Metachronous Contralateral Breast Cancer Research Articles

TP53-associated early breast cancer: new observations from a large cohort.

A large well-annotated recent international cohort of Li-Fraumeni (LFS) patients with early-stage breast cancer (BC) was examined for shared features. This multicentre cohort study included females with a germline TP53 pathogenic or likely pathogenic variant and nonmetastatic BC diagnosed between 2002-2022. Clinical and genetic data were obtained from institutional registries and clinical charts. Descriptive statistics were utilized to summarize proportions and differences were assessed by Chi square or Wilcoxon rank sum tests. Metachronous contralateral breast cancer (CBC) risk, radiation-induced sarcoma risk, and recurrence-free survival (RFS) were analyzed by Kaplan-Meier methodology. Among 227 females who met study criteria, the median age of first BC diagnosis was 37 years (range 21-71), 11.9% presented with bilateral synchronous BC and 18.1% had ductal carcinoma in situ (DCIS) only. In total, 166 (73.1%) underwent mastectomies including 67 bilateral mastectomies as first BC surgery. Among those with retained breast tissue, CBC rate was 25.3% at 5-years. Among 186 invasive tumors, 72.1% were stages I-II, 48.9% node-negative, and the most common subtypes were HR+/HER2- (40.9%) and HR+/HER2 + (34.4%). At a median follow-up of 69.9 months (IQR 32.6-125.9), invasive HR+/HER2- disease had the highest recurrence risk among the subtypes (5-year RFS 61.1%, p = .0012). Among those who received radiation therapy (n = 79), the 5-year radiation-induced sarcoma rate was 4.8%. We observed high rates of DCIS, HR+ and HER2+ breast cancers, with a worse outcome in the HR+/HER2- luminal tumors despite appropriate treatment. Confirmation of these findings in further studies could have implications for BC care in LFS.

The Relationship Between Breast Density and Breast Cancer Surgical Outcomes: A Systematic Review.

This study aims to investigate the relationship between mammographic breast density and the surgical outcomes of breast cancer. PubMed, SCOPUS, Web of Science, Science Direct, and the Wiley Library were systematically searched for relevant literature. Rayyan QRCI was employed throughout this comprehensive process. Our results included ten studies with a total of 5017 women diagnosed with breast cancer. The follow-up duration ranged from 1 year to 15.1 years. Eight out of the twelve included studies reported that low mammographic breast density was significantly associated with no local recurrence, metachronous contralateral breast cancer, and fewer challenges in the preoperative and intraoperative phases. On the other hand, four studies reported that mammographic breast density is not linked to disease recurrence, survival, re-excision, or an incomplete clinical and pathological response. There is a significant association between low mammographic breast density and reduced challenges in the preoperative and intraoperative phases, as well as no local recurrence and fewer mastectomy cases. However, the link between mammographic breast density and disease recurrence, survival, re-excision, and incomplete clinical and pathological response is less clear, with some studies reporting no significant association. The findings suggest that mammographic breast density may play a role in certain aspects of breast cancer outcomes, but further research is needed to fully understand its impact.

Omission of axillary lymph node dissection in breast cancer patients with micrometastasis or isolated tumor cells in sentinel lymph nodes: a 12-year experience in a tertiary breast unit.

After the IBCSG 23-01 trial, our breast center no longer performed axillary lymph node dissection (ALND) after detection of isolated tumor cells (ITC) or micrometastasis in the sentinel lymph nodes (SLN). A recent study suggested that up to half of the patients with micrometastasis in the SLN could benefit from ALND in terms of disease-free survival (DFS) and overall survival (OS). This retrospective, unicentric, study analyzed 261 consecutive cT1-3 cN0 breast cancer patients with ITC or micrometastasis in their SLN. Primary objective was comparison of ALND vs. SLN biopsy (SLNB) with regard to DFS and OS. Secondary objectives included analysis of factors associated with an increased rate of locoregional recurrence (LRR), distant metastasis (DM) and metachronous contralateral breast cancer (MCBC). DFS events occurred in 19 patients (7.3%) and 14 patients died (5.4%). Median follow-up time was 78months. 251 patients (96.2%) had micrometastasis in their SLN. There was no difference in the OS or DFS of ALND vs. SLNB patients. History of previous contralateral breast cancer and WBI were associated with an increased and decreased rate of LRR, respectively. Larger tumor size was associated with an increased rate of DM. Non-ductal histological types were associated with an increased rate of MCBC. Avoiding ALND may be safe in pN1mi/pN0(i+) patients. Besides, we strongly encourage clinicians to develop their own follow-up protocols based on the best available evidence, to rapidly identify and treat breast cancer recurrence.

Breast Magnetic Resonance Imaging for Preoperative Evaluation of Breast Cancer: A Systematic Review and Meta-Analysis.

Purpose: Preoperative breast magnetic resonance imaging (MRI) is known to detect additional cancers that are occult on mammography and ultrasound. There is debate as to whether these additional lesions affect clinical outcomes. The objective of this systematic review was to summarize the evidence on whether additional information on disease extent obtained with preoperative breast MRI in patients with newly diagnosed breast cancer affects surgical management, rates of recurrence, survival, re-excision, and early detection of bilateral cancer. Methods: Embase, MEDLINE, and Cochrane Central Register of Controlled Trials were searched until January 2021 (partial update July 2022) for studies comparing outcomes with versus without pre-operative MRI. Included were both randomized controlled trials and other comparative studies provided MRI and control groups had equivalent disease and patient characteristics or methods such as multivariable analysis or propensity score matching were used to control potential confounders. Results: The search resulted in 26,399 citations, of which 8 randomized control trials, 1 prospective cohort study, and 42 retrospective studies met the inclusion criteria. Use of MRI resulted in decreased rates of reoperations (OR = 0.73, 95% CI = 0.63 to 0.85), re-excisions (OR = 0.63, 95% CI = 0.45 to 0.89), and recurrence (HR = 0.77, 95% CI = 0.65 to 0.90). Increased detection of synchronous contralateral breast cancers led to a reduction in metachronous contralateral breast cancer (HR = 0.71, 95% CI = 0.59 to 0.85). Hazard ratios for recurrence-free and overall survival were 0.77 (95% CI = 0.53 to 1.12) and 0.89 (95% CI = 0.74 to 1.07). Conclusion: This systematic review indicates substantial benefits of pre-operative breast MRI in decreasing reoperations and recurrence.

Risk of metachronous contralateral breast cancer in patients with primary invasive lobular breast cancer: Results from a nationwide cohort.

Lobular primary breast cancer (PBC) histology has been proposed as a risk factor for contralateral breast cancer (CBC), but results have been inconsistent. We investigated CBC risk and the impact of systemic therapy in lobular versus ductal PBC. Further, CBC characteristics following these histologic subtypes were explored. We selected 74,373 women diagnosed between 2003 and 2010 with stage I-III invasive PBC from the nationwide Netherlands Cancer Registry. We assessed absolute risk of CBC taking into account competing risks among those with lobular (n= 8903), lobular mixed with other types (n= 3512), versus ductal (n= 62,230) histology. Hazard ratios (HR) for CBC were estimated in a cause-specific Cox model, adjusting for age at PBC diagnosis, radiotherapy, chemotherapy and/or endocrine therapy. Multivariable HRs for CBC were 1.18 (95% CI: 1.04-1.33) for lobular and 1.37 (95% CI: 1.16-1.63) for lobular mixed versus ductal PBC. Ten-year cumulative CBC incidences in patients with lobular, lobular mixed versus ductal PBC were 3.2%, 3.6% versus 2.8% when treated with systemic therapy and 6.6%, 7.7% versus 5.6% in patients without systemic therapy, respectively. Metachronous CBCs were diagnosed in a less favourable stage in 19%, 26% and 23% and less favourable differentiation grade in 22%, 33% and 27% than the PBCs of patients with lobular, lobular mixed and ductal PBC, respectively. In conclusion, lobular and lobular mixed PBC histology are associated with modestly increased CBC risk. Personalised CBC risk assessment needs to consider PBC histology, including systemic treatment administration. The impact on prognosis of CBCs with unfavourable characteristics warrants further evaluation.

Long-term oncological outcomes of oncoplastic breast-conserving surgery after a 10-year follow-up - a single center experience and systematic literature review.

AimWhile many studies reported the oncological outcomes of oncoplastic breast-conserving surgery (OBCS), there were inherent differences in the study population, surgeons’ expertise, and classifications of techniques used. There were also limited studies with long term follow up oncological outcomes beyond 5 years. This current study aimed to compare long-term oncological outcomes of ipsilateral breast tumor recurrence (IBTR) disease-free survival (DFS) and overall survival (OS) following conventional and oncoplastic breast-conserving surgery using volume displacement and replacement techniques.MethodsBetween 2009 and 2013, 539 consecutive patients who underwent breast conservation surgery including 174 oncoplastic and 376 conventional procedures were analysed. A systematic review of studies with at least five years of median follow up were performed to compare long term oncological outcomes.ResultsAt a median follow-up of 82.4 months, there were 23 (4.2%) locoregional recurrences, 17 (3.2%) metachronous contralateral breast cancer, 26 (4.8%) distant metastases, and 13 (2.4%) deaths. The hazard ratio of OBCS for IBTR, DFS and OS were 0.78 (95% confidence interval [CI] 0.21–2.94, p=0.78), 1.59 (95% CI, 0.88 to 2.87, p=0.12), and 2.1 (95% CI, 0.72 to 5.9, p=0.17) respectively. The 10-year IBTR-free, DFS and OS rate were 97.8%, 86.2%, and 95.7% respectively.ConclusionThere remained a dearth in well-balanced comparative studies with sufficient long-term follow-up, and our study reported long-term oncological outcomes for OBCS which were favourable of either VD or replacement techniques.

Abstract P3-03-21: Contralateral breast cancers detected by pre-operative MRI in patients diagnosed with DCIS: Whart do they mean?

Abstract Background: For patients with ductal carcinoma in situ (DCIS), data about contralateral breast cancers detected by MRI at primary diagnosis and the impact of MRI use on the incidence and stage of contralateral breast cancers during follow-up are scarce. Methods: We selected all women diagnosed with a primary DCIS in the Netherlands in 2011-2015 from the Netherlands Cancer Registry. The synchronous and metachronous detection of contralateral DCIS and contralateral invasive breast cancer was assessed for patients who did receive an MRI upon primary diagnosis (MRI group) and for an age-matched control group without MRI. Incidence of contralateral disease during follow-up was calculated using competing risk methods.Results: Of the 8486 patients diagnosed with primary DCIS, 1571 (19%) received an MRI. In the MRI group, 0.8% of patients were diagnosed with a synchronous contralateral DCIS and 1.3% with synchronous contralateral invasive breast cancer. Median follow-up time was 6.4 years (IQR: 5.1-7.6). The estimated five-year cumulative incidence of synchronous plus metachronous contralateral DCIS was 2.0% (95% CI: 1.4%-2.8%)) for the MRI group and 0.9% (95% CI: 0.5%-1.5%) for the age-matched control group. The five-year cumulative incidence of contralateral invasive breast cancer was 3.5% (95% CI: 2.7%-4.5%) for the MRI group and 2.3% (95% CI: 1.6%-3.1%) for the age-matched control group. In patients aged <50 years, the cumulative incidence of metachronous contralateral DCIS was statistically significantly higher in the MRI group than in the age-matched controls (sHR= 4.22 (95%CI: 1.19-14.99), P=0.03). This was not the case in patients aged 50-74 years (sHR=0.89 (95%CI: 0.41-1.93), P=0.77). Conclusions: MRI led to more frequent detection of synchronous contralateral invasive breast cancers without lowering the number of metachronous contralateral invasive breast cancers. In patients aged below 50 years, MRI added to conventional imaging led to a persisting higher rate of DCIS diagnosed in the opposite breast, also without influencing the occurrence of invasive breast cancers being detected during the first five years of follow-up. Footnotes Citation Format: Kristien Keymeulen, Sandra Geurts, Loes Kooreman, Lucien Duijm, Sanne Engelen, Sigrid Vanwetswinkel, Ernest Luiten, Sabine Siesling, Adri Voogd, Vivianne Tjan-Heijnen. Contralateral breast cancers detected by pre-operative MRI in patients diagnosed with DCIS: Whart do they mean? [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-03-21.

Metachronous Contralateral Breast Cancer in Ahmadu Bello University Teaching Hospital, Zaria, Northwestern Nigeria.

Breast cancer is the most frequent cancer of women. Metachronous contralateral breast cancer (MCBC) is a cancer in the contralateral breast after 6 months of the initial diagnosis of the first breast cancer. It is an important public health issue because of an increased incidence of a primary breast cancer and improved survival. There is a paucity of data in the Northwestern region of the country. The study was to document the incidence, the method of detection, clinicopathological features, and the treatment of MCBC in our hospital. It was a 7-year prospective study from January 2011 to December 2017. Patients who had treatment for nonmetastatic breast cancer, American Joint Committee on Cancer (AJCC) Stages 1-111, were followed up. Those that developed MCBC were studied. Age, the method of detection, stage at presentation, pathological types, hormone receptor status, and treatment were documented. Data obtained were analysed using SPSS version 21.0. Results were presented as simple percentages and charts. Of 1285 women with nonmetastatic breast cancer, 47 had MCBC (incidence of 3.7%); 30 (63.8%) were aged 21-50 years; 23 (48.9%) detected by self-breast examination; 13 (27.7%) by clinical breast examination; seven (14.9%) by mammography; and four (8.5%) by breast ultrasound scan. Fourteen (29.8%) were AJCC stage I; 23 (48.9%), stage II; seven (14.9%), stage III; and three (6.4%), stage IV. Thirty-nine (83%) were invasive ductal carcinoma; 22 (50.0%) were estrogen receptor/progesterone receptor (ER/PR) positive, human epidermal receptor (HER)-2 neu negative; nine were (20.5%) ER/PR and HER-2 neu positive; six (13.6%) were ER/PR negative, HER-2 neu positive, whereas seven (15.9%) were triple negative. Forty-three (91.5%) had modified radical mastectomy and 19 (40.4%) had cytotoxics. With an average of six cases in a year, MCBC is common in our hospital. Majority (63.8%) were young. The commonest method of detection was by self-breast examination. Majority (78.3%) presented at an early stage. Most (91.5%) still had modified radical mastectomy.

Breast Magnetic Resonance Imaging for Patients With Newly Diagnosed Breast Cancer: A Review.

Despite the high sensitivity and widespread use of preoperative magnetic resonance imaging (MRI), the American Cancer Society and the National Comprehensive Cancer Network guidelines do not recommend the routine use of preoperative MRI owing to the conflicting results and lack of clear benefit to the surgical outcome (reoperation and mastectomy) and long-term clinical outcomes (local recurrence and metachronous contralateral breast cancer). Preoperative MRI detects additional cancers that are occult at mammography and ultrasound but increases the rate of mastectomy. Concerns about overdiagnosis and overtreatment of preoperative MRI might be mitigated by adjusting the confounding factors when conducting studies, using the state-of-the-art image-guided biopsy technique, applying the radiologists’ cumulative experiences in interpreting MRI findings, and performing multiple lumpectomies in patients with multicentric cancer. Among the various imaging methods, dynamic contrast-enhanced MRI has the highest accuracy in predicting pathologic complete response after neoadjuvant chemotherapy. Prospective trials aimed at applying the MRI information to the de-escalation of surgical or radiation treatments are underway. In this review, current studies on the clinical outcomes of preoperative breast MRI are updated, and circumstances in which MRI may be useful for surgical planning are discussed.

Second invasive breast cancers in patients treated with breast-conserving therapy

ObjectiveSecond breast cancers after breast-conserving therapy (BCT) include ipsilateral breast tumor recurrence (IBTR) and metachronous contralateral breast cancer (CBC). Each IBTR is further classified as true recurrence (TR) or new primary tumor (NP). We aim to compare survival outcomes of TR, NP and CBC, and explore the optimal treatments. Methods168,427 patients with primary breast cancer who underwent BCT between 1990 and 2005 were identified in the SEER database. The risks of IBTR and CBC were estimated by annual hazard rate. The breast cancer-specific survival (BCSS) were assessed using multivariable Cox regression analysis. ResultsWith median follow-up of 13 years after BCT, 5413 patients developed an IBTR and 4050 patients had a CBC. The risk of IBTR peaked between 10 and 15 years after BCT, while the risk of CBC distributed evenly. 45.9% of IBTRs were classified as a TR and 54.1% as an NP. The time interval from primary breast cancer to NP was longer than to TR and CBC (P < 0.001). Patients with TR had a poorer BCSS than NP (P = 0.003) and CBC (P = 0.002). There was no difference in BCSS between mastectomy and repeat BCT for treating TR (P = 0.584) or NP (P = 0.243). The BCSS of CBCs treated with BCT was better than mastectomy (P = 0.010). Chemotherapy didn't improve the survival of patients with TR (P = 0.058). However, TRs with grade III or negative hormone receptors benefited from chemotherapy significantly. ConclusionPatients with TR had a poorer BCSS than NP and CBC. Classifying IBTR may provide clinical significance for treatments.

Mitochondrial DNA analysis efficiently contributes to the identification of metastatic contralateral breast cancers

PurposeIn daily practice, a contralateral breast cancer (CBC) is usually considered as a new independent tumor despite the indications of several studies showing that the second neoplasia may be a metastatic spread of the primary tumor. Recognition of clonal masses in the context of multiple synchronous or metachronous tumors is crucial for correct prognosis, therapeutic choice, and patient management. Mitochondrial DNA (mtDNA) sequencing shows high informative potential in the diagnosis of synchronous neoplasms, based on the fact that somatic mtDNA mutations are non-recurrent events, whereas tumors sharing them have a common origin. We here applied this technique to reveal clonality of the CBC with respect to the first tumor.MethodsWe analyzed 30 sample pairs of primary breast cancers and synchronous or metachronous CBCs with detailed clinical information available and compared standard clinico-pathological criteria with mtDNA sequencing to reveal the metastatic nature of CBCs.ResultsMtDNA analysis was informative in 23% of the cases, for which it confirmed a clonal origin of the second tumor. In addition, it allowed to solve two ambiguous cases where histopathological criteria had failed to be conclusive and to suggest a clonal origin for two additional cases that had been classified as independent by pathologists.ConclusionOverall, the mtDNA-based classification showed a more accurate predictive power than standard histopathology in identifying cases of metastatic rather than bilateral breast cancers in our cohort, suggesting that mtDNA sequencing may be a more precise and easy-to-use method to be introduced in daily routine to support and improve histopathological diagnoses.

Contralateral breast cancer risk in patients with ductal carcinoma in situ and invasive breast cancer

We aimed to assess contralateral breast cancer (CBC) risk in patients with ductal carcinoma in situ (DCIS) compared with invasive breast cancer (BC). Women diagnosed with DCIS (N = 28,003) or stage I–III BC (N = 275,836) between 1989 and 2017 were identified from the nationwide Netherlands Cancer Registry. Cumulative incidences were estimated, accounting for competing risks, and hazard ratios (HRs) for metachronous invasive CBC. To evaluate effects of adjuvant systemic therapy and screening, separate analyses were performed for stage I BC without adjuvant systemic therapy and by mode of first BC detection. Multivariable models including clinico-pathological and treatment data were created to assess CBC risk prediction performance in DCIS patients. The 10-year cumulative incidence of invasive CBC was 4.8% for DCIS patients (CBC = 1334). Invasive CBC risk was higher in DCIS patients compared with invasive BC overall (HR = 1.10, 95% confidence interval (CI) = 1.04–1.17), and lower compared with stage I BC without adjuvant systemic therapy (HR = 0.87; 95% CI = 0.82–0.92). In patients diagnosed ≥2011, the HR for invasive CBC was 1.38 (95% CI = 1.35–1.68) after screen-detected DCIS compared with screen-detected invasive BC, and was 2.14 (95% CI = 1.46–3.13) when not screen-detected. The C-index was 0.52 (95% CI = 0.50–0.54) for invasive CBC prediction in DCIS patients. In conclusion, CBC risks are low overall. DCIS patients had a slightly higher risk of invasive CBC compared with invasive BC, likely explained by the risk-reducing effect of (neo)adjuvant systemic therapy among BC patients. For support of clinical decision making more information is needed to differentiate CBC risks among DCIS patients.

Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.

569 Poster - ESR1 mutations in metachronous contralateral breast cancer

569 Poster - ESR1 mutations in metachronous contralateral breast cancer

Abstract 5749: The association between physical health-related quality of life, physical functioning and risk of contralateral breast cancer

Abstract Background: Physical limitations and disability among older cancer patients can lead to suboptimal treatment and surveillance for secondary cancers. Our objective was to evaluate the effects of poor physical health-related quality of life (PQOL) and physical functioning (PF) on contralateral breast cancer (CBC) risk among older women diagnosed with unilateral breast cancer (UBC). Methods: We performed a nested case-control study within a cohort from the Surveillance, Epidemiology and End Results Medicare Health Outcomes Survey (MHOS) database. Women were required to have first primary UBC without prophylactic contralateral mastectomy. Among 2,938 women ages 65 years and older with stages I-III UBC between 1997 and 2011, we identified 100 subsequent CBC cases and 915 controls using incidence density sampling without replacement matched on age, race, and quarter-year of diagnosis. PQOL and PF were determined from survey responses to the Medical Outcomes Trust Short Form 36 component scores. Conditional logistic regression models were used to estimate relative risks (RR) and 95% confidence intervals (CI) for metachronous CBC. Results: Cases and controls were similar with respect to comorbidities, stage, surgery and radiation treatments but differed by hormone receptor status (ER/PR-negative, cases 23% and controls 11%). Cases had lower mean PQOL (-1.8; 95% CI -4.3, 0.7) and PF (-2.2, 95% CI -4.9, 0.5) component scores, but these differences were not statistically significant. In multivariable models, estimates suggest increased CBC risk for women in the lowest quartile of PQOL compared to those in the upper quartile (RR=1.8; 95% CI 0.8, 4.3). Compared to women in the upper quartile of physical functioning scores, women in the lower three quartiles had a 2.6-fold (95% CI 1.2, 5.9) increased risk of CBC. Conclusions: Our findings indicate that low physical health-related quality of life is common among older women diagnosed with breast cancer, and poor physical functioning is related to risk of CBC. Efforts to understand and minimize declines in physical functioning post-breast cancer diagnosis may help optimize treatment strategies to reduce the risk of this adverse outcome. Citation Format: Nita Mukand, Nadia Nabulsi, Ali Alobaidi, Alemseged Asfaw, Brian C. Chiu, Naomi Y. Ko, Gregory S. Calip. The association between physical health-related quality of life, physical functioning and risk of contralateral breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5749.

Plasma membrane expression of G protein-coupled estrogen receptor (GPER)/G protein-coupled receptor 30 (GPR30) is associated with worse outcome in metachronous contralateral breast cancer.

BackgroundG protein-coupled estrogen receptor (GPER), or G protein-coupled receptor 30 (GPR30), is reported to mediate non-genomic estrogen signaling. GPR30 associates with breast cancer (BC) outcome and may contribute to tamoxifen resistance. We investigated the expression and prognostic significance of GPR30 in metachronous contralateral breast cancer (CBC) as a model of tamoxifen resistance.MethodsTotal GPR30 expression (GPR30TOT) and plasma membrane-localized GPR30 expression (GPR30PM) were analyzed by immunohistochemistry in primary (BC1; nBC1 = 559) and contralateral BC (BC2; nBC2 = 595), and in lymph node metastases (LGL; nLGL1 = 213; nLGL2 = 196). Death from BC (BCD), including BC death or death after documented distant metastasis, was used as primary end-point.ResultsGPR30PM in BC2 and LGL2 were associated with increased risk of BCD (HRBC2 = 1.7, p = 0.03; HRLGL2 = 2.0; p = 0.02). In BC1 and BC2, GPR30PM associated with estrogen receptor (ER)-negativity (pBC1<0.0001; pBC2<0.0001) and progesterone receptor (PR)-negativity (pBC1 = 0.0007; pBC2<0.0001). The highest GPR30TOT and GPR30PM were observed in triple-negative BC. GPR30PM associated with high Ki67 staining in BC1 (p<0.0001) and BC2 (p<0.0001). GPR30TOT in BC2 did not associate with tamoxifen treatment for BC1. However, BC2 that were diagnosed during tamoxifen treatment were more likely to express GPR30PM than BC2 diagnosed after treatment completion (p = 0.01). Furthermore, a trend was observed that patients with GPR30PM in an ER-positive BC2 had greater benefit from tamoxifen treatment.ConclusionPM-localized GPR30 staining is associated with increased risk of BC death when expressed in BC2 and LGL2. Additionally, PM-localized GPR30 correlates with prognostic markers of worse outcome, such as high Ki67 and a triple-negative subtype. Therefore, PM-localized GPR30 may be an interesting new target for therapeutic exploitation. We found no clear evidence that total GPR30 expression is affected by tamoxifen exposure during development of metachronous CBC, or that GPR30 contributes to tamoxifen resistance.

Abstract P6-05-09: G protein-coupled estrogen receptor expressed in the plasma membrane is associated with worse breast cancer outcome, but does not contribute to tamoxifen resistance

Abstract Introduction - G protein-coupled estrogen receptor (GPER), or GPR30, is a membrane receptor reported to mediate rapid, non-genomic estrogen responses. Multiple studies suggest that GPR30 expression associates with breast cancer outcome, although the clinical implications appear to depend on receptor subcellular localization and level of expression. Specifically, high plasma membrane localization of GPR30 has been reported to associate with a worse prognosis. Furthermore, in vitro studies show that tamoxifen up-regulates GPR30 in breast cancer cells, suggesting that GPR30 acts as a mediator of tamoxifen resistance. To further clarify the prognostic and treatment resistance role of GPR30 in vivo, we studied the receptor in patients developing contralateral breast cancer with or without tamoxifen treatment for the first primary tumor, serving as an in vivo model of tamoxifen resistance. Patients and methods - In a cohort of 688 patients with metachronous contralateral breast cancer, total and plasma membrane specific GPR30 expression were evaluated by immunohistochemistry. Total GPR30 was evaluated in five levels (0-4) and plasma membrane staining as positive or negative. Evaluation was successful for 559 first primary tumors and 595 contralateral tumors. In addition, matched lymph node and distant metastases were evaluated (lymph node matched to first primary tumor, n=213, matched to contralateral tumor, n=196, and distant metastasis, n=197). The relationship between GPR30 and breast cancer mortality was assessed by the Cox proportional hazards model, and illustrated by curves of cumulative incidence. The association between GPR30 and breast cancer outcome in relation to tamoxifen was assessed by comparing groups either untreated or treated with tamoxifen after the first primary tumor. Results - GPR30 expression in the plasma membrane associated with increased risk of breast cancer mortality both when expressed in the contralateral tumor (HR=1.7, p=0.03) and matched lymph node (HR=2.0; p=0.02). Additionally, GPR30 plasma membrane expression associated with high Ki67 staining both in the first primary tumor (p&amp;lt;0.0001) and contralateral tumor (p&amp;lt;0.0001). In both the first primary tumor and contralateral tumor, GPR30 plasma membrane expression associated with estrogen receptor α (ER)-negativity (p&amp;lt;0.0001 and p&amp;lt;0.0001, respectively) and progesterone receptor (PR)-negativity (p=0.0007 and p&amp;lt;0.0001, respectively). Furthermore, ER and PR expression associated with total GPR30 expression in a biphasic manner in both the first primary tumor and contralateral tumor, as previously observed in three cohorts of primary breast cancer. The highest total and plasma membrane GPR30 expression was observed in triple-negative breast cancer. Total GPR30 expression of the first primary tumor and contralateral tumor did not correlate, but it was significantly lower in the matched lymph node (first primary tumor p&amp;lt;0.0001, contralateral tumor p&amp;lt;0.0001). No clear evidence was found that tamoxifen treatment during contralateral tumor development correlated with GPR30 expression, or that GPR30 expression correlated with response to tamoxifen treatment. Conclusion - GPR30 expression in the plasma membrane associates with increased risk of breast cancer death when expressed in the contralateral tumor and match lymph node, and correlates strongly with multiple clinicopathological markers of poor outcome. On the other hand, prior tamoxifen treatment does not appear to affect GPR30 expression, suggesting that GPR30 does not mediate tamoxifen resistance. Future studies should aim to characterize the pathophysiological mechanisms and function of GPR30 when located in the plasma membrane. Here, GPR30 could be an novel target for breast cancer treatments. Citation Format: Julia Tutzauer, Martin Sjöström, Pär-Ola Bendahl, Lisa Rydén, Mårten Fernö, Fredrik Leeb-Lundberg, Sara Alkner. G protein-coupled estrogen receptor expressed in the plasma membrane is associated with worse breast cancer outcome, but does not contribute to tamoxifen resistance [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-05-09.

Abstract P6-08-25: Surgical decision making and clinical outcomes in breast cancer (BC) patients (pts) with germline alterations in moderate risk BC susceptibility genes (CHEK2, PALB2 and ATM)

Abstract Background: Multigene panel testing is being used increasingly for BC risk assessment. Following a new BC diagnosis, germline testing is primarily used to assess contralateral cancer risk. Presence of a BRCA1/2 mutation indicates a high risk of metachronous contralateral BC, and many women found to carry a BRCA1/2 mutation choose to undergo contralateral prophylactic mastectomy (CPM). There is limited data regarding surgical decisions among women with mutations in other, more moderate risk, susceptibility genes such as ATM, CHEK2, and PALB2. In addition, the contralateral cancer risk in women with these mutations who decline CPM is poorly understood. Here, we describe surgical decision making and outcomes in women with ATM, PALB2 or CHEK2 alterations (pathogenic or variants of uncertain significance (VUS)).Methods: We identified women who underwent peri-diagnostic genetic testing at our institution between 03/2012 and 10/2018. Pts with an early BC diagnosis (Stage 0-3) and an ATM, PALB2 or CHEK2 alteration were included. Records were reviewed to assess genetic testing details, and clinicopathologic variables. Pts surgical decision making, and clinical outcomes were the primary end points of this analysis. We compared the frequency of bilateral mastectomy (BM) and CPM of pts with pathogenic variants and VUS.Results: Of 597 consecutive pts tested, 54 pts were identified with an ATM, PALB2 or CHEK2 alteration. Pathogenic variants were present in 18 pts (3%), and 36 pts (6%) were identified with a VUS in at least one of the three genes. CHEK2 alterations were the most common (11 pathogenic and 17 VUS), followed by PALB2 alterations (3 pathogenic and 17 VUS) and ATM alterations (4 pathogenic and 8 VUS). Five pts were identified with more than one alteration. Median age of population was 43 years, 68% were Caucasians, 70% had an ER+/HER2 negative BC, 78% were pre-menopausal, 80% had pTis/T1, 68% were pN0. 33% received neoadjuvant chemotherapy. Three pts were diagnosed with synchronous bilateral BC. Among the 18 pts with pathogenic variants, 11 (61%) were managed with BM (2 due to synchronous bilateral disease and 9 for prophylaxis), the remaining 7 pts were managed with unilateral mastectomy (4/7) or unilateral lumpectomy (3/7). Among 36 pts with VUS, 8 (22%) underwent BM (1 pt due to synchronous bilateral disease and 7 for prophylaxis). Frequency of BM and CPM was significantly higher in pts with pathogenic variants compared with VUS (p = 0.004 and 0.02, respectively). Rates of BM for pathogenic gene mutations and VUS were, respectively: CHEK2 (9/11 - 82%; 5/17 - 30%), PALB2 (1/3 - 33%; 2/17 - 12%) and ATM (1/4 - 25%; 3/8 - 37%). With a median follow-up of 31.2 months, 4 pts developed a second primary BC (2 pts with pathogenic mutation and 2 pts with VUS), one pt developed local recurrence and one pt developed distant recurrence. No deaths were observed. Conclusion: In this analysis, 54/597 (9%) of tested pts had a germline alteration in ATM, CHEK2, or PALB2. Of those patients 3% had pathogenic variants and 6% had VUS. Frequency of BM and CPM was higher in pts with pathogenic mutations. Longer term follow-up in a larger cohort of patients is necessary to elucidate the true contralateral BC risk among this population. Citation Format: Carlos Henrique dos Anjos, Kimberly Amoros, Melissa Pilewskie, Lior Braunstein, Mark Robson. Surgical decision making and clinical outcomes in breast cancer (BC) patients (pts) with germline alterations in moderate risk BC susceptibility genes (CHEK2, PALB2 and ATM) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-25.

Oncoplastic mammaplasty with geometric compensation: Evolution of the technique, outcomes and follow‐up in a multicentre retrospective cohort

To report on the outcomes and evolution of an oncoplastic mammaplasty referred to as geometric compensation mammaplasty. Seventy-three patients with malignant tumours were operated on and followed up in five centres in two countries. Preoperative markings were performed using a Wise pattern. The resection of affected skin was geometrically compensated using another area of preserved skin. Mean pathological tumour size was 30.42 ± 21.98 mm. Twenty tumours (30.77%) were locally advanced and 15 (20.55%) were multicentric. Twenty-two patients (34.38%) were submitted to neoadjuvant chemotherapy. Cosmetic results were considered good or excellent in 59 cases (80.82%). Margins were positive in two cases (2.74%). Complications were partial wound dehiscence (n = 11; 15.07%), fat necrosis (n = 9; 12.33%), skin necrosis (n = 5; 6.85%), seromas (n = 5; 6.85%), enlarged scars (n = 7; 9.59%) and infection (n = 2; 2.74%). There were three cases of local recurrence (4.29%), two of bone metastasis (2.86%) and three of metachronous contralateral breast cancer (4.35%). No deaths were recorded within a mean follow-up of 35.33 ± 28.21 months. The technique allowed breast conservation in situations requiring a large resection of skin in difficult positions, with a high rate of free margins, correction of ptosis, satisfactory symmetry and few complications.

Therapy of isolated locoregional recurrent carcinoma of the breast.

Thereis widespread consent that isolated locoregional recurrence (ILRR) in breast cancer should be treated surgically. On searching literature and guidelines most studies include ipsilateral recurrence in breast tissue or on thoracic wall post-mastectomy, recurrence in scar tissue as well as in ipsilateral axillary lymph nodes. Some studies discuss metachronous contralateral breast cancer as ILRR. About 10-35% of women with primary breast cancer suffer from ILRR. The existing data concerning the role of systemic therapy in the treatment of ILRR are insufficient. We investigated the influence of chemotherapy on disease-free- (DFS) and overall-survival (OS). Retrospective analysis of all patients with ILRR and without distant metastasis was done, which were treated at the Department of Gynecology, Obstetrics and Reproductive Medicine, Saarland University between 2005 and 2013. Data collection used patients' database system and was followed via patient questionnaires. In total, we collected data of 93 patients with locally recurrent breast cancer and observed a 72.6% questionnaire response rate. Average timeline accounted for 99months between primary diagnosis and local recurrence; average age of patients at diagnosis of local recurrence was 60.6years. After a median follow-up of 63months DFS reached 76% with and 73% without chemotherapy, and after 74months overall survivalamounted to 94% and 70%, respectively. Almost all patients with ILRR were operated. Especially patients with hormone receptor-negative recurrent breast cancer seemed to show a benefit having been treated with chemotherapy. Most patients were without recurrence after their particular therapies.