Correction: The clinical significance of oestrogen receptor expression in breast ductal carcinoma in situ.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The clinical significance of oestrogen receptor expression in breast ductal carcinoma in situ.

BACKGROUND: Oestrogen receptor (ER) in invasive breast cancer (BC) predicts response to endocrine therapy (ET) and provides prognostic value. In this study, we investigated the value of ER expression in ductal carcinoma in situ (DCIS) in terms of outcome and the impact on ET decision. METHODS: In total, 643 pure DCIS, diagnosed at Nottingham University Hospitals, were assessed for ER. Clinicopathological data were correlated against ER status, together with assessment of recurrence rate. RESULTS: ER positivity was observed in 74% (475/643) of cases. ER positivity was associated with clinicopathological variables of good prognosis; however, outcome analysis revealed that ER status was not associated with local recurrence. In the intermediate- and high-grade ER-positive DCIS, 58% (11/19) and 63% (15/24) of the recurrences were invasive, respectively, comprising 7% and 6% of all ER-positive DCIS, respectively. Invasive recurrence in low-grade DCIS was infrequent (2%), and none of these patients died of BC. The ER status of the recurrent invasive tumours matched the primary DCIS ER status (94% in ipsilateral and 90% of contralateral recurrence). CONCLUSION: The strong correlation between DCIS and invasive recurrence ER status and the clinical impact of ET justify discussion of the use of ET in ER-positive DCIS treated by breast-conserving surgery. The excellent outcome of low-grade DCIS, which was almost always ER-positive, does not, in the opinion of authors, justify the use of risk-reducing ET. Therefore, the decision on ET for DCIS should be personalised and consider grade, ER status and other characteristics.

Therapeutic mammaplasty is a safe and effective alternative to mastectomy with or without immediate breast reconstruction.

BACKGROUND: Therapeutic mammaplasty (TM) may be an alternative to mastectomy, but few well designed studies have evaluated the success of this approach or compared the short-term outcomes of TM with mastectomy with or without immediate breast reconstruction (IBR). Data from the national iBRA-2 and TeaM studies were combined to compare the safety and short-term outcomes of TM and mastectomy with or without IBR. METHODS: The subgroup of patients in the TeaM study who underwent TM to avoid mastectomy were identified, and data on demographics, complications, oncology and adjuvant treatment were compared with those of patients undergoing mastectomy with or without IBR in the iBRA-2 study. The primary outcome was the percentage of successful breast-conserving procedures in the TM group. Secondary outcomes included postoperative complications and time to adjuvant therapy. RESULTS: A total of 2916 patients (TM 376; mastectomy 1532; mastectomy and IBR 1008) were included in the analysis. Patients undergoing TM were more likely to be obese and to have undergone bilateral surgery than those having IBR. However, patients undergoing mastectomy with or without IBR were more likely to experience complications than the TM group (TM: 79, 21·0 per cent; mastectomy: 570, 37·2 per cent; mastectomy and IBR: 359, 35·6 per cent; P < 0·001). Breast conservation was possible in 87·0 per cent of patients who had TM, and TM did not delay adjuvant treatment. CONCLUSION: TM may allow high-risk patients who would not be candidates for IBR to avoid mastectomy safely. Further work is needed to explore the comparative patient-reported and cosmetic outcomes of the different approaches, and to establish long-term oncological safety.

ANTECEDENTES: La mamoplastia terapéutica (therapeutic mammaplasty, TM) puede ser una alternativa a la mastectomía, pero hay pocos estudios bien diseñados que hayan evaluado el éxito de esta estrategia o hayan comparado los resultados a corto plazo de la TM con la mastectomía con o sin (+/-) reconstrucción mamaria inmediata (immediate breast reconstruction, IBR). Para comparar la seguridad y los resultados a corto plazo de la TM y la mastectomía +/- IBR se combinaron los datos de los estudios nacionales iBRA-2 y TeaM. MÉTODOS: En el estudio TeaM se identificó el subgrupo de pacientes al que se realizó una TM para evitar la mastectomía y se compararon los datos demográficos, las complicaciones, los resultados oncológicos y el tratamiento adyuvante con las pacientes sometidas a mastectomía +/- IBR del estudio iBRA-2. La variable principal fue el porcentaje de éxito de la cirugía conservadora de mama en el grupo TM. Las variables secundarias fueron las complicaciones postoperatorias y el intervalo de tiempo hasta el inicio del tratamiento adyuvante. RESULTADOS: Se incluyeron en el análisis 2.916 pacientes (TM n = 376; mastectomía n = 1.532; IBR n = 1.008). La TM era más frecuente en pacientes obesas o en las sometidas a cirugía bilateral en comparación con las pacientes con IBR. Sin embargo, las pacientes sometidas a una mastectomía +/- IBR tenían más probabilidades de desarrollar complicaciones que las del grupo TM (TM n = 79, 21,0%; mastectomía n = 570, 37,2%; mastectomía y IBR n = 359, 35,6%; P < 0,001). La conservación de la mama fue posible en el 87% de las pacientes con TM y el procedimiento no retrasó el inicio del tratamiento adyuvante. CONCLUSIÓN: La TM puede permitir que pacientes de alto riesgo que no serían candidatas a IBR eviten la mastectomía de una forma segura. Se necesitan más trabajos para comparar los resultados percibidos por las pacientes y los estéticos de las diferentes estrategias terapéuticas y establecer la seguridad oncológica a largo plazo.

Current practice and short-term outcomes of therapeutic mammaplasty in the international TeaM multicentre prospective cohort study.

BACKGROUND: Therapeutic mammaplasty, which combines breast reduction and mastopexy techniques with tumour excision, may extend the boundaries of breast-conserving surgery and improve outcomes for patients, but current practice is unknown and high-quality outcome data are lacking. This prospective multicentre cohort study aimed to explore the practice and short-term outcomes of the technique. METHODS: Consecutive patients undergoing therapeutic mammaplasty at participating centres between 1 September 2016 and 30 June 2017 were recruited to the study. Demographic, preoperative, operative, oncological and complication data were collected. The primary outcome was unplanned reoperation for complications within 30 days of surgery. Secondary outcomes included re-excision rates and time to adjuvant therapy. RESULTS: Overall, 880 patients underwent 899 therapeutic mammaplasty procedures at 50 centres. The most common indications were avoidance of poor cosmetic outcomes associated with standard breast-conserving surgery (702 procedures, 78·1 per cent) or avoidance of mastectomy (379, 42·2 per cent). Wise-pattern skin incisions were the most common (429 of 899, 47·7 per cent), but a range of incisions and nipple-areola pedicles were used. Immediate contralateral symmetrization was performed in one-third of cases (284 of 880, 32·3 per cent). In total, 205 patients (23·3 per cent) developed a complication, but only 25 (2·8 per cent) required reoperation. Median postoperative lesion size was 24·5 (i.q.r. 16-38) mm. Incomplete excision was seen in 132 procedures (14·7 per cent), but completion mastectomy was required for only 51 lesions (5·7 per cent). Median time to adjuvant therapy was 54 (i.q.r. 42-66) days. CONCLUSION: Therapeutic mammaplasty is a safe and effective alternative to mastectomy or standard breast-conserving surgery. Further work is required to explore the impact of the technique on quality of life, and to establish cost-effectiveness.

Intra-operative spectroscopic assessment of surgical margins during breast conserving surgery.

BACKGROUND: In over 20% of breast conserving operations, postoperative pathological assessment of the excised tissue reveals positive margins, requiring additional surgery. Current techniques for intra-operative assessment of tumor margins are insufficient in accuracy or resolution to reliably detect small tumors. There is a distinct need for a fast technique to accurately identify tumors smaller than 1 mm2 in large tissue surfaces within 30 min. METHODS: Multi-modal spectral histopathology (MSH), a multimodal imaging technique combining tissue auto-fluorescence and Raman spectroscopy was used to detect microscopic residual tumor at the surface of the excised breast tissue. New algorithms were developed to optimally utilize auto-fluorescence images to guide Raman measurements and achieve the required detection accuracy over large tissue surfaces (up to 4 × 6.5 cm2). Algorithms were trained on 91 breast tissue samples from 65 patients. RESULTS: Independent tests on 121 samples from 107 patients - including 51 fresh, whole excision specimens - detected breast carcinoma on the tissue surface with 95% sensitivity and 82% specificity. One surface of each uncut excision specimen was measured in 12-24 min. The combination of high spatial-resolution auto-fluorescence with specific diagnosis by Raman spectroscopy allows reliable detection even for invasive carcinoma or ductal carcinoma in situ smaller than 1 mm2. CONCLUSIONS: This study provides evidence that this multimodal approach could provide an objective tool for intra-operative assessment of breast conserving surgery margins, reducing the risk for unnecessary second operations.

Multicentre study of patient-reported and clinical outcomes following immediate and delayed Autologous Breast Reconstruction And Radiotherapy (ABRAR study).

BACKGROUND: Timing of autologous breast reconstruction in patients requiring adjuvant radiotherapy remains contentious. The primary objective of this study was to assess clinical and patient reported outcomes in immediate reconstruction with radiotherapy compared to delayed reconstruction after radiotherapy, the two relevant clinical pathways for patients who need radiotherapy. METHODS: This retrospective UK multi-centre study grouped patients into three categories: immediate reconstruction with post-operative radiotherapy (IBR); delayed reconstruction after radiotherapy (DBR); control group of immediate reconstruction without radiotherapy (noRT). Data collection utilised clinician questionnaire, patient questionnaire (BreastQ) and medical examination. Examination assessed fat necrosis, texture, symmetry and overall result. RESULTS: 412 patients were recruited (IBR 104; DBR 119; noRT 189) with median follow-up time of 57 months. Post-operative complications were higher in IBR & noRT (p <0.001). Total number of operations for completion of reconstruction was similar in all groups. Completion of reconstruction after mastectomy was three years longer in DBR versus IBR. BreastQ domain scores were lower in IBR versus DBR and noRT (p <0.01) but all scores were within acceptable range (satisfaction with outcome: IBR 71; DBR 85; noRT 81). Examination scores were similar for IBR and DBR but lower than noRT (p <0.01). Correlation between BreastQ and examination scores was poor. CONCLUSIONS: Acceptable results are observed with either IBR or DBR, with high rates of patient and clinician satisfaction, low rates of complications, and a similar number of operations to complete reconstruction in all groups suggesting all options should be considered for patients.

Comparing oncoplastic breast conserving surgery with mastectomy and immediate breast reconstruction: Case-matched patient reported outcomes.

BACKGROUND: Oncoplastic breast conserving surgery (OBCS) allows women who may otherwise have mastectomy and immediate reconstruction (MxIR) the choice to conserve their breast yet avoid deformity. We compared the outcome of these options. METHODS: Two cohorts meeting study criteria were identified from prospectively audited series of women undergoing OBCS or MxIR. After case matching for age, tumour size and date of surgery, stratification by breast size and controlling for radiotherapy; body image scale (BIS) scores of psychosocial function and patient reported outcome measures (PROMs) for breast appearance and return to function were analysed. RESULTS: A total of 567 women (286 treated by OBCS and 281 by MxIR) fulfilled inclusion criteria. Demographics were similar between the two unmatched cohorts, except for radiotherapy, age and tumour size (all p < 0.001). Overall, BIS score (p = 0.002), self-rated breast appearance, return to work and function (all p < 0.001) significantly favoured OBCS. Case-matched women with larger breasts treated by OBCS reported better BIS scores (mean 3.30 vs. 5.37, p = 0.011) and self-rated breast appearance score (p < 0.001) than MxIR, whereas no significant difference was observed for smaller breasts. BIS and appearance favoured OBCS, regardless of whether radiotherapy would have been avoided if treated by MxIR. CONCLUSION: OBCS offers suitable women the option to avoid MxIR while providing faster recovery. Better psychosocial and self-rated satisfaction with breast appearance is achieved for OBCS in all groups, regardless of the need for radiotherapy, apart from those women with smaller breasts for whom the results are comparable.

Oncoplastic Breast Surgery: What, When and for Whom?

Oncoplastic surgery is integral to all breast cancer surgeries. The use of an aesthetic approach to breast conservation or mastectomy greatly enhances the range of options that can be offered to women with breast cancer and facilitates better outomes from it. It should be the standard of care. However, a structured approach to selecting appropriate techniques is essential, and although many operative procedures are reported, this article sets out to describe a set of principles and an algorithm by which the what, when and for whom for oncoplastic surgery can be defined.

MYC functions are specific in biological subtypes of breast cancer and confers resistance to endocrine therapy in luminal tumours.

BACKGROUND: MYC is amplified in approximately 15% of breast cancers (BCs) and is associated with poor outcome. c-MYC protein is multi-faceted and participates in many aspects of cellular function and is linked with therapeutic response in BCs. We hypothesised that the functional role of c-MYC differs between molecular subtypes of BCs. METHODS: We therefore investigated the correlation between c-MYC protein expression and other proteins involved in different cellular functions together with clinicopathological parameters, patients' outcome and treatments in a large early-stage molecularly characterised series of primary invasive BCs (n=1106) using immunohistochemistry. The METABRIC BC cohort (n=1980) was evaluated for MYC mRNA expression and a systems biology approach utilised to identify genes associated with MYC in the different BC molecular subtypes. RESULTS: High MYC and c-MYC expression was significantly associated with poor prognostic factors, including grade and basal-like BCs. In luminal A tumours, c-MYC was associated with ATM (P=0.005), Cyclin B1 (P=0.002), PIK3CA (P=0.009) and Ki67 (P<0.001). In contrast, in basal-like tumours, c-MYC showed positive association with Cyclin E (P=0.003) and p16 (P=0.042) expression only. c-MYC was an independent predictor of a shorter distant metastases-free survival in luminal A LN+ tumours treated with endocrine therapy (ET; P=0.013). In luminal tumours treated with ET, MYC mRNA expression was associated with BC-specific survival (P=0.001). In ER-positive tumours, MYC was associated with expression of translational genes while in ER-negative tumours it was associated with upregulation of glucose metabolism genes. CONCLUSIONS: c-MYC function is associated with specific molecular subtypes of BCs and its overexpression confers resistance to ET. The diverse mechanisms of c-MYC function in the different molecular classes of BCs warrants further investigation particularly as potential therapeutic targets.

The TeaM (Therapeutic Mammaplasty) study: Protocol for a prospective multi-centre cohort study to evaluate the practice and outcomes of therapeutic mammaplasty.

INTRODUCTION: Wide local excision and adjuvant radiotherapy is the standard of care for early breast cancer. For large tumours, however, mastectomy is frequently recommended as conventional breast-conserving techniques often result in poor cosmetic outcomes. Therapeutic mammaplasty (TM) may extend the boundaries of breast-conserving surgery by combining breast reduction and mastopexy techniques with tumour excision, preserving a natural breast shape and avoiding the need for mastectomy. The prevalence of this operative option among surgeons in the UK and its success rate are unknown. The TeaM study is a multicentre prospective study that aims to investigate the practice and outcomes of TM. METHODS AND ANALYSIS: Breast centres performing TM will be invited to participate through the research collaborative network and the professional associations. All patients undergoing TM between September 2016 and March 2017 will be included. Demographic, operative, oncological and complication data within 30-days of surgery will be collected. The primary outcome will be unplanned re-operation for complications. Secondary outcomes will include unplanned readmission, re-excision rates and time to adjuvant therapy. Prospective data on 500 patients from 50 centres are anticipated. Exploratory analyses will identify predictors for complications and inform the design of a definitive study. ETHICS AND DISSEMINATION: Research ethics approval is not required for this study. This has been confirmed by the on-line Health Research Authority decision tool. This study will provide novel information regarding the practice and outcomes of TM in the UK. This will inform decision-making for patients and surgeons and inform future research. Dissemination of the study protocol will be via the Mammary Fold Academic and Research Collaborative, the Reconstructive Surgery Trials Network and the professional associations, the Association of Breast Surgery and British Association of Plastic, Reconstructive and Aesthetic Surgeons. Results will be presented at relevant surgical conferences and published in peer-reviewed journals.

A case-controlled study of the oncologic safety of fat grafting.

BACKGROUND: Currently, there is no clinical evidence of oncologic risk associated with fat grafting, although its safety has been questioned. The authors investigated the risk of relapse associated with fat grafting in women with a history of breast cancer. METHODS: Of 328 women with previously treated malignant breast disease who underwent fat grafting at the Nottingham Breast Institute, complete data were available for 211 (invasive carcinoma, n = 184; ductal carcinoma in situ, n = 27). Mean follow-up was 88 months after primary cancer surgery and 32 months after fat grafting. Control subjects were matched 2:1 for date of primary cancer operation (within 2 years), age (within 5 years), type of surgery, tumor histology, estrogen receptor status, and disease-free status by time equivalent to that of fat grafting. Final endpoints were tumor recurrence and death. Outcome results were compared with a systematic review of all patients undergoing fat grafting with adequate follow-up reported in the literature. RESULTS: No significant excess oncologic events were observed in patients who had fat grafting compared to controls with regard to local (0.95 percent versus 1.90 percent; p = 0.33), regional (0.95 percent versus 0 percent; p = 0.16), and distant recurrences (3.32 percent versus 2.61 percent; p = 0.65). A systematic review identified case series with a total of 1573 women who had fat grafting after primary oncologic breast surgery. The locoregional relapse rate for these patients was 2.92 percent (0.95 percent per year). CONCLUSION: This study has found no evidence of increased oncologic risk associated with fat grafting in women previously treated for breast cancer. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Lateral thoracic artery perforator (LTAP) flap in partial breast reconstruction.

BACKGROUND: Partial breast reconstruction using pedicled perforator flaps from the thoracodorsal (TDAP) and lateral intercostal arteries (LICAP) is well described. The article introduces the lateral thoracic artery perforator (LTAP) flap as an additional valuable option from the lateral chest wall and reports clinical experience and outcomes. METHODS: The anatomy of the LTAP flap is reviewed and the results of a consecutive series are reported. RESULTS: In a series of 75 consecutive cases of lateral chest wall perforator flaps used for reconstruction of partial breast defects, 12 (17%) were raised as pure LTAP flaps, and a further 19 (27%) as combined LTAP/LICAP flaps. The LTAP was therefore used in 44% of flaps overall. One LTAP flap (delayed case) had early venous compromise that settled spontaneously. DISCUSSION: The LTAP flap is a reliable option for partial breast reconstruction from the lateral chest wall, particularly in the immediate setting. It allows comparable flap size to be harvested compared to LICAP flaps. The LTAP flap can be raised on its own pedicle allowing greater mobilization or it can be incorporated into the more commonly used LICAP flap to augment perfusion.

DNA damage response markers are differentially expressed in BRCA-mutated breast cancers.

Cells have stringent DNA repair pathways that are specific for each different set of DNA lesions which is accomplished through the integration of complex array of proteins. However, BRCA-mutated breast cancer (BC) has defective DNA repair mechanisms. This study aims to investigate differential expression of a large panel of DNA repair markers to characterise DNA repair mechanisms in BRCA-associated tumours compared to sporadic tumours in an attempt to characterise these tumours in routine practice. Immunohistochemistry and tissue microarray technology were applied to a cohort of clinically annotated series of sporadic (n = 1849), BRCA1-mutated (n = 48), and BRCA2-mutated (n = 27) BC. The following DNA damage response (DDR) markers are used; BRCA1, BRCA2, RAD51, Ku70/Ku80, BARD, PARP1 (cleaved), PARP1 (non-cleaved), and P53 in addition to basal cytokeratins, ER, PR, and HER2. A significant proportion of BRCA1 tumours were positive for PARP1 (non-cleaved), and negative for BARD1 and RAD51 compared with sporadic BC. BRCA2 tumours were significantly positive for PARP1 (non-cleaved) compared with sporadic tumours. RAD51 was significantly higher in BRCA1 compared with BRCA2 tumours (p = 0.005). When BRCA1/2 BCs were compared to triple-negative (TN) sporadic tumours of the studied DDR proteins, BARD1 (p < 0.001), PARP1 (non-cleaved) (p < 0.001), and P53 (p = 0.002) remained significantly different in BRCA1/2 tumours compared with TN BC. DNA repair markers showed differential expression in BRCA-mutated tumours, with a substantial degree of disruption of DNA repair pathways in sporadic BC especially TN BC. DNA double-strand break (DSB) repair is assisted by PARP1 expression in BRCA-mutated tumours, whereas the loss of DSB repair via RAD51 is predominant in BRCA1 rather than BRCA2 BC.

Oncoplastic and reconstructive breast surgery in the elderly.

BACKGROUND: The recommendations of the UK All Party Parliamentary Group on Breast Cancer (2013) have been endorsed recently by the UK Association of Breast Surgeons and are in line with the 2007 Cancer Reform Strategy, which states that treatment in older British women should be equivalent to that in younger patients unless precluded by co-morbidity or patient choice. Oncoplastic and reconstructive techniques are increasingly available to women with breast cancer. A review of the literature was carried out to investigate use of these techniques in older patients. METHODS: A MEDLINE search was conducted to identify studies relating to oncoplastic and reconstructive surgery in the elderly. RESULTS AND CONCLUSION: Nine studies were identified and included in the review. Older patients undergoing reconstruction, particularly autologous reconstruction, have outcomes that are at least as good as those achieved in younger patients, yet are far less likely to be offered these techniques. Issues influencing oncoplastic and reconstructive surgery in the elderly include: lack of standard pathways of care, concerns regarding higher operative risk, lack of evidence regarding outcomes, preconceptions regarding body image and lack of engagement with the decision-making process. A minority of older women are likely to accept reconstruction, but those who do are pleased with the results and experience good quality of life. There is now a range of safe oncoplastic and reconstructive options that could be considered as an alternative to standard mastectomy or wide local excision in older patients.

Qualitative mammographic findings and outcomes of surveillance mammography after partial breast reconstruction with an autologous flap.

BACKGROUND: This study describes the qualitative mammographic features after partial breast reconstruction with an autologous flap, and evaluates the diagnostic accuracy and recall rates of surveillance mammography after volume replacement in breast conserving surgery. METHODS: Patients who had autologous partial breast reconstruction (N = 102) after breast-conserving surgery using either the myocutaneous latissimus dorsi mini-flap (N = 39) or fasciocutaneous chest wall perforator flap (N = 63) were reviewed. Mammograms done at one-year post surgery were analysed for characteristic qualitative features. All surveillance mammograms, diagnostic imaging and medical records were retrospectively reviewed. RESULTS: Mammograms of partially reconstructed breasts had distinctive features that correlated well with the surgical procedures. Median follow-up was 3 years, range 0-11 years. Of 295 surveillance mammograms, six (2%) resulted in a recall for further imaging and 3 (1%) proceeded to needle biopsy. Diagnostic imaging was performed for 13 (13/102, 12.7%) patients with symptoms, and only one (1/102, 1%) required a diagnostic biopsy. CONCLUSIONS: A conserved breast with an autologous flap within has characteristic mammographic features that differ from those after standard breast conserving surgery. Surveillance mammography after partial breast reconstruction is accurate, and recall/biopsy rates are low. Diagnostic breast ultrasound examination is effective evaluation for the symptomatic patient.

Biological and clinical significance of PARP1 protein expression in breast cancer.

Poly(ADP-ribose) polymerase-1 (PARP1) is a key facilitator of DNA repair. PARP inhibitors have gained recent attention as promising therapeutic agents for the treatment of solid tumours including breast cancer (BC). However, the biological and clinical significance of PARP1 expression in BC and its role in DNA-damage response (DDR) remain to be defined. We investigated the expression of PARP1 expression, cleaved (PARP1c) and non-cleaved (PAR1nc) forms, in a large and well-characterised cohort of clinically annotated stage I-III operable BCs (n = 1,269) and 43 BRCA1-mutated BCs using immunohistochemistry. PARP1 expression was correlated to clinicopathological variables, outcome and expression of other key DNA repair proteins (BRCA1, RAD51, Ku70/80, PIASγ and CHK1). Expression of PARP1 was exclusively nuclear. 49 and 85 % of sporadic BC showed expression PARP1nc and PARP1c, respectively. In BRCA1-mutated tumours, PARP1nc/PARP1c was highly expressed (95 and 79 %, respectively). PARP1nc expression was positively associated with premenopausal younger age patients, larger size and higher tumour grade. PARP1 was positively associated with DDR-proteins; RAD51, BRCA1, CHK1 and PIASγ (p < 0.001). Negative association was found between PARP1nc and Ki67. PARP1c was associated with ER (p < 0.001). Different associations between PARP1 and DDR-proteins were observed when stratified based on ER/BRCA1 status. PARP1 was not an independent predictor of outcome in sporadic or BRCA1-mutated BC. Our results demonstrate a potential biological role for PARP1c and PARP1nc in DNA repair in BC based on the significant association with other key DNA damage repair proteins. These associations were not restricted to ER-negative or triple-negative subgroup.