Clinical relevance of biomarker discordance between primary breast cancers and synchronous axillary lymph node metastases.

Clinical decision-making for patients with breast cancer (BC) is still primarily based on biomarker characteristics of the primary tumor, together with the evaluation of synchronous axillary lymph node metastasis (LNM). In this study, we investigated the prevalence of discordance in the biomarkers and surrogate subtyping between the primary BC and the LNM, and whether subsequent changes would have altered clinical treatment recommendations. In this retrospective study, 94 patients treated for unifocal primary BC and synchronous LNM at Sahlgrenska UniversityHospital during 2018 were included. Estrogen (ER) and progesterone (PR) receptor, Ki67, and HER2 status were assessed in the primary tumor and LNM using immunohistochemistry. Discordances between the primary tumor and the LNM were analyzed for each individual biomarker and surrogate subtyping. The concordance between the primary tumor and the LNM for ER, PR, Ki67, and HER2 status was 98.9%, 89.4%, 72.3%, and 95.8%, respectively. Discordance in surrogate subtyping was found in 28.7% of the tumors and matched LNMs, the majority (81.5%) of which changed to a more favorable subtype in the LNM; most commonly from Luminal B to Luminal A (48.6%). No changes in surrogate subtyping were detected where ER or HER2 status changed from negativity in the BC to positivity in the LNM, thereby showing no additional value in performing immunohistochemistry on the LNM from a treatment decision-making perspective. However, large studies need to be performed that test both the primary BCs and synchronous LNMs for more accurate diagnostics.

Clinical evaluation of molecular surrogate subtypes in patients with ipsilateral multifocal primary breast cancer.

BACKGROUND: When ipsilateral multifocal primary breast cancer (IMBC) is detected, standard routine is to evaluate the largest tumor with immunohistochemistry (IHC). As all foci are not routinely characterized, many patients may not receive optimal adjuvant treatment. Here, we assess the clinical relevance of examining at least two foci present in patients with IMBC. METHODS: Patients diagnosed and treated for IMBC at Sahlgrenska University Hospital (Gothenburg, Sweden) between 2012 and 2017 were screened. In total, 180 patients with ≥ 2 invasive foci (183 specimens) were assessed with IHC and included in this study. Expression of the estrogen (ER) and progesterone (PR) receptors, Ki67, HER2, and tumor grade were used to determine the molecular surrogate subtypes and discordance among the foci was recorded. An additional multidisciplinary team board was then held to re-assess whether treatment recommendations changed due to discordances in molecular surrogate subtype between the different foci. RESULTS: Discordance in ER, PR, HER2, and Ki67 was found in 2.7%, 19.1%, 7.7%, and 16.9% of invasive foci, respectively. Discordance in the molecular surrogate subtypes was found in 48 of 180 (26.7%) patients, which resulted in therapy changes for 11 patients (6.1%). These patients received additional endocrine therapy (n = 2), chemotherapy (n = 3), and combined chemotherapy and trastuzumab (n = 6). CONCLUSION: Taken together, when assessing at least two tumor foci with IHC, regardless of shared morphology or tumor grade between the different foci, 6.1% of patients with IMBC were recommended additional adjuvant treatment. A pathologic assessment using IHC of all foci is therefore recommended to assist in individualized treatment decision making.

Comparison of breast cancer surrogate subtyping using a closed-system RT-qPCR breast cancer assay and immunohistochemistry on 100 core needle biopsies with matching surgical specimens.

BACKGROUND: Routine clinical management of breast cancer (BC) currently depends on surrogate subtypes according to estrogen- (ER) and progesterone (PR) receptor, Ki-67, and HER2-status. However, there has been growing demand for reduced immunohistochemistry (IHC) turnaround times. The Xpert® Breast Cancer STRAT4* Assay (STRAT4)*, a standardized test for ESR1/PGR/MKi67/ERBB2 mRNA biomarker assessment, takes less than 2 hours. Here, we compared the concordance between the STRAT4 and IHC/SISH, thereby evaluating the effect of method choice on surrogate subtype assessment and adjuvant treatment decisions. METHODS: In total, 100 formalin-fixed paraffin-embedded core needle biopsy (CNB) samples and matching surgical specimens for 98 patients with primary invasive BC were evaluated using the STRAT4 assay. The concordance between STRAT4 and IHC was calculated for individual markers for the CNB and surgical specimens. In addition, we investigated whether changes in surrogate BC subtyping based on the STRAT4 results would change adjuvant treatment recommendations. RESULTS: The overall percent agreement (OPA) between STRAT4 and IHC/SISH ranged between 76 and 99% for the different biomarkers. Concordance for all four biomarkers in the surgical specimens and CNBs was only 66 and 57%, respectively. In total, 74% of surgical specimens were concordant for subtype, regardless of the method used. IHC- and STRAT4-based subtyping for the surgical specimen were shown to be discordant for 25/98 patients and 18/25 patients would theoretically have been recommended a different adjuvant treatment, primarily receiving more chemotherapy and trastuzumab. CONCLUSIONS: A comparison of data from IHC/in situ hybridization and STRAT4 demonstrated that subsequent changes in surrogate subtyping for the surgical specimen may theoretically result in more adjuvant treatment given, primarily with chemotherapy and trastuzumab.

Addition of chemotherapy to local therapy in women aged 70 years or older with triple-negative breast cancer: a propensity-matched analysis.

BACKGROUND: There is a scarcity of data exploring the benefits of adjuvant or neoadjuvant chemotherapy in the treatment of breast cancer in older women. We aimed to explore the effect of adding chemotherapy to local therapy on overall survival in older women with triple-negative breast cancer. METHODS: For this propensity-matched analysis, we used data from the National Cancer Database, a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. We included data from women aged 70 years or older with surgically treated, American Joint Committee on Cancer (AJCC) Stage I-III invasive triple-negative breast cancer diagnosed from 2004 to 2014. Patients with T1aN0M0 disease and those with incomplete data on oestrogen receptor status, progesterone receptor status, or HER2 status were excluded. To reduce bias, patients were subdivided into three groups: those who were recommended chemotherapy but did not receive it; those who received chemotherapy; and those for whom chemotherapy was not recommended and not given. The primary outcome was overall survival. Multivariate Cox regression analysis and propensity score matching were done to minimise bias. FINDINGS: Between Jan 1, 2004, and Dec, 31, 2014, 16 062 women with triple-negative breast cancer in the database met the inclusion criteria for this analysis. Median follow-up was 38·3 months (IQR 20·7-46·1, range 0-138·0; 95% CI 37·8-38·7). Collectively, the 5-year overall survival estimate of the 16 062 patients in the study cohort was 62·3% (95% CI 59·7-64·4). 5-year estimated overall survival was 68·5% (95% CI 66·4-70·6) for patients receiving chemotherapy, 61·1% (59·0-63·2) for patients recommended but not given chemotherapy, and 53·7% (51·8-55·8) for patients not recommended chemotherapy and not given chemotherapy (pooled log rank p<0·0001). Multivariate Cox regression analysis of a propensity score-matched sample comparing those who received chemotherapy with those who were recommended but not given chemotherapy (n=1884 matched pairs) identified improved overall survival with chemotherapy (hazard ratio [HR] 0·69 [95% CI 0·60-0·80]; p<0·0001). After stratifying the propensity score matching sample, this benefit persisted for node-negative women (HR 0·80 [95% CI 0·66-0·97]; p=0·007), node-positive women (0·76 [0·64-0·91]; p=0·006), and those with a comorbidity score greater than 0 (HR 0·74 [95% CI 0·59-0·94]; p=0·013). INTERPRETATION: These data support consideration of chemotherapy in the treatment of women aged 70 years or older with triple-negative breast cancer. FUNDING: None.

Adjuvant chemotherapy and survival in women aged 70 years and older with triple-negative breast cancer: a Swedish population-based propensity score-matched analysis.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer associated with poor survival, in which adjuvant systemic treatments are limited to chemotherapy. Due to competing mortality risks and comorbidities, older patients with TNBC are often undertreated with adjuvant chemotherapy, and clinical trials on this problem are scarce, despite a growing patient population. This study aimed to assess outcomes for patients aged 70 years and older with TNBC with or without chemotherapy in a national population-based registry, to provide information that can assist in treatment decisions for these patients. METHODS: In this population-based registry study, data on all patients aged 70 years and older diagnosed with primary early TNBC (larger than 5 mm in diameter and without distant metastasis) and surgically treated between Jan 1, 2009, and Dec 31, 2016, were retrieved from the Swedish National Breast Cancer Register, the Swedish Patient Register, and the Swedish Cause of Death Register. Patients with incomplete data (on oestrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2 status, surgical procedure in the breast, or information about chemotherapy) were excluded. A propensity score-matched (PSM) model was used to examine the outcomes of adjuvant chemotherapy on 5-year breast cancer-specific survival (BCSS) and 5-year overall survival (OS), adjusted for age, tumour size, tumour grade, nodal status, and comorbidities. FINDINGS: Of 1130 women eligible for analysis, 368 (32·6%) received adjuvant chemotherapy, 45 (4·0%) received neoadjuvant treatment, and 717 (63·5%) did not receive chemotherapy. 5-year BCSS was significantly improved in patients who received adjuvant chemotherapy (85% [95% CI 81-89]) compared with patients who did not receive chemotherapy (68% [64-72]; p<0·0001). A similar benefit was observed in 5-year OS (79% [95% CI 75-84] vs 49% [45-53]; p<0·0001). In our PSM analysis, 5-year BCSS in patients treated with adjuvant chemotherapy was 83% (95% CI 78-89), versus 73% (67-80; p=0·014) in patients not treated with chemotherapy. 5-year OS in patients treated with adjuvant chemotherapy was 75% (95% CI 69-82), versus 63% (57-71; p=0·029) in patients who did not receive chemotherapy. INTERPRETATION: In this PSM registry analysis of surgically treated female patients aged 70 years and older with TNBC without distant metastasis, we identified a significant benefit both in 5-year BCSS and 5-year OS with adjuvant chemotherapy versus no chemotherapy, which persisted when adjusting for age and comorbidities. These results underline the importance of considering adjuvant chemotherapy in older patients. FUNDING: Knut and Alice Wallenberg Foundation, Assar Gabrielsson Foundation.