had a RS determined on their diagnostic core biopsy (RS = 46, 58, 45, 47, 51 and 52); the RS on their surgical specimen was concordant (RS = 45, 54, 47, 48, 47, and 50). The ER status as determined by the Oncotype DX assay was positive for 8 (21%) patients. Adjuvant therapy included: chemotherapy and endocrine therapy in 13 (34.2%), chemotherapy alone in 13 (34.2%) and endocrine therapy alone in 4 (10.5%). 8 (21.1%) received no adjuvant therapy. After a median follow-up of 40 months (range 3-106), 3 patients have experienced a recurrence; all 3 had received chemotherapy. The 3-year recurrence free survival rate was 97.0% (95% CI: 96.9-97.1%). All 3 of these patients had a local recurrence; 2 also had a distant recurrence which they ultimately succumbed to. The 3-year disease-specific survival rate was also 97.0% (95% CI: 96.9-97.1%). Conclusions: The majority of the patients with low ER+/HER2- breast cancer had RS &gt; 25 suggesting these tumors are high-risk, more similar to ER- disease. The RS result is of limited utility in ER-low positive patients, as these data indicate that most would benefit from chemotherapy.

The impact of young age (

BackgroundThe role of young age (< 40 years) at diagnosis as an independent risk factor for adverse outcomes in female patients with breast cancer has been highlighted in several studies. In this prospective study, we assessed the difference in 10-year survival between two groups of patients diagnosed with non-metastatic breast cancer based on an age cutoff of 40 years. We also assessed the impact of factors including tumor characteristics, molecular markers and immunohistochemical markers on survival outcomes, highlighting the interaction of those variables with age.MethodsA total of 119 female patients with newly diagnosed non-metastatic breast cancer were recruited at the American University of Beirut Medical Center (AUBMC) between July 2011 and May 2014. Patients were recruited and divided into 2 age groups (< 40 and ≥ 40 years). In addition to clinical characteristics, we assessed immunohistochemistry including estrogen, progesterone and HER2 receptors, p53, cyclin B1, vascular endothelial growth factor receptor (VEGFR), and ki-67. Germline BRCA mutations were also performed on peripheral blood samples. Patient and tumor characteristics were compared between the age groups. 10-year overall survival (OS) and disease-free survival (DFS) were estimated accordingly. Cox regression analysis was performed in order to assess the effect of the different variables on clinical outcomes.ResultsAfter a median Follow-up of 96 (13–122) months, the estimated 10-year OS was 98.6% for patients ≥40 as compared to 77.6% in patients < 40 (p = 0.001). A similar trend was found for 10-year DFS reaching 90% for patients ≥40 and 70.4% for those < 40 (p = 0.004). On multivariate analysis for DFS and OS, only younger age (< 40 years), higher stage and triple negative phenotype among other parameters assessed significantly affected the outcome in this cohort.ConclusionThis prospective study confirms the association between younger age and adverse survival outcomes in patients with non-metastatic breast cancer. Future studies of the whole genome sequences may reveal the genomic basis underlying the clinical differences we have observed.

Transcription phenotype of circulating tumor cells in non-metastatic breast cancer

The objective of the study was to evaluate the clinical significance of circulating tumor cells (CTCs) and their transcriptional phenotype in relation to overall and progression-free survival in patients with non-metastatic breast cancer. The presence of CTCs was studied before the start of special antitumor treatment and after its completion in 102 patients with primary non-metastatic breast cancer (BC) stage I–IIIC. The statistically significant increase in PFS in the group of patients without CTCs before the start of the treatment was established in 89.2 (87.9–92.4 confidence interval (CI) 95%) versus 79.9 (77.6–82.2 CI 95%) in the group with CTCs before treatment at p Log-Rank=0.01. The presence of CTCs expressing ABC transporter superfamily genes in the peripheral blood statistically significantly reduces the values of overall survival (OS) and progression-free survival (PFS). Three-year OS was 79.2 (77.1–82.3 CI 95%), and 90.8 (87.4–91.9 CI 95%) without the expression with p Log-Rank=0.04. The presence of circulating tumor cells expressing BIRC5 and HER2-neu genes, and ABC transporter genes, before the initiation of special treatment and the preservation of CTCs after the completion of adjuvant anticancer therapy are independent risk predictors of disease recurrence.

Proton Reirradiation for Recurrent or New Primary Breast Cancer in the Setting of Prior Breast Irradiation

Local breast cancer recurrences and new primary breast cancers are an increasingly common clinical challenge without clear treatment guidelines. To date, photon reirradiation (reRT) has not been widely adopted due to concerns for toxicities. Proton beam therapy (PBT) can optimize normal tissue sparing and may allow for safer delivery of a second definitive radiotherapy (RT) course. We hypothesize salvage PBT reRT can be safely delivered, and we present clinical outcomes and toxicities of patients with recurrent or new primary non-metastatic breast cancer who received prior RT and PBT reRT.In an IRB-approved retrospective study, all consecutive patients with recurrent or new primary non-metastatic breast cancer treated with breast or chest wall (CW) RT and PBT reRT from a single institution were identified. Patient and tumor characteristics, treatment parameters, clinical outcomes and toxicities were collected. Distant metastasis-free survival (DMFS) and overall survival (OS) were defined from PBT reRT start to date of distant recurrence, death or last follow-up and estimated using Kaplan-Meier methodology.Forty-six consecutive patients were assessed. Eight patients (17.4%) were reirradiated to an intact breast, 13 (28.3%) to CW without reconstruction, 20 (43.5%) to CW with reconstruction, and 5 (10.9%) to regional lymph nodes (LN) alone. PBT reRT was delivered with uniform (70%) or pencil beam (30%) scanning PBT. Median first course dose was 60Gy (45-66Gy); median PBT reRT dose was 50.4Gy (RBE) (40-66.6Gy); median cumulative dose was 108.9Gy2, a/b = 3(RBE) (95.0-168.8 Gy2, a/b = 3 (RBE)). When regional LN were retreated, median first course dose was 50.4 Gy (48.6-66.6Gy) and median PBT reRT dose was 50 Gy2, a/b = 3 (46.7-66.0Gy2, a/b = 3). Four patients had significant brachial plexus overlap with cumulative doses up to 99.0 Gy. At a median follow-up of 21 months, there were no local or regional recurrences; 8 patients (17%) developed distant recurrence, of whom three died. Estimated 3-year DMFS and OS were 60% and 88%, respectively. Grade 3 acute toxicities were limited exclusively to RT dermatitis (30.4%). Grade 3 late toxicities occurred in 4 patients (8.7%) (3 capsular contracture requiring surgical intervention, 1 breast pain requiring mastectomy). Two patients developed rib fracture. No cases of neuropathies, skin ulceration or other acute or late grade ≥3 toxicities occurred.In the largest series to date of PBT reRT for breast cancer recurrence or new primary after prior definitive breast or CW RT, PBT reRT provided excellent locoregional control with a low rate of high-grade toxicities limited to target tissue not amenable to sparing from full reRT dose. These data are encouraging and suggest PBT reRT may provide patients with a relatively safe and highly effective salvage option. Longer follow-up and additional patients are needed to correlate composite normal tissue doses with toxicities and assess long-term outcomes.

Proton reirradiation for recurrent or new primary breast cancer in the setting of prior breast irradiation

Background and purposeLate local recurrences and second primary breast cancers are increasingly common. Proton beam therapy (PBT) reirradiation (reRT) may allow safer delivery of a second definitive radiotherapy (RT) course. We analyzed outcomes of patients with recurrent or new primary breast cancer who underwent reRT. Materials and methodsIn an IRB-approved retrospective study, patient/tumor characteristics, treatment parameters, outcomes, and toxicities were collected for all consecutive patients with recurrent or new primary non-metastatic breast cancer previously treated with breast or chest wall RT who underwent PBT reRT. ResultsForty-six patients received reRT using uniform (70%) or pencil beam (30%) scanning PBT. Median first RT, reRT, and cumulative doses were 60 Gy (range 45–66 Gy), 50.4 Gy(RBE) (40–66.6 Gy(RBE)), and 110 Gy(RBE) (96.6–169.4 Gy(RBE)), respectively. Median follow-up was 21 months. There were no local or regional recurrences; 17% developed distant recurrence. Two-year DMFS and OS were 92.0% and 93.6%, respectively. Nine of 13 (69.2%) patients who underwent implant or flap reconstruction developed capsular contracture, 3 (23.1%) requiring surgical intervention. One (7.7%) patient developed grade 3 breast pain requiring mastectomy after breast conserving surgery. No acute or late grade 4–5 toxicities were seen. Increased body mass index (BMI) was protective of grade ≥ 2 acute toxicity (OR = 0.84, 95%CI = 0.70–1.00). ConclusionIn the largest series to date of PBT reRT for breast cancer recurrence or new primary after prior definitive breast or chest wall RT, excellent locoregional control and few high-grade toxicities were encountered. PBT reRT may provide a relatively safe and highly effective salvage option. Additional patients and follow-up are needed to correlate composite normal tissue doses with toxicities and assess long-term outcomes.

Influence of adjuvant radiotherapy on circulating epithelial tumor cells and circulating cancer stem cells in primary non-metastatic breast cancer

Background: There is an unmet need to identify biomarkers that directly reflect response to adjuvant radiotherapy (RT). Circulating epithelial tumor cells (CETCs) represent the liquid component of solid tumors and are responsible for metastatic relapse. CETC subsets with cancer stem cell characteristics, circulating cancer stem cells (cCSCs), play a pivotal role in the metastatic cascade. Monitoring the most aggressive subpopulation of CETCs could reflect the aggressiveness of the remaining tumor burden. There is limited data on the detection and monitoring changes in CETC and cCSC numbers during RT in early breast cancer. Methods: CETC numbers were analyzed prior to, at midterm and at the end of RT in 52 primary non-metastatic breast cancer patients. Hormone receptor status was determined in CETCs prior to and at the end of RT. For the identification of cCSCs cell suspensions from the peripheral blood of patients were cultured in vitro under conditions favoring growth of tumorspheres. Results: Hormone receptor status in CETCs before RT was comparable to that in primary tumor tissue. Prior to RT numbers of CETCs correlated with aggressiveness of primary tumors. cCSCs could be successfully identified and monitored during RT. Prior to RT patients treated with neoadjuvant chemotherapy had significantly higher numbers of CETCs and tumorspheres compared to patients after adjuvant chemotherapy. During RT, the number of CETCs decreased continuously in patients after neoadjuvant chemotherapy but not after adjuvant chemotherapy. Conclusion: Monitoring the number of CETCs and the CETC subset with cancer stem cell properties during RT may provide additional clinically useful prognostic information.

Neo-Bioscore in Guiding Post-surgical Therapy in Patients With Triple-negative Breast Cancer Who Received Neoadjuvant Chemotherapy.

Patients with triple-negative breast cancer (TNBC) who have not achieved pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) were considered for adjuvant capecitabine. This study was to explore the utility of the Neo-Bioscore in guiding post-surgical therapy in TNBC. The Neo-Bioscore was calculated for patients with non-metastatic primary breast cancer who received NAC at National Cancer Center Hospital East, Japan. A total of 329 patients were evaluated. The Neo-Bioscore stratified prognosis after NAC better than clinical or pathological stage. The Neo-Bioscore performed well in the selection of patients with TNBC with excellent prognoses despite non-pCR; no death was observed in patients who had a Neo-Bioscore of 2, the lowest score in those with TNBC. The Neo-Bioscore can improve the prognostic stratification of patients after NAC for breast cancer over clinical and pathological staging and may enable the identification of patients with non-pCR TNBC who can avoid additional adjuvant chemotherapy.

Machine learning to predict the cancer-specific mortality of patients with primary non-metastatic invasive breast cancer.

We used five machine-learning algorithms to predict cancer-specific mortality after surgical resection of primary non-metastatic invasive breast cancer. This study was a secondary analysis of data for 1661 women with primary non-metastatic invasive breast cancer. The overall patient population was divided into a training group and a test group at a ratio of 8:2 and python was used for machine learning to establish the prognosis model. The machine-learning Gbdt algorithm for cancer-specific death caused by various factors showed the five most important factors, ranked from high to low as follows: the number of regional lymph node metastases, LDH, triglyceride, plasma fibrinogen, and cholesterol. Among the five algorithm models in the test group, the highest accuracy rate was by DecisionTree (0.841), followed by the gbm algorithm (0.838). Among the five algorithms, the AUC values from high to low were GradientBoosting (0.755), gbm (0.755), Logistic (0.733), Forest (0.715), and DecisionTree (0.677). Machine learning can predict cancer-specific mortality after surgery for patients with primary non-metastatic invasive breast.

Impact of patients' refusal to undergo adjuvant treatment measures on survival.

Breast cancer patients receive treatment recommendations from multidisciplinary tumour boards. To determine the consequences of patients' refusal of such recommendations, we analysed the database of the Centre for Breast Cancer at the Ortenau Clinic in Offenburg, Germany. A total of 4315 patients with non-metastatic primary breast cancer, treated between 1997 and 2019, were analysed with descriptive analyses, Kaplan-Meier survival analyses, and Cox regression analyses regarding the effects of their refusal. About 10.7% of the patients rejected the treatment advice. These were significantly elderly (F = 74.4; p < 0.001; one-way ANOVA), with greater tumour size (F = 36.7; p < 0.001; one-way ANOVA), a higher number of affected lymph nodes (F = 4.2; p = .039; one-way ANOVA), and more poorly differentiated tumours (χ2 = 16.8; df = 2; p < 0.001). The refusal of adjuvant treatment resulted in higher rates of local recurrences (χ2radiotherapy = 109.1; df = 1; p < 0.001, χ2chemotherapy = 18.3; df = 1; p < 0.001, χ2endocrine = 32.5; df = 1; p < 0.001) and poorer overall survival (χ2radiotherapy = 184.9; df = 6; p < 0.001; χ2chemotherapy = 191.8; df = 6; p < 0.001). All parts of the adjuvant treatment of breast cancer are clearly associated with improvements regarding disease-free and overall survival. To answer open questions about the background of patients' refusal, an analysis of prospective data collections seems necessary. In addition, patient communication should be improved so that patients understand the background of the multidisciplinary tumour board and the potential consequences of their refusal.

Abstract IA06: The tissue-specific microenvironment in primary tumors and metastases

Abstract Cancer cells within tumors exist in specialized niches in the microenvironment. The tumor cells are heterogeneous and can have properties as divergent as self-renewal, tumor initiation and repopulation potential, dormancy, evasion of cell death, and metastasis. Metastasis is the major cause of poor outcome in breast cancer. The microenvironment is critical for regulating multiple aspects of tumor progression and metastasis. Understanding the processes involved in metastasis is critical for developing new preventative and therapeutic strategies. We have analyzed the matrix environment and its function in tumor progression using in vivo imaging, genetic models of breast cancer, patient-derived xenografts, organotypic cultures, and patient samples. We have found that the matrix environment and the innate immune cells responding to the primary tumor and infiltrating the metastatic sites are critical for regulating tumor invasion and metastasis. Indeed, the inflammatory microenvironment of metastatic sites was distinct from that of the parental tumor and the normal tissue, even before metastasis takes hold. Interplay between nonmetastatic primary breast cancer and innate immune response acts to control metastatic progression. At the single-cell level, early-stage metastatic cells possess a distinct stemlike gene expression signature. The metastatic cells and the microenvironment are distinct in different metastatic sites and from the primary tumor. Micrometastatic cells are distinct due to their increased expression of basal, stem cell, prosurvival, and dormancy-associated genes. In contrast, cells from macrometastases are similar to primary tumor cells, which are more differentiated and heterogeneous. We validated our findings with a large primary breast cancer tissue microarray and pleural effusions from breast cancer patients. These results suggest that novel cancer immunotherapies that activate and augment the function of antitumoral myeloid subpopulations could have therapeutic potential and be clinically important for patients with advanced breast cancer. Citation Format: Zena Werb, Hugo Gonzalez, Juliane Winkler, Eric Berens. The tissue-specific microenvironment in primary tumors and metastases [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA06.

Young Women With Breast Cancer in Mexico: Results of the Pilot Phase of the Joven & Fuerte Prospective Cohort.

PURPOSEThe pilot-phase report of the Joven & Fuerte prospective cohort broadly characterizes and assesses the needs of Mexican young women with breast cancer (YWBC).PATIENTS AND METHODSWomen age ≤ 40 years with nonmetastatic primary breast cancer were consecutively accrued from 2 hospitals. Data were collected at the first/baseline oncology visit and 2 years later using a sociodemographic survey, European Organisation for Research and Treatment of Cancer Quality-of-Life (QOL) Questionnaire Core 30 (QLQ-C30) and Breast Cancer–Specific QOL Questionnaire (QLQ-BR23), Hospital Anxiety and Depression Scale (HADS), Female Sexual Functioning Index (FSFI), Sexual Satisfaction Inventory, and patients’ medical records. Pearson χ2 and 2-sided t tests were used for statistical analysis. An unadjusted P value < .05 was considered significant.RESULTSNinety patients were included, all with government health care coverage. Most had low monthly household incomes (98%) and at least a high school education (59%). There was a considerable prevalence of unpartnered patients (36%) and unmet parity (25%). Patients’ most common initial symptom was a palpable mass (84%), and they were most frequently diagnosed with stage III disease (48%), with 51% having had a physician visit ≤ 3 months since detection but 39% receiving diagnosis > 12 months later. At baseline, 66% of patients were overweight/obese, and this proportion had significantly increased by 2 years (P < .001). Compared with baseline, global QLQ-C30 had improved significantly by 2 years (P = .004), as had HADS-Anxiety (P < .001). However, both at baseline and at 2 years, nearly half of patients exhibited FSFI sexual dysfunction.CONCLUSIONThese preliminary findings demonstrate that YWBC in Mexico have particular sociodemographic and clinicopathologic characteristics, reinforcing the necessity to further describe and explore the needs of these young patients, because they may better represent the understudied and economically vulnerable population of YWBC in limited-resource settings.

Immune effector monocyte–neutrophil cooperation induced by the primary tumor prevents metastatic progression of breast cancer

Metastatic behavior varies significantly among breast cancers. Mechanisms explaining why the majority of breast cancer patients never develop metastatic outgrowth are largely lacking but could underlie the development of novel immunotherapeutic target molecules. Here we show interplay between nonmetastatic primary breast cancer and innate immune response, acting together to control metastatic progression. The primary tumor systemically recruits IFNγ-producing immune effector monocytes to the lung. IFNγ up-regulates Tmem173/STING in neutrophils and enhances their killing capacity. The immune effector monocytes and tumoricidal neutrophils target disseminated tumor cells in the lungs, preventing metastatic outgrowth. Importantly, our findings could underlie the development of immunotherapeutic target molecules that augment the function of immune effector monocytes and neutrophils.

Analysis of Circulating Epithelial Tumor Cells in Peripheral Blood in Patients With Primary Non-metastatic Breast Cancer Under Adjuvant Radiotherapy

Analysis of Circulating Epithelial Tumor Cells in Peripheral Blood in Patients With Primary Non-metastatic Breast Cancer Under Adjuvant Radiotherapy

Upregulation of programmed death ligand 1 (PD-L1) on circulating epithelial tumor cells (CETCs) as consequence of adjuvant radiation therapy in primary breast cancer patients.

3 Background: Radiation therapy (RT) is an integral part of the treatment of breast carcinoma but unfortunately many patients experience local recurrence. During the inflammatory response that accompanies radiation tumor cells may develop multiple resistance mechanisms for example the up-regulation of PD-L1 on tumor cells which leads to immune evasion. Since CETCs arise from the tumor it is conceivable that under evolutionary pressure they might share some of the immune escape mechanism inherent to tumor cells. In this study we demonstrate that RT leads to a transitory adaptive up-regulation of PD-L1 expression on CETCs. Methods: CETCs and the expression of PD-L1 and Ki-67 were analyzed from 25 patients with primary non-metastatic breast cancer using the maintrac method. The fraction of PD-L1 and Ki-67 positive CETCs were assessed at baseline, 3 and 6 weeks after start of RT and 6 weeks after end of therapy. Additionally, copy number status of PD-L1 was determined using FISH. Results: Fractionated-dose RT leads to a significant increase in PD-L1 expression on CETCs with the highest expression level midterm of irradiation as compared to baseline (49% vs. 74%, p &lt; 0.01). 6 weeks after end of RT the number of PD-L1 positive CETCs returned to baseline value. The up-regulation of PD-L1 was dose dependent. Patients who received higher total dose had significantly more PD-L1 positive CETCs as compared to patients treated with lower total dose midterm of RT (64% vs. 43, p &lt; 0.05). Before start of therapy there was a correlation between the fraction of PD-L1 and Ki-67 positive CETCs (r = 0.6, p &lt; 0.01). PD-L1 copy number gains were significantly associated with PD-L1 expression (r = 0.6, P &lt; 0.05). Conclusions: RT leads to an up-regulation of PD-L1 expression on CETCs, which could be a possible mechanism of acquired radioresistance. Combining immunomodulatory agents with radiation might have the potential to overcome this resistance and could improve clinical outcome in breast cancer.