Publications by authors named "Virginia F Borges"

98 Publications

Association of Local Therapy With Quality-of-Life Outcomes in Young Women With Breast Cancer.

JAMA Surg 2021 Sep 1:e213758. Epub 2021 Sep 1.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Importance: Increasing rates of bilateral mastectomy have been most pronounced in young women with breast cancer, but the association of surgery with long-term quality of life (QOL) remains largely unknown.

Objective: To examine the association of surgery with longer-term satisfaction and QOL in young breast cancer survivors.

Design, Setting, And Participants: This multicenter cross-sectional study of a prospective cohort was conducted from October 2016 to November 2017, at academic and community hospitals in North America. Women 40 years or older enrolled in the Young Women's Breast Cancer Study were assessed. Data analysis was performed from during a 1- to 2-year period after conclusion of the study.

Exposures: Primary breast surgery, reconstruction, and radiotherapy.

Main Outcomes And Measures: Mean BREAST-Q breast satisfaction and physical, psychosocial, and sexual well-being scores were compared by type of surgery; higher BREAST-Q scores (range, 0-100) indicate better QOL. Linear regression was used to identify demographic and clinical factors associated with BREAST-Q scores for each domain.

Results: A total of 560 women with stage 0 to III breast cancer (median age at diagnosis, 36 years; range, 17-40 years; 484 [86%] with stage 0-II disease) completed the BREAST-Q a median of 5.8 years (range, 1.9-10.4 years) from diagnosis. A total of 290 patients (52%) of patients underwent bilateral mastectomy, 110 patients (20%) underwent unilateral mastectomy, and 160 patients (28%) received breast-conserving therapy. Among mastectomy patients, 357 (89%) had reconstruction and 181 (45%) received radiotherapy. In multivariate analyses, implant-based reconstruction (vs autologous) was associated with decreased breast satisfaction (β = -7.4; 95% CI, -12.8 to -2.1; P = .007) and complex reconstruction (vs autologous) with worse physical well-being (β = -14.0; 95% CI, -22.2 to -5.7; P < .001).

Conclusions And Relevance: These results suggest that local therapy in young breast cancer survivors is persistently associated with poorer scores in multiple QOL domains, particularly among those treated with mastectomy and radiotherapy, irrespective of breast reconstruction. Socioeconomic stressors also appear to play a role.
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http://dx.doi.org/10.1001/jamasurg.2021.3758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8411359PMC
September 2021

Who are the women who enrolled in the POSITIVE trial: A global study to support young hormone receptor positive breast cancer survivors desiring pregnancy.

Breast 2021 Oct 3;59:327-338. Epub 2021 Aug 3.

Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA. Electronic address:

Background: Premenopausal women with early hormone-receptor positive (HR+) breast cancer receive 5-10 years of adjuvant endocrine therapy (ET) during which pregnancy is contraindicated and fertility may wane. The POSITIVE study investigates the impact of temporary ET interruption to allow pregnancy.

Methods: POSITIVE enrolled women with stage I-III HR + early breast cancer, ≤42 years, who had received 18-30 months of adjuvant ET and wished to interrupt ET for pregnancy. Treatment interruption for up to 2 years was permitted to allow pregnancy, delivery and breastfeeding, followed by ET resumption to complete the planned duration.

Findings: From 12/2014 to 12/2019, 518 women were enrolled at 116 institutions/20 countries/4 continents. At enrolment, the median age was 37 years and 74.9 % were nulliparous. Fertility preservation was used by 51.5 % of women. 93.2 % of patients had stage I/II disease, 66.0 % were node-negative, 54.7 % had breast conserving surgery, 61.9 % had received neo/adjuvant chemotherapy. Tamoxifen alone was the most prescribed ET (41.8 %), followed by tamoxifen + ovarian function suppression (OFS) (35.4 %). A greater proportion of North American women were <35 years at enrolment (42.7 %), had mastectomy (59.0 %) and received tamoxifen alone (59.8 %). More Asian women were nulliparous (81.0 %), had node-negative disease (76.2%) and received tamoxifen + OFS (56.0 %). More European women had received chemotherapy (69.3 %).

Interpretation: The characteristics of participants in the POSITIVE study provide insights to which patients and doctors considered it acceptable to interrupt ET to pursue pregnancy. Similarities and variations from a regional, sociodemographic, disease and treatment standpoint suggest specific sociocultural attitudes across the world.
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http://dx.doi.org/10.1016/j.breast.2021.07.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8365381PMC
October 2021

Treatment-related amenorrhea in a modern, prospective cohort study of young women with breast cancer.

NPJ Breast Cancer 2021 Jul 27;7(1):99. Epub 2021 Jul 27.

Dana-Farber Cancer Institute, Boston, MA, USA.

Young women with breast cancer experience unique treatment and survivorship issues centering on treatment-related amenorrhea (TRA), including fertility preservation and management of ovarian function as endocrine therapy. The Young Women's Breast Cancer Study (YWS) is a multi-center, prospective cohort study of women diagnosed at age ≤40, enrolled from 2006 to 2016. Menstrual outcomes were self-reported on serial surveys. We evaluated factors associated with TRA using logistic regression. One year post-diagnosis, 286/789 (36.2%) experienced TRA, yet most resumed menses (2-year TRA: 120/699; 17.2%). Features associated with 1-year TRA included older age (OR= 0.29 (0.17-0.48), OR= 0.67 (0.46-0.94), p = 0.02); normal body mass index (BMI) (OR =0.59 (0.41-0.83), p < 0.01); chemotherapy (OR = 5.55 (360-8.82), p < 0.01); and tamoxifen (OR = 1.55 (1.11-2.16), p = 0.01). TRA rates were similar across most standard regimens (docetaxel/carboplatin/trastuzumab +/- pertuzumab: 55.6%; docetaxel/cyclophosphamide +/- trastuzumab/pertuzumab: 41.8%; doxorubicin/cyclophosphamide/paclitaxel +/- trastuzumab/pertuzumab: 44.1%; but numerically lower with AC alone (25%) or paclitaxel/trastuzumab (11.1%). Among young women with breast cancer, lower BMI appears to be an independent predictor of TRA. This finding has important implications for interpretation of prior studies, future research, and patient care in our increasingly obese population. Additionally, these data describe TRA associated with use of docetaxel/cyclophosphamide, which is increasingly being used in lieu of anthracycline-containing regimens. Collectively, these data can be used to inform use of fertility preservation strategies for women who need to undergo treatment as well as the potential need for ovarian suppression following modern chemotherapy for young women with estrogen-receptor-positive breast cancer.Clinical trial registration: www.clinicaltrials.gov, NCT01468246.
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http://dx.doi.org/10.1038/s41523-021-00307-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316568PMC
July 2021

Vitamin D as a Potential Preventive Agent For Young Women's Breast Cancer.

Cancer Prev Res (Phila) 2021 Sep 9;14(9):825-838. Epub 2021 Jul 9.

Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, Oregon.

Clinical studies backed by research in animal models suggest that vitamin D may protect against the development of breast cancer, implicating vitamin D as a promising candidate for breast cancer prevention. However, despite clear preclinical evidence showing protective roles for vitamin D, broadly targeted clinical trials of vitamin D supplementation have yielded conflicting findings, highlighting the complexity of translating preclinical data to efficacy in humans. While vitamin D supplementation targeted to high-risk populations is a strategy anticipated to increase prevention efficacy, a complimentary approach is to target transient, developmental windows of elevated breast cancer risk. Postpartum mammary gland involution represents a developmental window of increased breast cancer promotion that may be poised for vitamin D supplementation. Targeting the window of involution with short-term vitamin D intervention may offer a simple, cost-effective approach for the prevention of breast cancers that develop postpartum. In this review, we highlight epidemiologic and preclinical studies linking vitamin D deficiency with breast cancer development. We discuss the underlying mechanisms through which vitamin D deficiency contributes to cancer development, with an emphasis on the anti-inflammatory activity of vitamin D. We also discuss current evidence for vitamin D as an immunotherapeutic agent and the potential for vitamin D as a preventative strategy for young woman's breast cancer.
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http://dx.doi.org/10.1158/1940-6207.CAPR-21-0114DOI Listing
September 2021

Impact of fertility concerns on endocrine therapy decisions in young breast cancer survivors.

Cancer 2021 Aug 22;127(16):2888-2894. Epub 2021 Apr 22.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: The diagnosis and treatment of breast cancer can have profound effects on a young woman's family planning and fertility, particularly among women with hormone receptor-positive breast cancer.

Methods: The Young Women's Breast Cancer Study was a multicenter cohort of women aged 40 years or younger and newly diagnosed with breast cancer from 2006 to 2016. Surveys included assessments of fertility concerns, endocrine therapy (ET) preferences, and use. Characteristics were compared between women who reported that fertility concerns affected ET decisions and those who did not. Logistic regression was used to identify factors associated with having an ET decision affected by fertility concerns.

Results: Of 643 eligible women with hormone receptor-positive, stage I to III breast cancer, one-third (213 of 643) indicated that fertility concerns affected ET decisions. In a multivariable analysis, only parity at diagnosis was significantly associated with fertility concerns affecting ET decisions (odds ratio for nulliparous vs ≥2 children, 6.96; 95% confidence interval, 4.09-11.83; odds ratio for 1 vs ≥2 children, 5.30; 95% confidence interval, 3.03-9.87). Noninitiation/nonpersistence was higher among women with fertility concerns versus those without fertility concerns (40% vs 20%; P < .0001). Among women with fertility-related ET concerns, 7% (15 of 213) did not initiate ET, and 33% (70 of 213) were nonpersistent over 5 years of follow-up. Of these women, 66% (56 of 85) reported 1 or more pregnancies or pregnancy attempts; 27% (15 of 56) had resumed ET at the last available follow-up through 5 years.

Conclusions: Concern about fertility is a contributor to adjuvant ET decisions among a substantial proportion of young breast cancer survivors. Ensuring family planning is addressed in the setting of ET recommendations should be a priority throughout the cancer care continuum.
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http://dx.doi.org/10.1002/cncr.33596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351455PMC
August 2021

Arm Morbidity After Local Therapy for Young Breast Cancer Patients.

Ann Surg Oncol 2021 Oct 21;28(11):6071-6082. Epub 2021 Apr 21.

Division of Breast Surgery, Department of Surgery, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA.

Background: The impact of patient demographics and local therapy choice on arm morbidity in young breast cancer patients is understudied despite its importance given the long survivorship period. This study assessed patient-reported arm morbidity in the Young Women's Breast Cancer Study (YWS), a prospective cohort study.

Methods: From 2006 to 2016, 1302 women with breast cancer diagnosed at the age of 40 years or younger enrolled in the YWS. The participants regularly complete surveys. The response rates are higher than 86%. Using the Breast Cancer Prevention Trial Checklist, this study examined the prevalence of patient-reported postoperative arm swelling and decreased range of motion (ROM) 1 year after diagnosis, stratified by local therapy strategy, in patients who had surgery for stages 1 to 3 disease. Logistic regression analysis was used to identify risk factors for arm morbidity.

Results: Among 888 eligible participants (median age, 37 years), 14% reported arm swelling and 34% reported decreased ROM at 1 year. Arm swelling was reported by 23.6% of the patients who had axillary lymph node dissection (ALND) and 24.6% of the patients who received ALND and post-mastectomy radiation therapy (PMRT). In the multivariable analysis, the patients who reported being financially uncomfortable or who had ALND were at higher risk of arm swelling at 1 year. Being overweight, receiving ALND after sentinel lymph node biopsy, and receiving PMRT were associated with decreased ROM at 1 year.

Conclusion: High rates of self-reported arm morbidity in young breast cancer survivors were reported, particularly in patients receiving ALND and PMRT. Attention to the risks and benefits of differing local therapy strategies for ALND and PMRT patients is warranted.
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http://dx.doi.org/10.1245/s10434-021-09947-3DOI Listing
October 2021

Clinical Outcomes for Patients With Metastatic Breast Cancer Treated With Immunotherapy Agents in Phase I Clinical Trials.

Front Oncol 2021 17;11:640690. Epub 2021 Mar 17.

Department of Medicine, University of Colorado Cancer Center, Aurora, CO, United States.

Background: Immuno-oncology (IO) agents have demonstrated efficacy across many tumor types and have led to change in standard of care. In breast cancer, atezolizumab and pembrolizumab were recently FDA-approved in combination with chemotherapy specifically for patients with PD-L1-positive metastatic triple-negative breast cancer (TNBC). However, the single agent PD-1/PD-L1 inhibitors demonstrate only modest single agent efficacy in breast cancer. The purpose of this study was to investigate the efficacy of novel IO agents in patients with metastatic breast cancer (MBC), beyond TNBC, treated in phase I clinical trials at the University of Colorado.

Methods: We performed a retrospective analysis using a database of patients with MBC who received treatment with IO agents in phase I/Ib clinical trials at the University of Colorado Hospital from January 1, 2012 to July 1, 2018. Patient demographics, treatments and clinical outcomes were obtained.

Results: We identified 43 patients treated with an IO agent either as a single agent or in combination. The average age was 53 years; 55.8% had hormone receptor-positive/HER2-negative breast cancer, 39.5% TNBC and 4.7% HER2-positive. Patients received an average of 2 prior lines of chemotherapy (range 0-7) in the metastatic setting. Most patients (72.1%) received IO alone and 27.9% received IO plus chemotherapy. Median progression-free survival (PFS) was 2.3 months and median overall survival (OS) was 12.1 months. Patients remaining on study ≥ 6 months (20.9%) were more likely to be treated with chemotherapy plus IO compared to patients with a PFS < 6 months (77.8% v. 14.7%). No differences in number of metastatic sites, prior lines of chemotherapy, breast cancer subtype, absolute lymphocyte count, or LDH were identified between patients with a PFS ≥ 6 months vs. < 6 months.

Conclusions: Our phase I experience demonstrates benefit from IO therapy that was not limited to patients with TNBC and confirms improved efficacy from IO agents in combination with chemotherapy. A subset of patients with MBC treated in phase I clinical trials with an IO agent derived prolonged clinical benefit. Predictors of response to immunotherapy in breast cancer remain uncharacterized and further research is needed to identify these factors.
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http://dx.doi.org/10.3389/fonc.2021.640690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010246PMC
March 2021

Postpartum breast cancer: mechanisms underlying its worse prognosis, treatment implications, and fertility preservation.

Int J Gynecol Cancer 2021 03;31(3):412-422

Department of Oncology, KU Leuven University Hospitals Leuven Gasthuisberg Campus, Leuven, Flanders, Belgium

Breast cancers that occur in young women up to 5 to 10 years' postpartum are associated with an increased risk for metastasis and death compared with breast cancers diagnosed in young, premenopausal women during or outside pregnancy. Given the trend to delay childbearing, this frequency is expected to increase. The (immuno)biology of postpartum breast cancer is poorly understood and, hence, it is unknown why postpartum breast cancer has an enhanced risk for metastasis or how it should be effectively targeted for improved survival. The poorer prognosis of women diagnosed within 10 years of a completed pregnancy is most often contributed to the effects of mammary gland involution. We will discuss the most recent data and mechanistic insights of the most important processes associated with involution and their role in the adverse effects of a postpartum diagnosis. We will also look into the effect of lactation on breast cancer outcome after diagnosis. In addition, we will discuss the available treatment strategies that are currently being used to treat postpartum breast cancer, keeping in mind the importance of fertility preservation in this group of young women. These additional insights might offer potential therapeutic options for the improved treatment of women with this specific condition.
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http://dx.doi.org/10.1136/ijgc-2020-002072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925817PMC
March 2021

Real-world evidence from a University Hospital system regarding the uptake of adjuvant pertuzumab and/or neratinib before and after their FDA approval.

Breast Cancer Res Treat 2021 Jun 24;187(3):883-891. Epub 2021 Feb 24.

Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO, USA.

Purpose: Adjuvant pertuzumab and neratinib are independently FDA-approved for treatment of early-stage HER2-positive breast cancer in combination with or following trastuzumab for one year, respectively. Both agents reduce the risk of recurrence; however, the absolute benefit is modest for many patients with added risk of adverse effects. The purpose of this study was to evaluate the clinical use of adjuvant pertuzumab and neratinib in patients with early-stage HER2-positive breast cancer.

Methods: Patients diagnosed with stage I-III HER2-positive breast cancer treated with trastuzumab at four University of Colorado Health hospitals between July 2016 and April 2019 were identified. Patient demographics, cancer stage, treatment, and administration of pertuzumab and/or neratinib were obtained.

Results: We identified a total of 350 patients who received adjuvant trastuzumab for stage I-III HER2-positive breast cancer; 253 (73.1%) had tumors that were ≥ T2 or node-positive disease. The rate of adjuvant pertuzumab use increased following FDA approval; pertuzumab was administered to the majority of patients with node-positive HER2-positive breast cancer. The use of adjuvant pertuzumab was associated with younger age, premenopausal status, and node-positive disease. Rates of administration of adjuvant neratinib were lower, with only 15.2% of patients receiving this therapy within 3 months of completing adjuvant trastuzumab.

Conclusion: In our cohort of patients treated within a diverse healthcare network, the majority of patients with node-positive HER2-positive breast cancer received adjuvant pertuzumab following FDA approval. The use of adjuvant neratinib was less common, potentially as a result of adverse effects, prolongation of therapy, previous administration of adjuvant pertuzumab, and modest benefit.
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http://dx.doi.org/10.1007/s10549-021-06132-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197701PMC
June 2021

New Persistent Opioid and Benzodiazepine Use After Curative-Intent Treatment in Patients With Breast Cancer.

J Natl Compr Canc Netw 2021 01 6;19(1):29-38. Epub 2021 Jan 6.

Division of Medical Oncology, Department of Medicine, and.

Background: Opioid and benzodiazepine use and abuse is a national healthcare crisis to which patients with cancer are particularly vulnerable. Long-term use and risk factors for opioid and benzodiazepine use in patients with breast cancer is poorly characterized.

Methods: We conducted a retrospective population-based study of patients with breast cancer diagnosed between 2008 and 2015 undergoing curative-intent treatment identified through the SEER-Medicare linked database. Primary outcomes were new persistent opioid use and new persistent benzodiazepine use. Factors associated with new opioid and benzodiazepine use were investigated by univariate and multivariable logistic regression.

Results: Among opioid-naïve patients, new opioid use was observed in 22,418 (67.4%). Of this group, 611 (2.7%) developed persistent opioid use at 3 months and 157 (0.7%) at 6 months after treatment. Risk factors for persistent use at 3 and 6 months included stage III disease (odds ratio [OR], 2.16; 95% CI, 1.49-3.12, and OR, 3.48; 95% CI, 1.58-7.67), surgery plus chemotherapy (OR, 1.44; 95% CI, 1.10-1.88, and OR, 2.28; 95% CI, 1.40-3.71), surgery plus chemoradiation therapy (OR, 1.47; 95% CI, 1.10-1.96, and OR, 2.34; 95% CI, 1.38-3.96), and initial tramadol use (OR, 2.66; 95% CI, 2.05-3.46, and OR, 3.12; 95% CI, 1.93-5.04). Among benzodiazepine-naïve patients, new benzodiazepine use was observed in 955 (10.3%), and 111 (11.6%) developed new persistent use at 3 months. Tamoxifen use was statistically significantly associated with new persistent benzodiazepine use at 3 months.

Conclusions: A large percentage of patients receiving curative-intent treatment of breast cancer were prescribed new opioids; however, only a small number developed new persistent opioid use. In contrast, a smaller proportion of patients received a new benzodiazepine prescription; however, new persistent use after completion of treatment was more likely and particularly related to concurrent treatment with tamoxifen.
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http://dx.doi.org/10.6004/jnccn.2020.7612DOI Listing
January 2021

Surgical Treatment after Neoadjuvant Systemic Therapy in Young Women with Breast Cancer: Results from a Prospective Cohort Study.

Ann Surg 2020 Dec 23;Publish Ahead of Print. Epub 2020 Dec 23.

Department of Surgery, University of Ulsan, College of Medicine, Asan Medical Center, Seoul, South Korea Dana-Farber Cancer Institute, Boston, MA, USA Brigham and Women's Hospital, Boston, MA, USA Mayo Clinic, Rochester, MN, USA Stanford University, Palo Alto, CA, USA Beth Israel Deaconess Medical Center, Boston, MA, USA Massachusetts General Hospital, Boston, MA, USA University of Colorado Cancer Center, Aurora, CO, USA Sunnybrook Health Sciences Centre, Toronto, Ontario, USA Metrowest Medical Center, Framingham, MA, USA.

Objective: We aimed to investigate eligibility for breast-conserving surgery (BCS) pre- and post-neoadjuvant systemic therapy (NST), and trends in the surgical treatment of young breast cancer patients.

Background: Young women with breast cancer are more likely to present with larger tumors and aggressive phenotypes, and may benefit from NST. Little is known about how response to NAC influences surgical decisions in young women.

Methods: The Young Women's Breast Cancer Study (YWS), a multicenter prospective cohort of women diagnosed with breast cancer at age ≤40, enrolled 1302 patients from 2006 to 2016. Disease characteristics, surgical recommendations, and reasons for choosing mastectomy among BCS-eligible patients were obtained through the medical record. Trends in use of NST, rate of clinical and pathologic complete response (cCR and pCR), and surgery were also assessed.

Results: Of 1117 women with unilateral stage I-III breast cancer, 315 (28%) received NST. Pre-NST, 26% were BCS eligible, 17% were borderline eligible, and 55% were ineligible. After NST, BCS eligibility increased from 26% to 42% (p < 0.0001). Among BCS-eligible patients after NST (n = 133), 41% chose mastectomy with reasons being patient preference (53%), BRCA or TP53 mutation (35%) and family history (5%). From 2006 to 2016, the rates of NST (p = 0.0012), cCR (p < 0.0001) and bilateral mastectomy (p < 0.0001) increased, but the rate of BCS did not increase (p = 0.34).

Conclusion: While the proportion of young women eligible for BCS increased after NST, many patients choose mastectomy, suggesting that surgical decisions are often driven by factors beyond extent of disease and treatment response.
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http://dx.doi.org/10.1097/SLA.0000000000004296DOI Listing
December 2020

S-nitrosylated and non-nitrosylated COX2 have differential expression and distinct subcellular localization in normal and breast cancer tissue.

NPJ Breast Cancer 2020 Nov 24;6(1):62. Epub 2020 Nov 24.

Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, 2720 SW Moody Ave., Mailing Code: KR-CDCB, Portland, OR, 97201, USA.

Immunohistochemical (IHC) staining in breast cancer shows both gain and loss of COX2 expression with disease risk and progression. We investigated four common COX2 antibody clones and found high specificity for purified human COX2 for three clones; however, recognition of COX2 in cell lysates was clone dependent. Biochemical characterization revealed two distinct forms of COX2, with SP21 recognizing an S-nitrosylated form, and CX229 and CX294 recognizing non-nitrosylated COX2 antigen. We found S-nitrosylated and non-nitrosylated COX2 occupy different subcellular locations in normal and breast cancer tissue, implicating distinct synthetic/trafficking pathways and function. Dual stains of ~2000 breast cancer cases show early-onset breast cancer had increased expression of both forms of COX2 compared to postmenopausal cases. Our results highlight the strengths of using multiple, highly characterized antibody clones for COX2 IHC studies and raise the prospect that S-nitrosylation of COX2 may play a role in breast cancer biology.
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http://dx.doi.org/10.1038/s41523-020-00204-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686348PMC
November 2020

Pregnancy after breast cancer: Results from a prospective cohort of young women with breast cancer.

Cancer 2021 Apr 1;127(7):1021-1028. Epub 2020 Dec 1.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: Many young women with newly diagnosed breast cancer are interested in future pregnancies. Prospective data regarding fertility interest and reproductive patterns after diagnosis are needed to counsel patients.

Methods: The Young Women's Breast Cancer Study is a multicenter, prospective cohort of women who were diagnosed with breast cancer at age ≤40 years between 2006 and 2016. Women complete surveys at baseline, every 6 months for 3 years, then annually. Here, the authors describe fertility interest and pregnancies within 5 years of diagnosis for women with stage 0 through III breast cancer.

Results: Of 1026 eligible participants, 368 (36%) reported interest in future biologic children at least once within 5 years after diagnosis, including 16% at 5 years after diagnosis. Among 130 women who attempted to become pregnant, 90 (69.2%) conceived; and, among 896 women who did not attempt to conceive, 18 (2.0%) became pregnant, with a total of 152 pregnancies resulting in 91 live births. Factors associated with pregnancy included younger versus older age at diagnosis (aged ≤30 vs 36-40 years: odds ratio [OR], 6.63; 95% CI, 3.18-13.83; P < .0001; aged 31-35 vs 36-40 years: OR, 5.86; 95% CI, 3.37-10.17; P < .0001) and being nulliparous versus parous (OR, 2.66; 95% CI, 1.56-4.53; P = .001). The receipt of endocrine therapy versus no endocrine therapy (OR, 0.35; 95% CI, 0.20-0.59; P = .001) was inversely associated with pregnancy.

Conclusions: Many women remain interested in future fertility in the 4 years after a breast cancer diagnosis, indicating that longitudinal fertility discussions are needed. Although a minority of those interested in having children attempted to become pregnant in the first 5 years, most who attempted to conceive did so and had live births.
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http://dx.doi.org/10.1002/cncr.33342DOI Listing
April 2021

Tumor phenotype and concordance in synchronous bilateral breast cancer in young women.

Breast Cancer Res Treat 2021 Apr 26;186(3):815-821. Epub 2020 Nov 26.

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA.

Purpose: Synchronous bilateral breast cancer is uncommon, and its pattern and incidence among younger women is unknown. Here we report the incidence, phenotypes, and long-term oncologic outcomes of bilateral breast cancer in women enrolled in the Young Women's Breast Cancer Study (YWS).

Methods: The YWS is a multi-center, prospective cohort study of women with breast cancer diagnosed at age ≤ 40 years. Those with synchronous bilateral breast cancer formed our study cohort. Tumor phenotypes were categorized as luminal A (hormone receptor (HR)+/HER2-/grade 1/2), luminal B (HR+ /HER2+ or HER2- and grade 3), HER2-enriched (HR-/HER2+), or basal-like (HR-/HER2-). Descriptive statistics were used to evaluate tumor phenotypes of bilateral cancers for concordance.

Results: Among 1302 patients enrolled in the YWS, 21 (1.6%) patients had synchronous bilateral disease. The median age of diagnosis was 38 years (range 18-40 years). Seventeen (81.0%) underwent genetic testing with 6 found to have pathogenic germline mutations in BRCA1, BRCA2, or TP53. The majority of patients (76.2%) underwent bilateral mastectomy. On pathology, 2 patients had bilateral in-situ disease, 6 had unilateral invasive and contralateral in-situ disease, and 13 had bilateral invasive disease. Of those with bilateral invasive disease, 10 (76.9%) had bilateral luminal tumors and, when fully characterized, 6 were of the same luminal subtype. Only 1 patient had bilateral basal-like breast cancer. At median follow-up of 8.2 years, 14 patients are alive with no recurrent disease.

Conclusions: Bilateral breast cancer is uncommon among young women diagnosed with breast cancer at age ≤ 40. In our cohort, the majority of invasive tumors were of the luminal phenotype, though some differed by grade or HER2 status. These findings support the need for thorough pathologic workup of bilateral disease when it is found in young women with breast cancer to determine risk and tailor treatment.
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http://dx.doi.org/10.1007/s10549-020-06027-0DOI Listing
April 2021

Extracellular vesicles from young women's breast cancer patients drive increased invasion of non-malignant cells via the Focal Adhesion Kinase pathway: a proteomic approach.

Breast Cancer Res 2020 11 23;22(1):128. Epub 2020 Nov 23.

Young Women's Breast Cancer Translational Program, Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Background: Extracellular vesicles (EVs) are small membrane particles that contribute to cancer progression and metastases by transporting biologically significant proteins and nucleic acids. They may also serve as biomarkers of various disease states or important therapeutic targets. Breast cancer EVs have the potential to change the behavior of other cells in their microenvironment. However, the proteomic content of EVs isolated from young women's breast cancer patients and the mechanisms underlying the influence of EVs on tumor cell behavior have not yet been reported.

Methods: In our current translational studies, we compared the proteomic content of EVs isolated from invasive breast cancer cell lines and plasma samples from young women's breast cancer (YWBC) patients and age-matched healthy donors using mass spectrometry. We analyzed the functionality of EVs in two dimensional tumor cell invasion assays and the gene expression changes in tumor cells after incubation with EVs.

Results: We found that treatment with EVs from both invasive breast cancer cell lines and plasma of YWBC patients altered the invasive properties of non-invasive breast cancer cells. Proteomics identified differences between EVs from YWBC patients and healthy donors that correlated with their altered function. Further, we identified gene expression changes in non-invasive breast cancer cells after treatment with EVs that implicate the Focal Adhesion Kinase (FAK) signaling pathway as a potential targetable pathway affected by breast cancer-derived EVs.

Conclusions: Our results suggest that the proteome of EVs from breast cancer patients reflects their functionality in tumor motility assays and may help elucidate the role of EVs in breast cancer progression.
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http://dx.doi.org/10.1186/s13058-020-01363-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681773PMC
November 2020

Response to neoadjuvant chemotherapy and the 21-gene Breast Recurrence Score test in young women with estrogen receptor-positive early breast cancer.

Breast Cancer Res Treat 2021 Feb 4;186(1):157-165. Epub 2020 Nov 4.

Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA.

Purpose: The 21-gene Breast Recurrence Score test predicts benefit from adjuvant chemotherapy in estrogen receptor-positive, HER2-negative (ER+/HER2-) breast cancer (BC). We examined whether the 21-gene assay predicts response to neoadjuvant chemotherapy (NCT).

Methods: We identified patients with stage I-III ER+/HER2- BC treated with NCT from the Young Women's Breast Cancer Study, a prospective cohort of women diagnosed with BC at age ≤40 years. The 21-gene assay was performed on tumor specimens removed prior to NCT either as part of clinical care or retrospectively for research. Pathological complete response (pCR) was defined as ypT0/is ypN0. The relationship between Recurrence Score result and pCR was evaluated using logistic regression modeling.

Results: 76 women received NCT for ER+/HER2- BC and were eligible for this analysis. Median age at diagnosis was 37 years (range 24-40). Scores ranged between 5 and 77 with 50% >25 and 5% <11. Median Recurrence Score result was significantly higher among tumors achieving pCR vs. non-pCR response (61.5 vs. 23, p = 0.0005). pCR rate in patients with scores >25 was 21% (8/38) vs. 5% in patients with scores <25 (2/38) (p = 0.09), with both pCRs in the <25 group in patients with scores between 21 and 25. In multivariable analysis, only Recurrence Score result was significantly associated with pCR (OR: 1.07, 95%CI 1.01-1.12, p = 0.01).

Conclusions: In young women with ER+/HER2- BC who received NCT, higher pretreatment Recurrence Score result was associated with an increased likelihood of pCR. Gene expression profile assays may have a role in decision making in young women in need of neoadjuvant therapy.
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http://dx.doi.org/10.1007/s10549-020-05989-5DOI Listing
February 2021

Semaphorin 7a is a biomarker for recurrence in postpartum breast cancer.

NPJ Breast Cancer 2020 19;6:56. Epub 2020 Oct 19.

Young Women's Breast Cancer Translational Program, University of Colorado Cancer Center, Aurora, CO USA.

Breast cancer is a global health threat and cases diagnosed in women during the years after childbirth, or postpartum breast cancers (PPBCs), have high risk for metastasis. In preclinical murine models, semaphorin 7a (SEMA7A) drives the metastatic potential of postpartum mammary tumors. Thus, we hypothesize that SEMA7A may drive metastasis of PPBC in women. We report that SEMA7A protein expression is increased in PPBCs compared to their nulliparous counterparts in our University of Colorado cohort. Additionally, tumors from PPBC patients with involved lymph nodes and lymphovascular invasion were higher on average suggesting a potential role for SEMA7A as a prognostic biomarker. Consistent with this hypothesis we identify a level of SEMA7A expression in tumors that can predict for recurrence. We propose SEMA7A as a potential biomarker and therapeutic target for PPBC patients, who currently lack strong predictors of outcome and unique targeted therapy options.
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http://dx.doi.org/10.1038/s41523-020-00198-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572422PMC
October 2020

Characterization of weaning-induced breast involution in women: implications for young women's breast cancer.

NPJ Breast Cancer 2020 16;6:55. Epub 2020 Oct 16.

Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, 2720 S Moody Avenue, Mailing Code: KR-CDCB, Portland, OR 97201 USA.

In rodents, weaning-induced mammary gland involution supports increased mammary tumor incidence, growth, and progression to metastasis. Further, the protumor attributes of gland involution are COX-2 dependent and mitigated by short-duration non-steroidal anti-inflammatory drugs (NSAIDs), suggesting a potential prevention strategy. However, the transition from lactation to postweaning breast involution has not been rigorously evaluated in healthy women. Here we queried breast biopsies from healthy women ( = 112) obtained at nulliparity, lactation, and multiple postweaning time points using quantitative immunohistochemistry. We found that mammary remodeling programs observed in rodents are mirrored in the human breast. Specifically, lactation associates with the expansion of large, secretory mammary lobules and weaning associates with lobule loss concurrent with epithelial cell death and stromal hallmarks of wound healing, including COX-2 upregulation. Altogether, our data demonstrate that weaning-induced breast involution occurs rapidly, concurrent with protumor-like attributes, and is a potential target for NSAID-based breast cancer prevention.
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http://dx.doi.org/10.1038/s41523-020-00196-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568540PMC
October 2020

Clinical outcomes of breast cancer patients treated in phase I clinical trials at University of Colorado Cancer Center.

Cancer Med 2020 12 16;9(23):8801-8808. Epub 2020 Oct 16.

Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Patients with metastatic breast cancer (MBC) refractory to standard of care therapies have a poor prognosis. The purpose of this study was to assess patient characteristics and clinical outcomes for patients with MBC treated on phase I clinical trials. We performed a retrospective review of all patients with MBC who were enrolled in phase I clinical trials at the University of Colorado Cancer Center from January 2012 to June 2018. A total of 208 patients were identified. Patients had a mean age of 57 years and received on average 2.1 (range 0-10) prior lines of chemotherapy. The majority of patients had hormone receptor-positive/HER2-negative breast cancer (58.6%) and 30.3% had triple-negative breast cancer. The median progression free survival (PFS) was 2.8 months (95% CI, 2.3-3.9) and median overall survival (OS) was 11.5 months (95% CI, 9.6-13.2). Independent factors associated with longer PFS in multivariable analysis were treatment in a breast cancer-selective trial or cohort (p = 0.016), age >50 years (p = 0.002), and ≤2 prior lines of chemotherapy in the metastatic setting (p = 0.025). Phase I clinical trials remain a valuable option for select patients with MBC and enrollment should be encouraged when available.
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http://dx.doi.org/10.1002/cam4.3487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724484PMC
December 2020

Sexual health after a breast cancer diagnosis in young women: clinical implications for patients and providers.

Breast Cancer Res Treat 2020 Dec 23;184(3):655-663. Epub 2020 Sep 23.

University of Colorado Cancer Center, Aurora, CO, USA.

Purpose: Sexual dissatisfaction after breast cancer treatment is a common phenomenon that, unfortunately, places a significant strain on young women and is becoming more common as treatment regimens rely more and more on anti-endocrine therapies.

Methods: A PubMed review of peer reviewed manuscripts between the years 1998-2020 evaluating sexual health and wellbeing in cancer patients, primarily young women with breast cancer, was conducted.

Results: There are several categories of sexual dissatisfaction women may experience as a result of her breast cancer diagnosis, including menopausal symptoms and dyspareunia, negative body image, reduced sexual desire, strained relationships and partner communication, and anxiety about cancer disclosure in dating relationships. Several methods of addressing each domain have been studied. While hormonal replacement therapy remains controversial, other medication regimens have been shown to be effective in treating menopausal symptoms and dyspareunia. Cognitive behavioral therapy, sex therapy, and couples' therapy are all effective in addressing a variety of symptoms across multiple domains.

Conclusions: Oncologists are often not prepared to discuss sexual health concerns as frequently as women need. Further work is needed to bring easily digestible and meaningful educational opportunities into clinical practice so young breast cancer survivors can receive comprehensive post-cancer survivorship care.
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http://dx.doi.org/10.1007/s10549-020-05880-3DOI Listing
December 2020

Association of Breast Cancer Surgery With Quality of Life and Psychosocial Well-being in Young Breast Cancer Survivors.

JAMA Surg 2020 11;155(11):1035-1042

Dana-Farber Cancer Institute, Boston, Massachusetts.

Importance: Young women with breast cancer are increasingly choosing bilateral mastectomy (BM), yet little is known about short-term and long-term physical and psychosocial well-being following surgery in this population.

Objective: To evaluate the differential associations of surgery with quality of life (QOL) and psychosocial outcomes from 1 to 5 years following diagnosis.

Design, Setting, And Participants: Cohort study.

Setting: Multicenter, including academic and community hospitals in North America.

Participants: Women age ≤40 when diagnosed with Stage 0-3 with unilateral breast cancer between 2006 and 2016 who had surgery and completed QOL and psychosocial assessments.

Exposures (for Observational Studies): Primary breast surgery including breast-conserving surgery (BCS), unilateral mastectomy (UM), and BM.

Main Outcomes And Measures: Physical functioning, body image, sexual health, anxiety and depressive symptoms were assessed in follow-up.

Results: Of 826 women, mean age at diagnosis was 36.1 years; most women were White non-Hispanic (86.7%). Regarding surgery, 45% had BM, 31% BCS, and 24% UM. Of women who had BM/UM, 84% had reconstruction. While physical functioning, sexuality, and body image improved over time, sexuality and body image were consistently worse (higher adjusted mean scores) among women who had BM vs BCS (body image: year 1, 1.32 vs 0.64; P < .001; year 5, 1.19 vs 0.48; P < .001; sexuality: year 1, 1.66 vs 1.20, P < .001; year 5, 1.43 vs 0.96; P < .001) or UM (body image: year 1, 1.32 vs 1.15; P = .06; year 5, 1.19 vs 0.96; P = .02; sexuality: year 1, 1.66 vs 1.41; P = .02; year 5, 1.43 vs 1.09; P = .002). Anxiety improved across groups, but adjusted mean scores remained higher among women who had BM vs BCS/UM at 1 year (BM, 7.75 vs BCS, 6.94; P = .005; BM, 7.75 vs UM, 6.58; P = .005), 2 years (BM, 7.47 vs BCS, 6.18; P < .001; BM, 7.47 vs UM, 6.07; P < .001) and 5 years (BM, 6.67 vs BCS, 5.91; P = .05; BM, 6.67 vs UM, 5.79; P = .05). There were minimal between-group differences in depression levels in follow-up.

Conclusions And Relevance: While QOL improves over time, young breast cancer survivors who undergo more extensive surgery have worse body image, sexual health, and anxiety compared with women undergoing less extensive surgery. Ensuring young women are aware of the short-term and long-term effects of surgery and receive support when making surgical decisions is warranted.
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http://dx.doi.org/10.1001/jamasurg.2020.3325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495332PMC
November 2020

Postpartum Involution and Cancer: An Opportunity for Targeted Breast Cancer Prevention and Treatments?

Cancer Res 2020 05 19;80(9):1790-1798. Epub 2020 Feb 19.

Young Women's Breast Cancer Translational Program, University of Colorado Cancer Center, Aurora, Colorado.

Childbirth at any age confers a transient increased risk for breast cancer in the first decade postpartum and this window of adverse effect extends over two decades in women with late-age first childbirth (>35 years of age). Crossover to the protective effect of pregnancy is dependent on age at first pregnancy, with young mothers receiving the most benefit. Furthermore, breast cancer diagnosis during the 5- to 10-year postpartum window associates with high risk for subsequent metastatic disease. Notably, lactation has been shown to be protective against breast cancer incidence overall, with varying degrees of protection by race, multiparity, and lifetime duration of lactation. An effect for lactation on breast cancer outcome after diagnosis has not been described. We discuss the most recent data and mechanistic insights underlying these epidemiologic findings. Postpartum involution of the breast has been identified as a key mediator of the increased risk for metastasis in women diagnosed within 5-10 years of a completed pregnancy. During breast involution, immune avoidance, increased lymphatic network, extracellular matrix remodeling, and increased seeding to the liver and lymph node work as interconnected pathways, leading to the adverse effect of a postpartum diagnosis. We al discuss a novel mechanism underlying the protective effect of breastfeeding. Collectively, these mechanistic insights offer potential therapeutic avenues for the prevention and/or improved treatment of postpartum breast cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-3448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285071PMC
May 2020

Postpartum breast cancer progression is driven by semaphorin 7a-mediated invasion and survival.

Oncogene 2020 03 4;39(13):2772-2785. Epub 2020 Feb 4.

Division of Medical Oncology, Department of Medicine, CU Anschutz Medical Campus, Aurora, CO, 80045, USA.

Young women diagnosed with breast cancer (BC) have poor prognosis due to increased rates of metastasis. In addition, women diagnosed within 10 years of most recent childbirth are approximately three times more likely to develop metastasis than age- and stage-matched nulliparous women. We define these cases as postpartum BC (PPBC) and propose that the unique biology of the postpartum mammary gland drives tumor progression. Our published results revealed roles for SEMA7A in breast tumor cell growth, motility, invasion, and tumor-associated lymphangiogenesis, all of which are also increased in preclinical models of PPBC. However, whether SEMA7A drives progression in PPBC remains largely unexplored. Our results presented herein show that silencing of SEMA7A decreases tumor growth in a model of PPBC, while overexpression is sufficient to increase growth in nulliparous hosts. Further, we show that SEMA7A promotes multiple known drivers of PPBC progression including tumor-associated COX-2 expression and fibroblast-mediated collagen deposition in the tumor microenvironment. In addition, we show for the first time that SEMA7A-expressing cells deposit fibronectin to promote tumor cell survival. Finally, we show that co-expression of SEMA7A/COX-2/FN predicts for poor prognosis in breast cancer patient cohorts. These studies suggest SEMA7A as a key mediator of BC progression, and that targeting SEMA7A may open avenues for novel therapeutic strategies.
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http://dx.doi.org/10.1038/s41388-020-1192-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103487PMC
March 2020

NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2.

J Clin Oncol 2020 02 10;38(5):444-453. Epub 2019 Dec 10.

NRG Oncology, Pittsburgh, PA.

Purpose: Adjuvant trastuzumab reduces invasive breast cancer (IBC) recurrence and risk for death in patients with HER2-amplified or overexpressing IBC. A subset of patients in the landmark trastuzumab adjuvant trials who originally tested HER2-positive but were HER2-negative by central HER2 testing appeared to possibly benefit from trastuzumab. The objective for the NSABP B-47 trial was to determine whether the addition of trastuzumab to adjuvant chemotherapy (CRx) would improve invasive disease-free survival (IDFS) in patients with HER2-negative breast cancer.

Patients And Methods: A total of 3,270 women with high-risk primary IBC were randomly assigned to CRx with or without 1 year of trastuzumab. Eligibility criteria included immunohistochemistry (IHC) score 1+ or 2+ with fluorescence in situ hybridization ratio (FISH) < 2.0 or, if ratio was not performed, HER2 gene copy number < 4.0. CRx was either docetaxel plus cyclophosphamide or doxorubicin and cyclophosphamide followed by weekly paclitaxel for 12 weeks.

Results: At a median follow-up of 46 months, the addition of trastuzumab to CRx did not improve IDFS (5-year IDFS: 89.8% with CRx plus trastuzumab [CRxT] 89.2% with CRx alone; hazard ratio [HR], 0.98; 95% CI, 0.76 to 1.25; = .85). These findings did not differ by level of HER2 IHC expression, lymph node involvement, or hormone-receptor status. For distant recurrence-free interval, 5-year estimates were 92.7% with CRxT compared with 93.6% for CRx alone (HR, 1.10; 95% CI, 0.81 to 1.50; = .55) and for overall survival (OS) were 94.8% with CRxT and 96.3% in CRx alone (HR, 1.33; 95% CI, 0.90 to 1.95; = .15). There were no unexpected toxicities from the addition of trastuzumab to CRx.

Conclusion: The addition of trastuzumab to CRx did not improve IDFS, distant recurrence-free interval, or OS in women with non-HER2-overexpressing IBC. Trastuzumab does not benefit women without IHC 3+ or FISH ratio-amplified breast cancer.
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http://dx.doi.org/10.1200/JCO.19.01455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007289PMC
February 2020

Prognostic Impact of the 21-Gene Recurrence Score Assay Among Young Women With Node-Negative and Node-Positive ER-Positive/HER2-Negative Breast Cancer.

J Clin Oncol 2020 03 6;38(7):725-733. Epub 2019 Dec 6.

Dana-Farber Cancer Institute, Boston, MA.

Purpose: The 21-gene recurrence score (RS) assay is prognostic among women with early-stage estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer and is used to inform recommendations for chemotherapy. Women ≤ 40 years of age represent a minority of patients studied using gene expression profiles.

Methods: The Young Women's Breast Cancer Study is a prospective cohort of women diagnosed with breast cancer at age ≤ 40 years and enrolled patients between 2006 and 2016 (N = 1,302). We identified patients with stage I-III ER+/HER2- breast cancer. The RS assay was performed on banked specimens for patients who had not been tested clinically. Distant recurrence-free survival (DRFS) was assessed by TAILORx and traditional RS risk groups among patients with axillary node-negative (N0) and limited node-positive (N1) breast cancer.

Results: Among eligible women (N = 577), 189 (33%) had undergone RS testing, and 320 (56%) had banked specimens sufficient for testing. Median follow-up was 6.0 years. Median age at diagnosis was 37.2 years; 300 of 509 patients (59%) had N0 breast cancer, of whom 195 (65%) had an RS of 11-25 and fewer than half (86 of 195; 44%) received chemotherapy. Six-year DRFS rates were 94.4% and 92.3% (RS < 11), 96.9% and 85.2% (RS 11-25), and 85.1% and 71.3% (RS ≥ 26) among women with N0 and N1 disease, respectively.

Conclusion: The RS assay is prognostic among young women with node-negative and limited node-positive breast cancer, representing a valuable tool for risk stratification. Disease outcomes with a median follow-up of 6 years among young women with N0 disease and an RS of 0-25, a minority of whom received chemotherapy, and node-positive disease with an RS < 11 were very good, whereas those with N0 disease and an RS ≥ 26 or N1 disease with an RS ≥ 11 experienced substantial risk of early distant recurrence.
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http://dx.doi.org/10.1200/JCO.19.01959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048163PMC
March 2020

IL-6 and IL-8 Are Linked With Myeloid-Derived Suppressor Cell Accumulation and Correlate With Poor Clinical Outcomes in Melanoma Patients.

Front Oncol 2019 8;9:1223. Epub 2019 Nov 8.

Division of Surgical Oncology, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.

We sought to identify tumor-secreted factors that altered the frequency of MDSCs and correlated with clinical outcomes in advanced melanoma patients. We focused our study on several of the many factors involved in the expansion and mobilization of MDSCs. These were identified by measuring circulating concentrations of 13 cytokines and growth factors in stage IV melanoma patients ( = 55) and healthy controls ( = 22). Based on these results, we hypothesized that IL-6 and IL-8 produced by melanoma tumor cells participate in the expansion and recruitment of MDSCs and together would be predictive of overall survival in melanoma patients. We then compared the expression of IL-6 and IL-8 in melanoma tumors to the corresponding plasma concentrations and the frequency of circulating MDSCs. These measures were correlated with clinical outcomes. Patients with high plasma concentrations of either IL-6 (40%) or IL-8 (63%), or both (35%) had worse median overall survival compared to patients with low concentrations. Patients with low peripheral concentrations and low tumoral expression of IL-6 and IL-8 showed decreased frequencies of circulating MDSCs, and patients with low frequencies of MDSCs had better overall survival. We have previously shown that IL-6 is capable of expanding MDSCs, and here we show that MDSCs are chemoattracted to IL-8. Multivariate analysis demonstrated an increased risk of death for subjects with both high IL-6 and IL-8 (HR 3.059) and high MDSCs (HR 4.265). Together these results indicate an important role for IL-6 and IL-8 in melanoma patients in which IL-6 potentially expands peripheral MDSCs and IL-8 recruits these highly immunosuppressive cells to the tumor microenvironment. This study provides further support for identifying potential therapeutics targeting IL-6, IL-8, and MDSCs to improve melanoma treatments.
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http://dx.doi.org/10.3389/fonc.2019.01223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857649PMC
November 2019

Combined inhibition of Aurora A and p21-activated kinase 1 as a new treatment strategy in breast cancer.

Breast Cancer Res Treat 2019 Sep 28;177(2):369-382. Epub 2019 Jun 28.

University of Colorado Denver, Young Women's Breast Cancer Translational Program, Aurora, CO, 80045, USA.

Purpose: The serine-threonine kinases Aurora A (AURKA) and p21-activated kinase 1 (PAK1) are frequently overexpressed in breast tumors, with overexpression promoting aggressive breast cancer phenotypes and poor clinical outcomes. Besides the well-defined roles of these proteins in control of cell division, proliferation, and invasion, both kinases support MAPK kinase pathway activation and can contribute to endocrine resistance by phosphorylating estrogen receptor alpha (ERα). PAK1 directly phosphorylates AURKA and its functional partners, suggesting potential value of inhibiting both kinases activity in tumors overexpressing PAK1 and/or AURKA. Here, for the first time, we evaluated the effect of combining the AURKA inhibitor alisertib and the PAK inhibitor FRAX1036 in preclinical models of breast cancer.

Methods: Combination of alisertib and FRAX1036 was evaluated in a panel of 13 human breast tumor cell lines and BT474 xenograft model, with assessment of the cell cycle by FACS, and signaling changes by immunohistochemistry and Western blot. Additionally, we performed in silico analysis to identify markers of response to alisertib and FRAX1036.

Results: Pharmacological inhibition of AURKA and PAK1 synergistically decreased survival of multiple tumor cell lines, showing particular effectiveness in luminal and HER2-enriched models, and inhibited growth and ERα-driven signaling in a BT474 xenograft model. In silico analysis suggested cell lines with dependence on AURKA are most likely to be sensitive to PAK1 inhibition.

Conclusion: Dual targeting of AURKA and PAK1 may be a promising therapeutic strategy for treatment of breast cancer, with a particular effectiveness in luminal and HER2-enriched tumor subtypes.
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http://dx.doi.org/10.1007/s10549-019-05329-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661032PMC
September 2019

PD-1 Blockade During Post-partum Involution Reactivates the Anti-tumor Response and Reduces Lymphatic Vessel Density.

Front Immunol 2019 11;10:1313. Epub 2019 Jun 11.

Division of Medical Oncology, Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Denver, CO, United States.

Post-partum breast cancer patients, or breast cancer patients diagnosed within 10 years of last childbirth, are ~3-5 times more likely to develop metastasis in comparison to non-post-partum, or nulliparous, patients. Additionally, post-partum patients have increased tumor-associated lymphatic vessels and LN involvement, including when controlled for size of the primary tumor. In pre-clinical, , mouse mammary tumor models of post-partum breast cancer (PPBC), tumor growth and lymphogenous tumor cell spread occur more rapidly in post-partum hosts. Here we report on PD-L1 expression by lymphatic endothelial cells and CD11b+ cells in the microenvironment of post-partum tumors, which is accompanied by an increase in PD-1 expression by T cells. Additionally, we observed increases in PD-L1 and PD-1 in whole mammary tissues during post-partum mammary gland involution; a known driver of post-partum tumor growth, invasion, and metastasis in pre-clinical models. Importantly, implantation of murine mammary tumor cells during post-partum mammary gland involution elicits a CD8+ T cell population that expresses both the co-inhibitory receptors PD-1 and Lag-3. However, upon anti-PD-1 treatment, during post-partum mammary gland involution, the involution-initiated promotional effects on tumor growth are reversed and the PD-1, Lag-3 double positive population disappears. Consequently, we observed an expansion of poly-functional CD8+ T cells that produced both IFNγ and TNFα. Finally, lymphatic vessel frequency decreased significantly following anti-PD-1 suggesting that anti-PD-1/PD-L1 targeted therapies may have efficacy in reducing tumor growth and dissemination in post-partum breast cancer patients.
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http://dx.doi.org/10.3389/fimmu.2019.01313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579890PMC
July 2020

Nonadherent behaviors among young women on adjuvant endocrine therapy for breast cancer.

Cancer 2019 09 23;125(18):3266-3274. Epub 2019 May 23.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: Young age is a known factor associated with suboptimal adherence to endocrine therapy (ET) for adjuvant breast cancer (BC) treatment. This study was aimed at assessing nonadherent behaviors and associated factors among young women with early-stage hormone receptor-positive BC.

Methods: As part of a multicenter, prospective cohort of women with a diagnosis of BC at or under the age of 40 years, participants were surveyed 30 months after their diagnosis about adherent behaviors. Among those who reported taking ET, adherence was measured with a 3-item Likert-type scale: Do you ever forget to take your ET? If you feel worse when you take your ET, do you stop taking it? Did you take your ET exactly as directed by your doctor over the last 3 months? Women reporting at least 1 nonadherent behavior were classified as nonadherers. Variables with a P value <.20 were included in a multivariable logistic model.

Results: Among 384 women, 194 (51%) were classified as nonadherers. Univariate factors that retained significance in the multivariable model included educational level (odds ratio [OR], 0.50 for high vs low; P = .04), level of social support according to the Medical Outcome Study Social Support Survey (OR, 0.98 per 1 point; P = .01), and confidence with the decision regarding ET measured on a 0 to 10 numerical scale (OR, 0.63 for high vs low; P = .04).

Conclusions: Findings from this study could help to identify young patients at higher risk for nonadherence. Interventions adapted to the level of education and aimed at reinforcing support and patients' confidence in their decision to take ET could improve adherence and associated outcomes in this population.
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http://dx.doi.org/10.1002/cncr.32192DOI Listing
September 2019
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