Ongoing controversy over the optimal approach to breast cancer screening has led to discordant professional society recommendations, particularly in women age 40 to 49 years. One potential solution ...is risk-based screening, where decisions around the starting age, stopping age, frequency, and modality of screening are based on individual risk to maximize the early detection of aggressive cancers and minimize the harms of screening through optimal resource utilization. We present a novel approach to risk-based screening that integrates clinical risk factors, breast density, a polygenic risk score representing the cumulative effects of genetic variants, and sequencing for moderate- and high-penetrance germline mutations. We demonstrate how thresholds of absolute risk estimates generated by our prediction tools can be used to stratify women into different screening strategies (biennial mammography, annual mammography, annual mammography with adjunctive magnetic resonance imaging, defer screening at this time) while informing the starting age of screening for women age 40 to 49 years. Our risk thresholds and corresponding screening strategies are based on current evidence but need to be tested in clinical trials. The Women Informed to Screen Depending On Measures of risk (WISDOM) Study, a pragmatic, preference-tolerant randomized controlled trial of annual vs personalized screening, will study our proposed approach. WISDOM will evaluate the efficacy, safety, and acceptability of risk-based screening beginning in the fall of 2016. The adaptive design of this trial allows continued refinement of our risk thresholds as the trial progresses, and we discuss areas where we anticipate emerging evidence will impact our approach.
Leukocyte composition of human breast cancer Ruffell, Brian; Au, Alfred; Rugo, Hope S ...
Proceedings of the National Academy of Sciences - PNAS,
02/2012, Volume:
109, Issue:
8
Journal Article
Peer reviewed
Open access
Retrospective clinical studies have used immune-based biomarkers, alone or in combination, to predict survival outcomes for women with breast cancer (BC); however, the limitations inherent to ...immunohistochemical analyses prevent comprehensive descriptions of leukocytic infiltrates, as well as evaluation of the functional state of leukocytes in BC stroma. To more fully evaluate this complexity, and to gain insight into immune responses after chemotherapy (CTX), we prospectively evaluated tumor and nonadjacent normal breast tissue from women with BC, who either had or had not received neoadjuvant CTX before surgery. Tissues were evaluated by polychromatic flow cytometry in combination with confocal immunofluorescence and immunohistochemical analysis of tissue sections. These studies revealed that activated T lymphocytes predominate in tumor tissue, whereas myeloid lineage cells are more prominant in "normal" breast tissue. Notably, residual tumors from an unselected group of BC patients treated with neoadjuvant CTX contained increased percentages of infiltrating myeloid cells, accompanied by an increased CD8/CD4 T-cell ratio and higher numbers of granzyme B-expressing cells, compared with tumors removed from patients treated primarily by surgery alone. These data provide an initial evaluation of differences in the immune microenvironment of BC compared with nonadjacent normal tissue and reveal the degree to which CTX may alter the complexity and presence of selective subsets of immune cells in tumors previously treated in the neoadjuvant setting.
Abstract
Few patients with triple negative breast cancer (TNBC) benefit from immune checkpoint inhibitors with complete and durable remissions being quite rare. Oncogenes can regulate tumor immune ...infiltration, however whether oncogenes dictate diminished response to immunotherapy and whether these effects are reversible remains poorly understood. Here, we report that TNBCs with elevated MYC expression are resistant to immune checkpoint inhibitor therapy. Using mouse models and patient data, we show that MYC signaling is associated with low tumor cell PD-L1, low overall immune cell infiltration, and low tumor cell MHC-I expression. Restoring interferon signaling in the tumor increases MHC-I expression. By combining a TLR9 agonist and an agonistic antibody against OX40 with anti-PD-L1, mice experience tumor regression and are protected from new TNBC tumor outgrowth. Our findings demonstrate that MYC-dependent immune evasion is reversible and druggable, and when strategically targeted, may improve outcomes for patients treated with immune checkpoint inhibitors.
To assess the long-term (20-year) endocrine therapy benefit in premenopausal patients with breast cancer.
Secondary analysis of the Stockholm trial (STO-5, 1990-1997) randomly assigning 924 ...premenopausal patients to 2 years of goserelin (3.6 mg subcutaneously once every 28 days), tamoxifen (40 mg orally once daily), combined goserelin and tamoxifen, or no adjuvant endocrine therapy (control) is performed. Random assignment was stratified by lymph node status; lymph node-positive patients (n = 459) were allocated to standard chemotherapy (cyclophosphamide, methotrexate, and fluorouracil). Primary tumor immunohistochemistry (n = 731) and gene expression profiling (n = 586) were conducted in 2020. The 70-gene signature identified genomic low-risk and high-risk patients. Kaplan-Meier analysis, multivariable Cox proportional hazard regression, and multivariable time-varying flexible parametric modeling assessed the long-term distant recurrence-free interval (DRFI). Swedish high-quality registries allowed a complete follow-up of 20 years.
In estrogen receptor-positive patients (n = 584, median age 47 years), goserelin, tamoxifen, and the combination significantly improved long-term distant recurrence-free interval compared with control (multivariable hazard ratio HR, 0.49; 95% CI, 0.32 to 0.75, HR, 0.57; 95% CI, 0.38 to 0.87, and HR, 0.63; 95% CI, 0.42 to 0.94, respectively). Significant goserelin-tamoxifen interaction was observed (
= .016). Genomic low-risk patients (n = 305) significantly benefitted from tamoxifen (HR, 0.24; 95% CI, 0.10 to 0.60), and genomic high-risk patients (n = 158) from goserelin (HR, 0.24; 95% CI, 0.10 to 0.54). Increased risk from the addition of tamoxifen to goserelin was seen in genomic high-risk patients (HR, 3.36; 95% CI, 1.39 to 8.07). Moreover, long-lasting 20-year tamoxifen benefit was seen in genomic low-risk patients, whereas genomic high-risk patients had early goserelin benefit.
This study shows 20-year benefit from 2 years of adjuvant endocrine therapy in estrogen receptor-positive premenopausal patients and suggests differential treatment benefit on the basis of tumor genomic characteristics. Combined goserelin and tamoxifen therapy showed no benefit over single treatment. Long-term follow-up to assess treatment benefit is critical.
Using pre-treatment gene expression, protein/phosphoprotein, and clinical data from the I-SPY2 neoadjuvant platform trial (NCT01042379), we create alternative breast cancer subtypes incorporating ...tumor biology beyond clinical hormone receptor (HR) and human epidermal growth factor receptor-2 (HER2) status to better predict drug responses. We assess the predictive performance of mechanism-of-action biomarkers from ∼990 patients treated with 10 regimens targeting diverse biology. We explore >11 subtyping schemas and identify treatment-subtype pairs maximizing the pathologic complete response (pCR) rate over the population. The best performing schemas incorporate Immune, DNA repair, and HER2/Luminal phenotypes. Subsequent treatment allocation increases the overall pCR rate to 63% from 51% using HR/HER2-based treatment selection. pCR gains from reclassification and improved patient selection are highest in HR+ subsets (>15%). As new treatments are introduced, the subtyping schema determines the minimum response needed to show efficacy. This data platform provides an unprecedented resource and supports the usage of response-based subtypes to guide future treatment prioritization.
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•The I-SPY2-990 Data Resource contains mRNA, protein, and response data over 10 drugs•Biomarkers are combined to create breast cancer subtypes to match modern treatments•Best subtyping schemas incorporate Immune, DNA repair, Luminal, and HER2 phenotypes•Treatment assignment using these response predictive subtypes may improve outcomes
Wolf et al. use gene expression, protein levels, and response data from 10 drug arms of the I-SPY2 neoadjuvant trial to create new breast cancer subtypes that incorporate tumor biology beyond clinical hormone receptor (HR) and HER2 status. Use of these response-predictive subtypes to guide treatment prioritization may improve patient outcomes.
Breast cancer patients with estrogen receptor (ER)-positive disease have a continuous long-term risk for fatal breast cancer, but the biological factors influencing this risk are unknown. We aimed to ...determine whether high intratumor heterogeneity of ER predicts an increased long-term risk (25 years) of fatal breast cancer.
The STO-3 trial enrolled 1780 postmenopausal lymph node-negative breast cancer patients randomly assigned to receive adjuvant tamoxifen vs not. The fraction of cancer cells for each ER intensity level was scored by breast cancer pathologists, and intratumor heterogeneity of ER was calculated using Rao's quadratic entropy and categorized into high and low heterogeneity using a predefined cutoff at the second tertile (67%). Long-term breast cancer-specific survival analyses by intra-tumor heterogeneity of ER were performed using Kaplan-Meier and multivariable Cox proportional hazard modeling adjusting for patient and tumor characteristics.
A statistically significant difference in long-term survival by high vs low intratumor heterogeneity of ER was seen for all ER-positive patients (P < .001) and for patients with luminal A subtype tumors (P = .01). In multivariable analyses, patients with high intratumor heterogeneity of ER had a twofold increased long-term risk as compared with patients with low intratumor heterogeneity (ER-positive: hazard ratio HR = 1.98, 95% confidence interval CI = 1.31 to 3.00; luminal A subtype tumors: HR = 2.43, 95% CI = 1.18 to 4.99).
Patients with high intratumor heterogeneity of ER had an increased long-term risk of fatal breast cancer. Interestingly, a similar long-term risk increase was seen in patients with luminal A subtype tumors. Our findings suggest that intratumor heterogeneity of ER is an independent long-term prognosticator with potential to change clinical management, especially for patients with luminal A tumors.
Journal
Journal of Clinical Oncology
It is important to reflect on how far we as a medical community have come when treating breast cancer. Ongoing research, clinical trials, and better understanding ...of biology have transformed our understanding and treatment of breast cancer. There is still much to learn. Although progress was slow for decades, treatments have evolved more quickly in the recent past. The Halsted radical mastectomy, first popularized in 1894, was performed for almost a century, and although it decreased local recurrence, it did not improve survival. This well-intentioned surgery disfigured women and was abandoned as better systemic therapies were introduced and less aggressive surgical procedures were found to be equivalent in clinical trials. The evolution of trials in the modern era has taught us an important lesson. De-escalation of surgical interventions in the setting of improved systemic therapy can lead to better patient outcomes. We present a case of a clinician with an early-stage invasive ductal carcinoma responsive to neoadjuvant endocrine therapy and who subsequently underwent a partial mastectomy with axillary sentinal lymph node biopsy. Although clinically node-negative, she was pathologically node-positive, and concerned about both optimizing her outcomes and minimizing the risk of lymphedema. The release of 10-year follow-up data from the AMAROS trial furthers our knowledge and understanding of the impact of local control measures of the axilla. The concepts illustrated by the findings of AMAROS may be applied in clinical practice and ultimately help us make rational treatment choices and support shared decision making for patients like ours.
It has been demonstrated that, in early breast cancer, there is no survival benefit to additional treatment once a patient has achieved a pathologic complete response (pCR). Together with the ...well-established prognostic association between pCR and survival, this presents a strong rationale for escalation/deescalation of neoadjuvant treatment based upon response.
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