Prophylactic mastectomy and occult malignancy: Surgical and imaging considerations.

BACKGROUND: Sentinel node biopsy (SLNB) is not routinely recommended for patients undergoing prophylactic mastectomy (PM), yet omission remains a subject of debate among surgeons. A modern patient cohort was examined to determine occult malignancy (OM) incidence within PM specimens to reinforce current recommendations. METHODS: All PM performed over a 5-year period were retrospectively identified, including women with unilateral breast cancer who underwent synchronous or delayed contralateral PM or women with elevated cancer risk who underwent bilateral PM. RESULTS: The study population included 772 patients (598 CPM, 174 BPM) with a total of 39 OM identified: 17 invasive cancers (14 CPM, 3 BPM) and 22 DCIS (19 CPM, 3 BPM). Of the 86 patients for whom SLNB was selectively performed, 1 micrometastasis was identified. In the CPM cohort, risk of OM increased with age, presence of LCIS of either breast, or presence of a non-BRCA high-penetrance gene mutation, while preoperative magnetic resonance imaging was associated with lower likelihood of OM. CONCLUSIONS: Given the low incidence of invasive OM in this updated series, routine SLNB is of low value for patients undergoing PM. For patients with indeterminate radiographic findings, discordant preoperative biopsies, LCIS, or non-BRCA high-penetrance gene mutations, selective SLNB implementation could be considered.

Management of early stage HER2 positive breast cancer and increased implementation of axillary imaging to improve identification of nodal metastasis.

BACKGROUND AND OBJECTIVES: Given the significant benefit of targeted therapies for HER2+ breast cancer patients in both the neoadjuvant and adjuvant settings, it is critical to identify all eligible patients for these treatments. We sought to investigate cT1cN0 HER2+ patients to determine the rate of postsurgical nodal positivity, and to identify presurgical factors associated with nodal positivity. We hypothesize there is a subset of underdiagnosed HER2+ patients who would benefit from preoperative axillary imaging and inclusion in neoadjuvant chemotherapy regimens. METHODS: We performed a 10-year retrospective analysis of T1 HER2+ breast cancer patients. Clinicopathologic characteristics were evaluated based on surgical nodal data. RESULTS: We identified 38 patients with cT1cN0 HER2+ cancer. Of this cohort, 24% had positive lymph nodes on final pathology. High tumor grade (p = 0.035) on core needle biopsy and the presence of lymphovascular invasion (p = 0.0036) were associated with an increased likelihood of lymph node positivity. The majority (66%) of lymph node positive patients were clinically T1c. CONCLUSIONS: We identified a 24% nodal positivity rate in clinically node negative T1 HER2+ breast cancer patients. In particular, HER2+ patients with high-grade T1c cancers should undergo preoperative diagnostic axillary imaging to expand potential benefit from targeted therapies.

Factors influencing scalp cooling discussions and use at a large academic institution: a single-center retrospective review.

PURPOSE: Chemotherapy-induced alopecia (CIA) is a stigmatizing and psychologically devasting side effect of cancer treatment. Scalp cooling therapy (SCT) is the most effective method to reduce CIA, yet it is underutilized. We investigated factors that may impact scalp cooling discussion and use. METHODS: We performed a retrospective review of cancer patients from 2000 to 2019 who had documentation of SCT discussion in the electronic medical record. The University of Michigan Rogel Cancer Center registry was used to identify the total number of cancer patients eligible for SCT during 2015-2019. Chi-square tests were used for outcome and patient characteristic comparisons (p < 0.05). RESULTS: From 2000 to 2019, 194 patients had documentation of SCT discussion. Of those, 72 (43.6%) used SCT, 93 (47.9%) did not use SCT, and the remaining 29 (17.8%) had unknown SCT use. A total of 5615 cancer patients were eligible for SCT from 2015 to 2019. As compared to those who did not have documented SCT discussions, patients who had documentation of SCT discussions in that period (n = 161, 3.0%) were more likely to be female, have breast cancer, be less than 45 years old, and live in a zip code with average income > US $100,000 (all p < 0.0001). Between 2015 and 2019, 57 patients (1.02%) used SCT. On univariate analysis, patient-initiated conversation about SCT (p = 0.01) and age less than 65 (p = 0.03) were significantly associated with decision to use SCT. CONCLUSION: There were distinctions in the types of patients who have documented discussions about SCT. Improving patient knowledge about the availability of SCT and increasing access to this technology for all eligible cancer patients may enable more patients to achieve improved quality of life by reducing or preventing CIA.

Predictors and outcomes in breast cancer patients who did or did not pursue fertility preservation.

PURPOSE: Breast cancer is the most common cancer in reproductive age women, and treatment can affect fertility; however, there is often concern regarding the safety of increased estradiol (E2) levels and potential delays in treatment with ovarian stimulation for fertility preservation (FP). The aim of this study was to compare recurrence and survival in breast cancer patients who pursued FP without concurrent letrozole to those who did not (non-FP). METHODS: We reviewed charts of women with breast cancer who contacted the FP patient navigator (PN) at Northwestern University from 01/2005-01/2018. Oncology and fertility outcome data were collected. Data were analyzed by Chi-square test or regression, as appropriate. Kaplan-Meier curves were used to examine breast cancer recurrence and survival. Statistical analyses were performed with SPSS IBM Statistics 26.0 for Windows. RESULTS: 332 patients were included, of which 157 (47.3%) underwent FP. Median days to treatment after consulting the PN was 35 in the FP group and 21 in non-FP (p < 0.05). Cancer recurrence was noted in 7 (4.7%) FP patients and 13 (7.9%) non-FP patients (NS), and mortality in 5 (3.2%) FP patients and 7 (4.2%) non-FP patients (NS). Within the FP group, no significant differences were found in recurrence or mortality based on ER status, age, BMI, peak E2 level or total gonadotropin dose. Likelihood of pursuing FP was primarily a function of age and parity, and was not affected by breast cancer stage. To date, 21 have used cryopreserved specimens, and 13 (62%) had a live birth. CONCLUSIONS: FP is safe and effective in breast cancer patients, regardless of receptor status; E2 elevations and the 2-week delay in treatment start are unlikely to be clinically significant. These findings are unique in that our institution does not use concomitant letrozole during stimulation to minimize E2 elevations in breast cancer patients.

Trends in Breast Cancer Treatment De-Implementation in Older Patients with Hormone Receptor-Positive Breast Cancer: A Mixed Methods Study.

INTRODUCTION: Guidelines allow for the omission of sentinel lymph node biopsy (SLNB) and post-lumpectomy radiotherapy in women ≥ 70 years of age with hormone receptor-positive (HR +) breast cancer. Despite this, national data suggest these procedures have not been widely de-implemented. OBJECTIVES: Our objectives were to evaluate trends in SLNB and post-lumpectomy radiotherapy utilization in patients who are eligible for omission, and evaluate patient preferences as a target for de-implementation of low-value care. METHODS: We performed a sequential explanatory mixed-methods study by first analyzing an institutional database of patients ≥ 70 years of age with HR + breast cancer who received surgical treatment from 2014 to 2018. Based on the quantitative data, we conducted semi-structured interviews with women identified as high or low utilizers of breast cancer treatments to elicit patient perspectives on de-implementation. RESULTS: SLNB and post-lumpectomy radiotherapy were performed in 68% and 43% of patients, respectively, who met the criteria for omission. There was a significant decrease in SLNB rates from 2014 to 2018. Forty-nine percent of patients were classified as high utilizers and 26% were classified as low utilizers. Qualitative analysis found that the most important factors influencing decision making regarding SLNB and post-lumpectomy radiotherapy omission for both high and low utilizers were trust in their provider and a desire for peace of mind. CONCLUSIONS: Despite efforts to de-implement low-value care, older women with HR + breast cancer remain at risk of overtreatment. Patient perspectives suggest that multi-level de-implementation strategies will need to target provider practice patterns and patient-provider communication to promote high-quality decision making and reduction in breast cancer overtreatment.

Impact of Breast Cancer Pretreatment Nodal Burden and Disease Subtype on Axillary Surgical Management.

BACKGROUND: The management of clinically node-positive breast cancer after neoadjuvant chemotherapy (NAC) has progressed with the potential to avoid the morbidity of axillary lymph node dissection in patients with complete response to therapy. This study addresses the impact of pretreatment nodal burden and tumor subtype on axillary pathologic complete response (AXpCR) in patients treated with NAC to better inform axillary surgical management. METHODS: A prospective database was reviewed to identify clinically node-positive patients who underwent NAC followed by axillary lymph node dissection. Patients were stratified in accordance with abnormal nodal burden on pretreatment axillary imaging defined as low (1-2 nodes) or high (≥3 nodes), and biologic subtype defined by hormone receptor (HR+, HR-) and HER2 (human epidermal growth factor receptor 2) status. The primary outcome was AXpCR. RESULTS: AXpCR was 43% in the study population. There was no difference in AXpCR between low and high nodal burden groups (44% versus 42%, P = 0.87). Subtype correlated to AXpCR (P < 0.001) with the highest rate (78%) in the HR-/HER2+ group. Overall, HER2+ patients had a significantly higher AXpCR than HER2- subtypes (66% versus 28% P < 0.001). HR and HER2 status were also predictive of AXpCR when comparing patient, tumor, and treatment variables. CONCLUSIONS: Biologic subtype better correlated with rates of AXpCR than nodal burden alone with the highest rates of AXpCR in HER2+ patients. Consideration of tumor biology is more informative than nodal burden when evaluating options for axillary management after NAC.

A View from the past into our collective future: the oncofertility consortium vision statement.

PURPOSE: Today, male and female adult and pediatric cancer patients, individuals transitioning between gender identities, and other individuals facing health extending but fertility limiting treatments can look forward to a fertile future. This is, in part, due to the work of members associated with the Oncofertility Consortium. METHODS: The Oncofertility Consortium is an international, interdisciplinary initiative originally designed to explore the urgent unmet need associated with the reproductive future of cancer survivors. As the strategies for fertility management were invented, developed or applied, the individuals for who the program offered hope, similarly expanded. As a community of practice, Consortium participants share information in an open and rapid manner to addresses the complex health care and quality-of-life issues of cancer, transgender and other patients. To ensure that the organization remains contemporary to the needs of the community, the field designed a fully inclusive mechanism for strategic planning and here present the findings of this process. RESULTS: This interprofessional network of medical specialists, scientists, and scholars in the law, medical ethics, religious studies and other disciplines associated with human interventions, explore the relationships between health, disease, survivorship, treatment, gender and reproductive longevity. CONCLUSION: The goals are to continually integrate the best science in the service of the needs of patients and build a community of care that is ready for the challenges of the field in the future.

Microporous scaffolds loaded with immunomodulatory lentivirus to study the contribution of immune cell populations to tumor cell recruitment in vivo.

Metastases are preceded by stochastic formation of a hospitable microenvironment known as the premetastatic niche, which has been difficult to study. Herein, we employ implantable polycaprolactone scaffolds as an engineered premetastatic niche to independently investigate the role of interleukin-10 (IL10), CXCL12, and CCL2 in recruiting immune and tumor cells and impacting breast cancer cell phenotype via lentiviral overexpression. Lentivirus delivered from scaffolds in vivo achieved sustained transgene expression for 56 days. IL10 lentiviral expression, but not CXCL12 or CCL2, significantly decreased tumor cell recruitment to scaffolds in vivo. Delivery of CXCL12 enhanced CD45+ immune cell recruitment to scaffolds while delivery of IL10 reduced immune cell recruitment. CCL2 did not alter immune cell recruitment. Tumor cell phenotype was investigated using conditioned media from immunomodulated scaffolds, with CXCL12 microenvironments reducing proliferation, and IL10 microenvironments enhancing proliferation. Migration was enhanced with CCL2 and reduced with IL10-driven microenvironments. Multiple linear regression identified populations of immune cells associated with tumor cell abundance. CD45+ immune and CD8+ T cells were associated with reduced tumor cell abundance, while CD11b+Gr1+ neutrophils and CD4+ T cells were associated with enhanced tumor cell abundance. Collectively, biomaterial scaffolds provide a tool to probe the formation and function of the premetastatic niche.

Patient and provider factors associated with the noninitiation of tamoxifen for young women at high-risk for the development of breast cancer.

We sought to identify factors associated with disparities in tamoxifen utilization among young patients at high-risk for developing breast cancer. We identified 67 premenopausal, high-risk women age 35-45, without surgical prophylaxis, who did not initiate tamoxifen. Factors associated with noninitiation were examined. About 37% of patients had no documented provider-based discussion regarding initiation. Type of high-risk diagnosis was the only factor associated with a provider-based discussion (P = .03). For patients offered tamoxifen, primary reasons for noninitiation were perceived minimal benefit (66.7%), fertility concerns (16.7%), and concerns about side effects (7.1%). Implementation of comprehensive educational strategies regarding the benefits of tamoxifen should be facilitated to improve initiation among young high-risk patients.

Young Women with Breast Cancer: Fertility Preservation Options and Management of Pregnancy-Associated Breast Cancer.

BACKGROUND: Breast cancer is the most common malignancy diagnosed in women of childbearing age. A breast cancer diagnosis in this young patient population can be uniquely complex to navigate when considering the potential impact of fertility loss associated with specific gonadotoxic therapies. Another unique challenge for young breast cancer patients is pregnancy-associated breast cancer (PABC), which occurs in approximately 1 of every 3000 pregnancies. Pregnancy adds a layer of complexity to breast cancer treatment planning as many therapies can affect the developing fetus. These two clinical challenges require nuanced multidisciplinary approaches to facilitate optimal treatment outcomes. We sought to review and summarize the management strategy options for both fertility preservation and PABC. METHODS: A guideline and literature review was performed for fertility preservation, young patients with breast cancer, and pregnancy-associated breast cancer. RESULTS: Fertility preservation options, both established and experimental, are detailed. Suggested clinical practice guidelines for PABC are also presented, which delineate breast cancer treatment recommendations based on pregnancy trimester. CONCLUSION: A multidisciplinary approach to patient care, including oncologists and early referral to reproductive specialists, can provide young breast cancer patients with options for fertility preservation. Under the guidance of a multidisciplinary treatment team, PABC can also be diagnosed and treated to permit the best possible outcomes for the mother and the developing fetus.

Axillary Pathologic Complete Response in Inflammatory Breast Cancer Patients: Implications for SLNB?

BACKGROUND: Sentinel lymph node biopsy (SLNB) is increasingly utilized after neoadjuvant chemotherapy (NAC) in responsive adenopathy, particularly with placement of a marking clip in the involved node(s). This may allow a subset of patients to avoid axillary lymph node dissection. SLNB is still discouraged in inflammatory breast cancer (IBC). The purpose of this study is to examine the axillary pathologic complete response (AXpCR) in IBC patients with clinical adenopathy. There may be an implication to approach a subset of IBC patients for SLNB after NAC. METHODS: A single-institution institutional review board-approved database was reviewed. Inclusion criteria were clinicopathologic diagnosis of IBC and age ≥ 18 years. Stage IV disease was excluded. We collected data on demographics, tumor characteristics including histology and subtype, axillary status, and treatment effect details. RESULTS: Sixty-six patients fulfilled criteria. Mean follow-up was 4.1 years. The AXpCR was 6% for luminal A and luminal B [human epidermal growth factor receptor (HER)2 -] subtypes, and 24% for basal subtype. The AXpCR rate was 64% for HER2-enriched and luminal B (HER2 +) patients. Achievement of AXpCR among these HER2-positive patients was statistically significant (p = 0.0001). There was minimal difference in achieving AXpCR in HER2-overexpressing patients regardless of hormone receptor status (p = 1.000). CONCLUSIONS: Understanding the best patients to select for use of SLNB or targeted lymph node dissection after treatment is evolving. This unique series identified and described the axillary pathologic characteristics of IBC patients following NAC. Further research is needed to confirm that the approach, axillary node clip placement prior to treatment, is feasible and accurate in IBC.

Dynamic microRNA activity identifies therapeutic targets in trastuzumab-resistant HER2+ breast cancer.

MicroRNAs (miRNAs) are implicated in numerous physiologic and pathologic processes, such as the development of resistance to chemotherapy. Determining the role of miRNAs in these processes is often accomplished through measuring miRNA abundance by polymerase chain reaction, sequencing, or microarrays. We have developed a system for the large-scale monitoring of dynamic miRNA activity and have applied this system to identify the contribution miRNA activity to the development of trastuzumab resistance in a cell model of HER2+ breast cancer. MiRNA activity measurements identified significantly different activity levels between BT474 cells (HER2 + breast cancer) and BT474R cells (HER2 + breast cancer cells selected for resistance to trastuzumab). We created a library of 32 miRNA reporter constructs, which were delivered by lentiviral transduction into cells, and miRNA activity was quantified by bioluminescence imaging. Upon treatment with the bioimmune therapy, trastuzumab, the activity of 11 miRNAs were significantly altered in parental BT474 cells, and 20 miRNAs had significantly altered activity in the therapy-resistant BT474R cell line. A combination of statistical, network and classification analysis was applied to the dynamic data, which identified miR-21 as a controlling factor in trastuzumab response. Our data suggested downregulation of miR-21 activity was associated with resistance, which was confirmed in an additional HER2 + breast cancer cell line, SKBR3. Collectively, the dynamic miRNA activity measurements and analysis provided a system to identify new potential therapeutic targets in treatment-resistant cancers.

Retrievable hydrogels for ovarian follicle transplantation and oocyte collection.

Cancer survivorship rates have drastically increased due to improved efficacy of oncologic treatments. Consequently, clinical concerns have shifted from solely focusing on survival to quality of life, with fertility preservation as an important consideration. Among fertility preservation strategies for female patients, ovarian tissue cryopreservation and subsequent reimplantation has been the only clinical option available to cancer survivors with cryopreserved tissue. However, follicle atresia after transplantation and risk of reintroducing malignant cells have prevented this procedure from becoming widely adopted in clinics. Herein, we investigated the encapsulation of ovarian follicles in alginate hydrogels that isolate the graft from the host, yet allows for maturation after transplantation at a heterotopic (i.e., subcutaneous) site, a process we termed in vivo follicle maturation. Survival of multiple follicle populations was confirmed via histology, with the notable development of the antral follicles. Collected oocytes (63%) exhibited polar body extrusion and were fertilized by intracytoplasmic sperm injection and standard in vitro fertilization procedures. Successfully fertilized oocytes developed to the pronucleus (14%), two-cell (36%), and four-cell (7%) stages. Furthermore, ovarian follicles cotransplanted with metastatic breast cancer cells within the hydrogels allowed for retrieval of the follicles, and no mice developed tumors after removal of the implant, confirming that the hydrogel prevented seeding of disease within the host. Collectively, these findings demonstrate a viable option for safe use of potentially cancer-laden ovarian donor tissue for in vivo follicle maturation within a retrievable hydrogel and subsequent oocyte collection. Ultimately, this technology may provide novel options to preserve fertility for young female patients with cancer.

Strategies to Maintain Fertility in Young Breast Cancer Patients.

Breast cancer is the most frequently occurring cancer in women of reproductive age. Treatments for breast cancer may eliminate or diminish fertility, making discussions about fertility preservation essential prior to initiation of gonadotoxic therapies. Additionally, even in patients who do not require chemotherapy, the use of adjuvant endocrine therapy will often push patients out of the reproductive window before treatment is completed. The only established methods for fertility preservation are oocyte or embryo cryopreservation, but experimental methods, such as ovarian suppression with GnRH agonists and ovarian tissue cryopreservation, show great promise. Early referral to a fertility specialist for interested patients affords patients the most fertility preservation options, with only minimal delay to cancer treatment.

The National Physicians Cooperative: transforming fertility management in the cancer setting and beyond.

Once unimaginable, fertility management is now a nationally established part of cancer care in institutions, from academic centers to community hospitals to private practices. Over the last two decades, advances in medicine and reproductive science have made it possible for men, women and children to be connected with an oncofertility specialist or offered fertility preservation soon after a cancer diagnosis. The Oncofertility Consortium's National Physicians Cooperative is a large-scale effort to engage physicians across disciplines - oncology, urology, obstetrics and gynecology, reproductive endocrinology, and behavioral health - in clinical and research activities to enable significant progress in providing fertility preservation options to children and adults. Here, we review the structure and function of the National Physicians Cooperative and identify next steps.

Surgeon and Radiation Oncologist Views on Omission of Adjuvant Radiotherapy for Older Women with Early-Stage Breast Cancer.

PURPOSE: Although clinical trials have shown no survival advantage and only a modest improvement in local control from adjuvant radiotherapy after lumpectomy in older women with stage I, estrogen receptor-positive (ER+) breast cancer, radiotherapy is commonly administered, raising concerns about overtreatment. Therefore, we sought to evaluate physician views on omission of radiotherapy in older women with favorable prognosis breast cancer. METHODS: We surveyed a national sample of 713 radiation oncologists and 879 surgeons. Of these, 1504 were eligible and 825 responded (55%). We assessed responses to clinical scenarios, knowledge of pertinent risk information, and correlates of views on radiotherapy omission. RESULTS: Omission of radiotherapy in patients age ≥70 years with stage I, ER+ breast cancer, treated with lumpectomy and endocrine therapy, was felt to be unreasonable by 40% of surgeons and 20% of radiation oncologists. Many surgeons (29%) and radiation oncologists (10%) erroneously associated radiotherapy in older women with improvement in survival. Similarly, 32% of surgeons and 19% of radiation oncologists tended to substantially overestimate the risk of locoregional recurrence in older women with omission of RT. In a scenario with an 81-year-old with multiple comorbidities, 31% of surgeons and 35% of radiation oncologists would still recommend radiotherapy. CONCLUSIONS: Many radiation oncologists and surgeons continue to consider omission of radiotherapy as substandard therapy and overestimate the benefits of radiotherapy. Surgeons, in addition to radiation oncologists, may have an opportunity to play a pivotal role in reducing overuse of aggressive care in this setting.

Systems analysis of dynamic transcription factor activity identifies targets for treatment in Olaparib resistant cancer cells.

The development of resistance to targeted therapeutics is a challenging issue for the treatment of cancer. Cancers that have mutations in BRCA, a DNA repair protein, have been treated with poly(ADP-ribose) polymerase (PARP) inhibitors, which target a second DNA repair mechanism with the aim of inducing synthetic lethality. While these inhibitors have shown promise clinically, the development of resistance can limit their effectiveness as a therapy. This study investigated mechanisms of resistance in BRCA-mutated cancer cells (HCC1937) to Olaparib (AZD2281) using TRACER, a technique for measuring dynamics of transcription factor (TF) activity in living cells. TF activity was monitored in the parental HCC1937 cell line and two distinct resistant cell lines, one with restored wild-type BRCA1 and one with acquired resistance independent of BRCA1 for 48 h during treatment with Olaparib. Partial least squares discriminant analysis (PLSDA) was used to categorize the three cell types based on TF activity, and network analysis was used to investigate the mechanism of early response to Olaparib in the study cells. NOTCH signaling was identified as a common pathway linked to resistance in both Olaparib-resistant cell types. Western blotting confirmed upregulation of NOTCH protein, and sensitivity to Olaparib was restored through co-treatment with a gamma secretase inhibitor. The identification of NOTCH signaling as a common pathway contributing to PARP inhibitor resistance by TRACER indicates the efficacy of transcription factor dynamics in identifying targets for intervention in treatment-resistant cancer and provides a new method for determining effective strategies for directed chemotherapy. Biotechnol. Bioeng. 2017;114: 2085-2095. © 2017 Wiley Periodicals, Inc.

Oncofertility program implementation increases access to fertility preservation options and assisted reproductive procedures for breast cancer patients.

BACKGROUND AND OBJECTIVES: Breast cancer treatment can cause premature ovarian failure, yet the majority of young cancer patients do not receive adequate education about treatment effects before initiating chemotherapy. We studied the impact of an oncofertility program on access to fertility preservation. METHODS: An oncofertility program was initiated to foster collaboration between oncologists and reproductive endocrinologists, and to help increase access to fertility preservation. Documented conversations about fertility concerns, specialist referrals, appointments, and fertility preservation procedures were compared between breast cancer patients from 2004 to 2006, before oncofertility program initiation, and 2007-2012, after program initiation. The study included women <45, stages 0-III, diagnosed before (n = 278) and after (n = 515) program initiation. RESULTS: Demographics for the cohorts were similar. Fertility discussions (P < 0.0001), patients interested in maintaining fertility at diagnosis (P = 0.0041), referrals to reproductive endocrinologists (P < 0.0001), appointments (P < 0.0001), and fertility preservation procedures (P < 0.0183) increased significantly after programmatic implementation. CONCLUSIONS: An oncofertility program increased discussions about fertility preservation and access to assisted reproductive procedures. This program positively impacted compliance with national guidelines advising reproductive-age cancer patients to be offered fertility preservation counseling as an initial component of the multidisciplinary care plan. J. Surg. Oncol. 2017;115:116-121. © 2016 Wiley Periodicals, Inc.

Phase II neoadjuvant clinical trial of carboplatin and eribulin in women with triple negative early-stage breast cancer (NCT01372579).

The purpose of this study is to evaluate the efficacy and safety of neoadjuvant treatment with carboplatin and eribulin in patients with early-stage triple negative breast cancer (TNBC), and to explore biomarkers based on DNA and protein expression profiles as predictors of response. Patients with histologically confirmed early-stage TNBC received carboplatin AUC 6 iv every 21 days, and eribulin 1.4 mg/m(2) day 1 and day 8 every 21 days for four cycles. The primary endpoint of the study was pathologic complete response (pCR), with secondary endpoints including clinical response and safety of the combination. Exploratory studies assessed DNA-based biomarkers [homologous recombination deficiency (HRD) score, and HR deficiency status (HRD score + BRCA1/BRCA2 mutation status)], protein-based biomarkers (Ki67, TP53, androgen receptor, Cyclin E, CDK2, Cyclin D, CDK4, Pin1 and Smad3), and clinical pretreatment factors as predictors of pCR. 13/30 (43.3 %) patients enrolled in the study achieved pCR. 24 (80.0 %) had a clinical complete or partial response. The combination was safe with mostly grade 1 and 2 toxicities. HRD score (P = 0.0024) and HR deficiency status (P = 0.0012) significantly predicted pCR. Pretreatment cytoplasmic CDK2 was also associated with pCR (P = 0.021). Significant differences in pre- versus post-treatment expression levels of nuclear Cyclin D (P = 0.020), nuclear CDK4 (P = 0.0030), and nuclear Smad3 (P = 0.015) were detected. The combination of carboplatin and eribulin is safe and efficacious in the treatment of early-stage TNBC. HRD score, HR deficiency status, and cytoplasmic CDK2 predicted pCR in this patient population.