Prognostic Value of Breast Cancer Subtypes,Ki‐67 Proliferation Index,Age, and Pathologic Tumor Characteristics on Breast Cancer Survival in Caucasian Women

Estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor 2 (HER2) status are well‐established prognostic markers in breast cancer management. The triple negative breast carcinoma subtype (ER‐/PR‐/HER2‐) has been associated with worse overall prognosis in comparison with other subtypes in study populations consisting of ethnic minorities and young women. We evaluated the prognostic value of breast cancer subtypes, Ki‐67 proliferation index (Ki‐67PI), and pathologic tumor characteristics on breast cancer survival in Caucasian women in our institution, where greater than 90% of the total patient population is white. From 628 new invasive breast cancer cases in our data base (2000‐late 2004), 593 (94%) were identified in Caucasian women. ER/PR/HER2 breast cancer subtypes were classified based on St. Gallen International Expert Consensus recommendations from 2011. ER/PR/HER2 status and its effect on survival were analyzed using a Kaplan–Meier curve. ER/PR/HER2 status, grade, tumor‐node‐metastasis status (TNM)/anatomic stage, and age were analyzed in terms of survival in a multivariate fashion using a Cox regression. Ki‐67PI was analyzed between ER/PR/HER2 groups using the Kruskal–Wallis, Mann–Whitney U‐tests, and 2 × 5 ANOVA. Our results showed that patients with stage IIB through stage IV breast carcinomas were 2.1–16 times more likely to die than patients with stages IA‐B and IIA disease, respectively (95% CI 1.17–3.81 through 9.68–28.03, respectively), irrespective of ER/PR/HER2 subtype. Similar effect was seen with T2, N2/N3, or M1 tumors in comparison with T1, N0/N1, and M0 tumors. Chances of dying increase approximately 5% for every year increase in age. There was a significant main effect of Ki‐67PI between ER/PR/HER2 subtypes, p < .001, but Ki‐67PI could not predict survival. In summary, TNM status/anatomic stage of breast carcinomas and age are predictive of survival in our patient population of Caucasian women, but breast carcinoma subtypes and Ki‐67 proliferation index are not.     

Breast Cancer Subtypes as Defined by the Estrogen Receptor (ER), Progesterone Receptor (PR), and the Human Epidermal Growth Factor Receptor 2 (HER2) among Women with Invasive Breast Cancer in California, 1999–2004

Abstract: Breast cancer research examining either molecular profiles or biomarker subtypes has focused on the estrogen receptor negative/progesterone receptor negative/human epidermal growth factor receptor 2 negative (ER−/PR−/HER2−) and ER−/PR−/HER2+ subtypes. Less is known about the epidemiology or clinical outcome of the other subtypes. This study examines the eight combinations of ER/PR/HER2 in patients with invasive breast cancer. The 5‐year relative survival and the distribution among demographic, socioeconomic, and tumor characteristics of each of the subtypes are examined. Using the California Cancer Registry, 61,309 women with primary invasive breast cancer were classified according to ER/PR/HER2 status. Five‐year relative survival was computed for the eight subtypes. Bivariate analyses were used to assess the distribution of cases across all subtypes. Multivariate logistic regression was used to compute the adjusted odds of having one of the five subtypes with the best and worst survival. Survival varied from 96% (ER+/PR+/HER2−) to 76% (ER−/PR−/HER2+ and ER−/PR−/HER2−). The four subtypes with the poorest survival were all ER negative. Women who were younger than age 50, non‐Hispanic black or Hispanic, of the lowest SES groups, and had stage IV tumors that were undifferentiated were overrepresented in ER−/PR−/HER2+ and triple negative (ER−/PR−/HER2−) subtypes. Asian Pacific Islanders had increased odds (OR = 1.41; 95% confidence interval [CI] = 1.26–1.57) of having the ER−/PR−/HER2+ subtype. Stage III tumors (OR = 1.25; 95% CI = 1.08–1.44) and stage IV tumors (OR = 1.58; 95% CI = 1.27–1.98) had higher odds than stage I tumors of being ER−/PR−/HER2+. Stage IV tumors (OR = 0.54; 95% CI = 0.44–0.67) strongly decreased the odds of the ER−/PR−/HER2− subtype. Poorly differentiated and undifferentiated tumors were over 20 times as likely as well‐differentiated tumors of being ER−/PR−/HER2− or ER−/PR−/HER2+. There are considerable differences in survival, demographics, and tumor characteristics among the eight subtypes. We recommend reporting breast cancer as an ER/PR/HER2 subtype and precisely documenting demographic and tumor characteristics.     

Impact of Her‐2‐Targeted Therapy on Overall Survival in Patients With Her‐2 Positive Metastatic Breast Cancer

Upon disease progression on trastuzumab‐based therapy, patients with HER‐2 positive metastatic breast cancer (MBC) may switch to lapatinib or continue on trastuzumab. We aimed to assess the impact of both strategies on overall survival (OS) in all patients treated for HER‐2 positive MBC at the Medical University Vienna from 1999 until 2009. A total of 201 patients were identified from a breast cancer data base. Of these 115 (57.2%) received multiple lines of trastuzumab‐based therapy, whereas 58 (28.9%) were treated with a single line. A control group of 28 patients (13.9%) had never received trastuzumab as they were treated before 1999, when trastuzumab was registered. OS from diagnosis of metastatic disease was defined as primary study endpoint. Trastuzumab significantly prolonged OS in HER‐2 positive MBC (41 versus 13 months; p < 0.001). Administration of multiple lines further improved OS; this, however, did not reach statistical significance (47 versus 28 months; p = 0.069). Positive estrogen receptor (ER) status (HR 1.6; 95% CI 1.13–2.27) was associated with better outcome compared to negative estrogen receptor status (p = 0.02). Addition of lapatinib did not improve OS significantly in patients with prior trastuzumab‐based therapy (62 versus 47 months; p = n.s.). Patients receiving lapatinib after diagnosis of BM, however, experienced an improvement of OS (22 versus 5 months; p = 0.022). Trastuzumab improves OS in patients with HER‐2 positive MBC with further nonsignificant improvement when administered in multiple lines. Lapatinib did not further improve OS in the entire population; however, lapatinib might improve OS in patients with BM.     

HER2 positivity is not associated with adverse prognosis in high-risk estrogen receptor-positive early breast cancer patients treated with chemotherapy and trastuzumab

Co-expression of human epidermal growth factor receptor-2 (HER2) and hormone receptor (HR) predicted worse prognosis in early breast cancer before trastuzumab was developed. We aimed to investigate whether HER2 positivity was still associated with worse outcome in high-risk estrogen receptor (ER) positive patients treated with trastuzumab and chemotherapy. In the present study, 227 ER+/HER2+ patients treated with trastuzumab and chemotherapy (HER2-pos-T group) and 1097 ER+/HER2-patients treated with chemotherapy alone (HER2-neg group) during 2009 and 2015 were retrospectively enrolled for the comparison of disease-free survival (DFS) and overall survival (OS). At a median follow-up of 59 months, 174 DFS events and 69 deaths were observed. The estimated 5-year DFS rate was 94.2% in the HER2-pos-T group and 87.4% in the HER2-neg group (Log-rank P = 0.014). HER2-pos-T group was associated with significantly better DFS in multivariate analysis (HR 0.38, 95% CI: 0.22–0.67, Log-rank P = 0.001). The estimated 5-year OS rates for the two groups were 97.2% and 95.7%, respectively (Log-rank P = 0.183). In multivariable analysis, patients in the HER2-pos-T group had significantly better OS compared with those in the HER2-neg group (HR 0.40, 95% CI: 0.17–0.95, Log-rank P = 0.037). We concluded that high-risk ER+/HER2+ breast cancer patients treated with chemotherapy and trastuzumab had superior prognosis compared with ER+/HER2-patients. Therefore, HER2 positivity itself may not be considered as an unfavorable factor for ER + patients in the era of trastuzumab.     

Heterogeneity of Breast Cancer Clinical Characteristics and Outcome in US Black Women—Effect of Place of Birth

Breast cancer mortality in black women is disproportionately high; reasons for this phenomenon are still unclear. In addition to socioeconomic factors, the biology of the tumor may play a role. We analyzed 1,097 incident invasive breast cancer cases diagnosed between 2000 and 2010 in black US women from Long Island and Brooklyn. Thirty‐five percent of women had an estrogen receptor (ER) negative tumor, 46% a progesterone receptor (PR) negative tumor. ER, PR negative tumors were diagnosed at an earlier age (55.8 versus 55.3 years), at a later stage (p = 0.06), were larger in size (p = 0.04), and more frequently treated with neo‐adjuvant chemotherapy (p = 0.06) than ER, PR positive tumors. Determinants of shorter survival were: ER, PR negativity (HR: 2.2, 95% CI: 1.4–3.4), age, and stage at diagnosis (HR: 2.0; 95% CI: 1.5–2.7). ER, PR negative breast cancer born outside of the US experienced a significantly worse survival than ER, PR negative women who were born in the US. ER, PR negative tumors in black women born outside the US, mainly in the Caribbean, are biologically more aggressive than the same size and age‐matched tumors in black women born in the US. Our study suggests that environmental exposures in the country of origin may impact on host cancer interactions and cancer outcome.     

Outcome Following Local‐Regional Recurrence in Women with Early‐Stage Breast Cancer: Impact of Biologic Subtype

Local‐regional recurrence (LRR) after breast‐conserving therapy (BCT) can result in distant metastasis and decreased disease‐free survival (DFS). This study examines factors associated with DFS following LRR. The initial population included 2,233 consecutive women who underwent BCT from 1998 to 2007. Biologic subtype was approximated using a combination of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and tumor grade. Cumulative incidence of DFS after LRR was calculated. The association of clinical, pathologic, and treatment parameters with DFS was evaluated using a Cox regression model. At a median follow‐up of 105 months, 82 patients (3.7%) had a LRR. Of these, 66 (80%) were in‐breast and 16 (20%) involved the ipsilateral lymph nodes. Twenty patients subsequently developed distant metastases. Five‐year DFS after initial recurrence was 69.6% for the overall cohort. On univariate analysis, triple‐negative disease (ER/PR/HER2 negative, TNBC) was associated with reduced DFS (HR = 3.8; 95% CI: 1.8–8.1; p < 0.001). Other factors associated with reduced DFS were larger tumor size (HR = 1.3; 95% CI: 1.03–1.6; p = 0.02), shorter interval from initial diagnosis to LRR (HR = 0.98 per month; 95% CI: 0.97–0.99; p = 0.02), and no salvage surgery (HR = 0.2; 95% CI: 0.09–0.5; p = 0.001). On multivariate analysis, TNBC remained the most significant factor associated with reduced DFS (HR = 4.8; 95% CI: 2.25–10.4; p < 0.001). Compared to women with luminal A disease, those with TNBC had significantly worse DFS (37.5% versus 88.3% at 5 years; p < 0.001). Women with TNBC who developed LRR were at high risk of subsequent recurrence. Efforts should be targeted toward both preventing initial recurrence and decreasing subsequent metastasis.     

The 2003 Revised TNM Staging System for Breast Cancer: Results of Stage Re-classification on Survival and Future Comparisons among Stage Groups

BACKGROUND: Changes to TNM staging criteria for breast cancer, introduced in 2003, have resulted in stage re-classification for some tumors. The most frequently implemented change has resulted in tumors associated with more than three positive axillary nodes being upstaged.We hypothesize these TNM staging changes would result in more TNM Stage IIB, IIIA, and IIIB tumors and that disease-specific survival estimates would change under the new staging system. METHODS: A review of data was completed for patients diagnosed with breast cancer between 1 January 1995 and 31 December 2000. Tumors that would have been staged differently under the 2003 system were identified and re-classified. Clinical outcomes were determined and disease-specific survival estimates were compared relative to TNM Stage using the old and new staging systems. Data were analyzed using the log-rank test and the method of Kaplan and Meier was used to generate survival curves. RESULTS: Data were available for 2492 tumors, of which 919 were candidates for re-classification, including 829 old Stage II, 59 old Stage III, and 31 old Stage IV. Of these 919, 159 (17%) underwent stage re-classification using the new system. Separate survival estimates for patients who had been under old stage IIA/B, IIIA/B were generated; patients upstaged from IIA or IIB demonstrated a significant difference in survival. CONCLUSIONS: Stage specific survival curves indicated decreased survival for patients whose tumors had been upstaged from IIA or IIB under the old system; survival for all other patients remained unchanged.     

Loco‐regional Control After Neo‐adjuvant Chemotherapy and Conservative Treatment for Locally Advanced Breast Cancer Patients

Breast‐conserving treatment (BCT) has been validated for breast cancer patients receiving adjuvant chemotherapy. Our objective was to evaluate the difference in loco‐regional recurrence (LRR) rates between BCT and mastectomy in patients receiving radiation therapy after neo‐adjuvant chemotherapy (NCT). A retrospective data base was used to identify all patients with breast cancer undergoing NCT from 2002 to 2007. Patients with initial metastatic disease were excluded from this analysis. LRR was compared between those undergoing BCT and mastectomy. Individual variables associated with LRR were evaluated. Two hundred eighty‐four patients were included, 111 (39%) underwent BCT and 173 (61%) mastectomy. Almost all patients (99%) in both groups received postoperative radiation. Pathologic complete response was seen in 37 patients, of which 28 underwent BCT (p < 0.001). Patients receiving mastectomy had more invasive lobular carcinoma (p = 0.007) and a higher American Joint Committee on Cancer (AJCC) stage (p < 0.001) at diagnosis than those with BCT. At a median follow‐up of 6.3 years, the loco‐regional control rate was 91% (95% CI: 86–94%). The 10‐year LRR rate was similar in the BCT group (9.2% [95% CI: 4.9–16.7%]) and in the mastectomy group (10.7% [95% CI: 5.9–15.2%]; p = 0.8). Ten‐year overall survival (OS) rates (63% [95% CI: 46–79%] in the BCT group; 60% [95% CI: 47–73%] in the mastectomy group, p = 0.8) were not statistically different between the two patient populations. Multivariate analysis showed that AJCC stage ≥ III (HR: 2.6; 95% CI: 1.2–5.8; p = 0.02), negative PR (HR: 6; 95% CI: 1.2–30.6, p = 0.03), and number of positive lymph nodes ≥3 (HR: 2.5; 95% CI: 1.1–5.9; p = 0.03) were independent predictors of LRR. Ten‐year OS was similar in the BCT and in the mastectomy group (p = 0.1). The rate of LRR was low and did not significantly differ between the BCT and the mastectomy group after NCT. Randomized trials assessing whether mastectomy can be safely omitted in selected breast cancer patients (nonstage III tumors or those which do not require adjuvant hormone suppression) which respond to NCT are required.     

Prognostic Value of PD‐L1 in Breast Cancer: A Meta‐Analysis

Programmed cell death 1 ligand 1 (PD‐L1) is a promising therapeutic target for cancer immunotherapy. However, the correlation between PD‐L1 and breast cancer survival remains unclear. Here, we present the first meta‐analysis to investigate the prognostic value of PD‐L1 in breast cancer. We searched Pubmed, Embase, and Cochrane Central Register of Controlled Trials databases for relevant studies evaluating PD‐L1 expression and breast cancer survival. Fixed‐ and random‐effect meta‐analyses were conducted based on heterogeneity of included studies. Publication bias was evaluated by funnel plot and Begg's test. Overall, nine relevant studies with 8583 patients were included. PD‐L1 overexpression was found in 25.8% of breast cancer patients. PD‐L1 (+) associated with several high‐risk prognostic indicators, such as ductal cancer (p = 0.037), high tumor grade (p = 0.000), ER negativity (p = 0.000), PR negativity (p = 0.000), HER2 positivity (p = 0.001) and aggressive molecular subtypes (HER2‐rich and Basal‐like p = 0.000). PD‐L1 overexpression had no significant impact on metastasis‐free survival (HR 0.924, 95% CI = 0.747–1.141, p = 0.462), disease‐free survival (HR 1.122, 95% CI = 0.878–1.434, p = 0.357) and overall specific survival (HR 0.837, 95% CI = 0.640–1.093, p = 0.191), but significantly correlated with shortened overall survival (HR 1.573, 95% CI = 1.010–2.451, p = 0.045). PD‐L1 overexpression in breast cancer associates with multiple clinicopathological parameters that indicated poor outcome, and may increase the risk for mortality. Further standardization of PD‐L1 assessment assay and well‐controlled clinical trials are warranted to clarify its prognostic and therapeutic value.     

ER and PR Immunohistochemistry and HER2 FISH versus Oncotype DX: Implications for Breast Cancer Treatment

Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor (HER2) concordance between immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), and Oncotype DX, a commercially available RT‐PCR‐based assay which recently began reporting biomarker results was assessed. ER concordance was 98.9% (262/265), Pearson correlation coefficient (r) = 0.42, and Spearman's rank correlation (ρ) = 0.25. Positive percent agreement for ER was 98.9% (262/265). One patient with discordant ER results was not offered hormone therapy based on the preferential use of Oncotype DX. PR was concordant in 91.3% (242/265), r = 0.80, ρ = 0.75, and Cohen's kappa (κ) = 0.63. Positive percent agreement for PR was 90.5% (218/241) and negative percent agreement was 100% (24/24). HER2 concordance was 99.2% (245/247), r = 0.35, ρ = 0.28, and κ = 0.12. Positive percent agreement for HER2 was 0% (0/2) and negative percent agreement was 100% (245/245). Of the three FISH HER2‐amplified cases, two were negative and one was equivocal, and all FISH HER2‐equivocal cases (n = 3) were negative by Oncotype DX. Patients that were FISH HER2‐amplified, Oncotype DX HER2‐negative did not receive trastuzumab. Although our results demonstrated high concordance between IHC and Oncotype DX for ER and PR, our data showed poor positive percent agreement for HER2. Compared to FISH, Oncotype DX does not identify HER2‐positive breast carcinomas. The preferential use of Oncotype DX biomarker results over IHC and FISH is discouraged.     

Race and the Prognostic Influence of p53 in Women with Breast Cancer

Background

Prior study suggests that p53 status behaves as an independent marker of prognosis in African American (AA) women with breast cancer. We investigate whether the influence of p53 is unique to AAs or is present in other race/ethnic groups, and how this compares with known prognostic factors.

Methods

Cox regression models [hazard ratios (HRs), 95% confidence intervals (CIs)] were used to select and evaluate factors prognostic for all-cause mortality in 331 AA and 203 non-AA consecutively treated women.

Results

Statistically significant baseline prognostic factors were as follows. For AAs: stage [(III/I) HR 5.57; 95% CI 3.08?C10.09], grade [(higher/low) HR 1.55; 95% CI 1.14?C2.11], estrogen receptor (ER)/progesterone receptor (PR) status [(?/+) HR 2.01; 95% CI 1.38?C2.93], triple negative (ER?, PR?, HER2?) subtype [(+/?) HR 1.95; 95% CI 1.33?C2.85], and p53 status [(+/?) HR 1.69; 95% CI 1.10?C2.58]. For non-AAs: stage [HR 11.93; 95% CI 2.80?C50.84], grade [HR 1.61; 95% CI 0.96?C2.71], and ER/PR status [HR 2.13; 95% CI 1.19?C3.81]. There was a differential effect of race within p53 groups (P?=?0.05) and in multivariate modeling p53-positive status remained an adverse prognostic factor in AAs only [HR 1.82; 95% CI 1.04?C3.17]. Compared to non-AAs, 5-year unadjusted survival was worse for AAs overall (73.4% vs. 63.6%; P?=?0.032), and also for AAs with p53-positive status (80.3% vs. 54.2%; P?=?0.016), but not for AAs with p53-negative disease (68.4% vs. 67.9%; P?=?0.81).

Conclusions

Among women with breast cancer of different race/ethnicity, an adverse prognostic effect as a result of p53 positivity was only observed in AA women.     

Comparison of the Nottingham Prognostic Index and OncotypeDX© recurrence score in predicting outcome in estrogen receptor positive breast cancer

IntroductionTraditionally, Nottingham prognostic index (NPI) informed prognosis in patients with estrogen receptor positive, human epidermal growth factor receptor-2 negative, node negative (ER+/HER2-/LN-) breast cancer. At present, OncotypeDX© Recurrence Score (RS) predicts prognosis and response to adjuvant chemotherapy (AC).AimsTo compare NPI and RS for estimating prognosis in ER + breast cancer.MethodsConsecutive patients with ER+/HER2-/LN- disease were included. Disease-free (DFS) and overall survival (OS) were determined using Kaplan-Meier and Cox regression analyses.Results1471 patients met inclusion criteria. The mean follow-up was 110.7months. NPI was calculable for 1382 patients: 19.8% had NPI≤2.4 (291/1471), 33.0% had NPI 2.41–3.4 (486/1471), 30.0% had NPI 3.41–4.4 (441/1471), 10.9% had NPI 4.41–5.4 (160/1471), and 0.3% had NPI>5.4 (4/1471). In total, 329 patients underwent RS (mean RS: 18.7) and 82.1% had RS < 25 (270/329) and 17.9% had RS ≥ 25 (59/329). Using multivariable Cox regression analyses (n = 1382), NPI independently predicted DFS (Hazard ratio (HR): 1.357, 95% confidence interval (CI): 1.140–1.616, P < 0.001) and OS (HR: 1.003, 95% CI: 1.001–1.006, P = 0.024). When performing a focused analysis of those who underwent both NPI and RS (n = 329), neither biomarker predicted DFS or OS. Using Kaplan Meier analyses, NPI category predicted DFS (P = 0.008) and (P = 0.026) OS. Conversely, 21-gene RS group failed to predict DFS (P = 0.187) and OS (P = 0.296).ConclusionIn our focused analysis, neither NPI nor RS predicted survival outcomes. However, in the entire series, NPI independently predicted both DFS and OS. On the 40th anniversary since its derivation, NPI continues to provide accurate prognostication in breast cancer, outperforming RS in the current study.     

Impact of biomarkers and genetic profiling on breast cancer prognostication: A comparative analysis of the 8th edition of breast cancer staging system

The 8th edition of the American Joint Committee on Cancer (AJCC) staging guidelines combine traditional TNM system with biomarkers to reflect our current understanding of tumor biology and targeted therapy. In this study, we investigated the impact of the TNM + Biomarkers staging system and the additive value of Oncotype Dx? genomic profile recurrence score (RS) (TNM + Biomarkers+RS <11) for the staging of breast cancer (BC) using data from two tertiary referral cancer centers. Compared to TNM alone, the TNM + Biomarkers system changed the stage group in 32.7% of BCs (27% downstage, 5.7% upstage). Most (98.3%) of the downstaged BCs were estrogen receptor (ER)+/progesterone receptor (PR)+, whereas 78% of the upstaged BCs were ER?/PR?/human epidermal growth factor receptor 2 (HER2)?. Compared to TNM + Biomarkers staging, the addition of genetic profile data (TNM + Biomarker+RS <11) downstaged only <1% BCs. Our analysis suggests that for T1‐T2N0 ER+/HER2? BCs, Oncotype Dx? RS <11 provides added value as a staging parameter only in a very small group of cases compared to TNM + Biomarkers alone.     

Male breast cancer: Looking for better prognostic subgroups

PurposeMale Breast Cancer (MBC) remains a poor understood disease. Prognostic factors are not well established and specific prognostic subgroups are warranted.Patients/methodsRetrospectively revision of 111 cases treated in the same Cancer Center. Blinded-central pathological revision with immunohistochemical (IHQ) analysis for estrogen (ER), progesterone (PR) and androgen (AR) receptors, HER2, ki67 and p53 was done. Cox regression model was used for uni/multivariate survival analysis. Two classifications of Female Breast Cancer (FBC) subgroups (based in ER, PR, HER2, 2000 classification, and in ER, PR, HER2, ki67, 2013 classification) were used to achieve their prognostic value in MBC patients. Hierarchical clustering was performed to define subgroups based on the six-IHQ panel.ResultsAccording to FBC classifications, the majority of tumors were luminal: A (89.2%; 60.0%) and B (7.2%; 35.8%). Triple negative phenotype was infrequent (2.7%; 3.2%) and HER2 enriched, non-luminal, was rare (≤1% in both). In multivariate analysis the poor prognostic factors were: size >2 cm (HR:1.8; 95%CI:1.0–3.4years, p = 0.049), absence of ER (HR:4.9; 95%CI:1.7–14.3years, p = 0.004) and presence of distant metastasis (HR:5.3; 95%CI:2.2–3.1years, p < 0.001). FBC subtypes were independent prognostic factors (p = 0.009, p = 0.046), but when analyzed only luminal groups, prognosis did not differ regardless the classification used (p > 0.20). Clustering defined different subgroups, that have prognostic value in multivariate analysis (p = 0.005), with better survival in ER/PR+, AR-, HER2-and ki67/p53 low group (median: 11.5 years; 95%CI: 6.2–16.8 years) and worst in PR-group (median:4.5 years; 95%CI: 1.6–7.8 years).ConclusionFBC subtypes do not give the same prognostic information in MBC even in luminal groups. Two subgroups with distinct prognosis were identified in a common six-IHQ panel. Future studies must achieve their real prognostic value in these patients.     

Risk of Positive Sentinel Lymph Node After Neoadjuvant Systemic Therapy in Clinically Node-Negative Breast Cancer: Implications for Postmastectomy Radiation Therapy and Immediate Breast Reconstruction

Background

Residual axillary lymph node involvement after neoadjuvant systemic therapy (NST) is the determining factor for postmastectomy radiation therapy (PMRT). Preoperative identification of patients needing PMRT is essential to enable shared decision-making when choosing the optimal timing of breast reconstruction. We determined the risk of positive sentinel lymph node (SLN) after NST in clinically node-negative (cN0) breast cancer.

Methods

All cT1-3N0 patients treated with NST followed by mastectomy and SLNB between 2010 and 2016 were identified from the Netherlands Cancer Registry. Rate of positive SLN for different breast cancer subtypes was determined. Logistic regression analysis was performed to determine correlated clinicopathological variables with positive SLN.

Results

In total 788 patients were included, of whom 25.0% (197/788) had positive SLN. cT1-3N0 ER+HER2+, cT1-3N0 ER−HER2+ , and cT1-2N0 triple-negative patients had the lowest rate of positive SLN: 7.2–11.5%, 0–6.3%, and 2.9–6.2%, respectively. cT1-3N0 ER+HER2− and cT3N0 triple-negative patients had the highest rate of positive SLN: 23.8–41.7% and 30.4%, respectively. Multivariable regression analysis showed that cT2 (odds ratio [OR] 1.93; 95% confidence interval [CI] 1.01–3.96), cT3 (OR 2.56; 95% CI 1.30–5.38), grade 3 (OR 0.44; 95% CI 0.21–0.91), and ER+HER2− subtype (OR 3.94; 95% CI 1.77–8.74) were correlated with positive SLN.

Conclusions

In cT1-3N0 ER+HER2+, cT1-3N0 ER−HER2+, and cT1-2N0 triple-negative patients treated with NST, immediate reconstruction can be considered an acceptable option due to low risk of positive SLN. In cT1-3N0 ER+HER2− and cT3N0 triple-negative patients treated with NST, risks and benefits of immediate reconstruction should be discussed with patients due to the relatively high risk of positive SLN.

     

Prognostic impact of HER2-low expression in hormone receptor positive early breast cancer

BackgroundRecent data suggest that human epidermal growth factor receptor 2 (HER2)-low breast cancer may represent a distinct entity. We aimed to compare disease characteristics and outcomes between HER2-low and HER2-0 in estrogen receptor (ER) positive, early-stage breast cancer.MethodsA single center retrospective study comprising all women with ER positive, HER2 negative early breast cancer, for whom an Oncotype DX test was performed between 2005 and 2012. Women were grouped to HER2-low (immunohistochemistry +1 or +2 and in situ hybridization not amplified) or HER2-0. Clinico-pathological features and Oncotype recurrence score (RS) were collected. Data on overall-survival (OS), disease-free survival (DFS) and distant disease-free survival (DDFS) were evaluated according to HER2 expression status.Results608 women were included, of which 304 women had HER2-0 and 304 had HER2-low disease. Lobular subtype was significantly more common in HER-0 compared to HER2-low disease (17% vs. 8%, p = 0.005). The prevalence of other clinic-pathological characteristics and long-term prognosis were comparable between both groups. For women with high genomic risk (RS > 25), HER2-low expression was associated with significantly favorable OS (HR = 0.31, 95% CI 0.11–0.78, p = 0.01), DFS (HR = 0.40, 95% CI 0.20–0.82, p = 0.01) and DDFS (HR = 0.26, 95% CI 0.11–0.63, P = 0.002) compared to women with HER2-0. For women with low genomic risk (RS ≤ 25), long-term prognosis was unrelated to HER2 expression.ConclusionThe prognostic impact of HER2-low expression in early-stage luminal disease varies across the genomic risk, with significant favorable outcomes of HER2-low expression compared to HER2-0 in women with high genomic risk.     

Isolated pachymeningeal metastasis from breast cancer: Clinical features and prognostic factors

PurposeTo evaluate the clinical features and prognoses of patients with isolated pachymeningeal metastasis (IPM) from breast cancer.MethodsWe reviewed the medical records of all patients with metastatic breast cancer (MBC) treated from January 2009 to August 2016. Eligibility criteria included diagnosis of pachymeningeal metastasis based on brain magnetic resonance imaging and histologic diagnosis of primary breast cancer. We excluded patients with concomitant parenchymal or leptomeningeal metastases.ResultsThirty-eight patients who matched our inclusion criteria were included in this study. The incidence of IPM in breast cancer was 1.5% of all patients with MBC. The molecular subtype distribution was: triple negative, 29.0%; ER+/HER2−, 44.7%; ER+/HER2+, 18.4%; and ER−/HER2+, 7.9%. All isolated pachymeningeal involvement resulted from the direct extension of skull metastases. The median time to IPM from systemic metastasis was 28.6 (95% CI: 23.6–33.6) months. The median time to IPM from skull metastasis was 5.2 (95% CI: 0–10.9) months. The median overall survival (OS) from IPM was 4.0 (95% CI: 2.5–5.5) months. In patients who received chemotherapy the OS was longer than for those who received radiotherapy or supportive care only [median OS 8.9 (95% CI: 0.0–18.4), 2.8 (95% CI: 0.5–5.0), and 0.8 (95% CI: 0.6–1.1) months, respectively (p = 0.006)]. Multivariate analysis revealed that good performance status and chemotherapy were associated with better survival outcomes.ConclusionStratified evaluation is required for patients with skull metastasis from breast cancer, as pachymeningeal involvement can develop and be associated with unsuspected outcomes.     

The assessment of 8th edition AJCC prognostic staging system and a simplified staging system for breast cancer: The analytic results from the SEER database

The prognostic value of the prognostic staging system that incorporated estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor‐2 (Her‐2), and histological grade has been validated in breast cancer (BC) patients, but the staging system seems to be somewhat complex. Recently, an updated bioscore system based on these tumor biological factors was proposed. The purpose of this study was to compare the prognostic stratification between prognostic staging system of American Joint Commission on Cancer (AJCC) and a simplified staging system based on the bioscore system and anatomic TNM staging for BC patients. A total of 44 593 patients with invasive ductal carcinoma who underwent radical resection between 2010 and 2011 were reviewed using the SEER database. The patients were reclassified into different groups according to the anatomic staging system, prognostic staging system, risk bioscore system, and simplified staging system, respectively. The prognostic differences between different groups were compared and clinicopathologic features were analyzed. The anatomic TNM staging failed to clearly distinguish the prognostic difference between stage IIIB and stage IIIC. Therefore, we proposed an adjusted anatomic staging, in which T1N3 and T2N3 were downstaged from stage IIIC to stage IIIB, and T4N2 was upstaged from stage IIIB to stage IIIC. Histological grade III, ER(?), PR(?), and Her‐2(?) were identified as independent prognostic factors in the multivariate analysis, and these factors were separately marked as 1 point. There were significant survival differences among different risk points except for the comparison between 0 and 1 point. The higher the risk points, the poorer the prognosis of BC patients. In addition, the curve distance between stage IIA and stage IIB was not significantly broaden according to the prognostic staging system. However, the prognostic stratification for BC patients could be significantly improved by the simplified staging system incorporated the bioscore system and adjusted anatomic staging. Several drawbacks may still exist in the prognostic staging system of AJCC. A simplified staging system that incorporated risk score system and the anatomic staging could provide more accurate prognostic information for BC patients.     

Clinical and Pathological Factors Affecting the Sentinel Lymph Node Metastasis in Patients with Breast Cancer

Sentinel lymph node biopsy has become the routine procedure in axilla-negative breast cancer patients at most medical centers for axillary staging and local control in the recent years. Sentinel lymph node is the only focus in axillary lymph metastasis in a large portion of patients. In our trial, we investigated the clinical and pathological factors that affect the positive status of sentinel lymph node. We included 89 patients, who underwent sentinel lymph node biopsy (SLNB) with methylene blue and/or technetium-99 m Sulphur Colloid due to early-stage breast cancer. Five patients, in whom SLN was not detected and who underwent axillary dissection, were excluded from the trial. The patient age, location of the tumor, the type of the tumor, the T stage by the TNM staging system, the histological grade and type of the tumor, the status of multifocality, the lymphovascular invasion status of the tumor, and the ER, PR, and HER-neu2 status were recorded. The median age of the 89 patients was 52, 9 (±10) years. Fifty-seven (64 %) and 32 (36 %) of the 89 patients were detected to have positive and negative SLN, respectively. Assessing the SLNB positivity and the patient age, tumor size, tumor grade, multifocality, tumor localization, the T stage by the TNM staging, the ER/PR positivity/negativity, and the HER/neu2 and p53 status, the data revealed no statistically significant results with respect to SLN metastasis. The lymphovascular invasion status (LVI) was observed to statistically affect the SLN positivity (p?<?0.016). We showed that LVI could be an important marker in predicting the SLN positivity in patients with axilla-negative early-stage breast cancer. In the future, upon introduction of new biomarkers and with relevant studies, it may be possible to predict the SLNB status of patients at an adequately high accuracy and a low risk.