Randomized trial promoting cancer genetic risk assessment when genetic counseling cost removed: 1-year follow-up.

PURPOSE: Cancer genetic risk assessment (CGRA) is recommended for women with ovarian and high-risk breast cancer. However, the underutilization of CGRA has long been documented, and cost has been a major barrier. In this randomized controlled trial, a tailored counseling and navigation (TCN) intervention significantly improved CGRA uptake at 6-month follow-up, compared with targeted print (TP) and usual care (UC). We aimed to examine the effect of removing genetic counseling costs on CGRA uptake by 12 months. METHODS: We recruited racially and geographically diverse women with breast and ovarian cancer from cancer registries in Colorado, New Jersey, and New Mexico. Participants assigned to TCN received telephone-based psychoeducation and navigation. After 6 months, the trial provided free genetic counseling to participants in all arms. RESULTS: At 12 months, more women in TCN obtained CGRA (26.6%) than those in TP (11.0%; odds ratio [OR] = 2.77, 95% confidence interval [CI] = 1.56 to 4.89) and UC (12.2%; OR = 2.46, 95% CI = 1.41 to 4.29). There were no significant differences in CGRA uptake between TP and UC. The Kaplan-Meier curve shows that the divergence of cumulative incidence slopes (TCN vs UC, TCN vs TP) appears primarily within the initial 6 months. CONCLUSION: TCN significantly increased CGRA uptake at the 12-month follow-up. Directly removing the costs of genetic counseling attenuated the effects of TCN, highlighting the critical enabling role played by cost coverage. Future policies and interventions should address multilevel cost-related barriers to expand patients' access to CGRA. TRIAL REGISTRATION: This trial was registered with the NIH clinical trial registry, clinicaltrials.gov, NCT03326713. https://clinicaltrials.gov/ct2/show/NCT03326713.

Ovarian Suppression: Early Menopause, Late Effects.

PURPOSE OF REVIEW: Pre-menopausal women diagnosed with hormone receptor (HR) breast cancer are candidates for prolonged hypoestrogenism to improve cancer outcomes. However, the disease benefit eclipses the toxicities associated with ovarian function suppression (OFS), which are often under-reported. RECENT FINDINGS: Increased risk of mortality from cardiovascular disease, bone disorders, and metabolic disorders is well reported in women with no history of cancer, after surgical oophorectomy or premature ovarian failure. Vasomotor symptoms, urogenital atrophy, weight gain, sexual dysfunction, cognitive decline, and sleep disturbances contribute to the increased non-compliance associated with OFS, especially in younger women. Balancing the toxicities of prolonged OFS with its benefits should be critically analyzed by providers when making recommendations for their patients. Supportive care to manage multi-system toxicities and to counteract the long-term impact on all-cause mortality should be emphasized by every cancer program. Future studies with OFS should incorporate patient outcomes and strategies for symptom management in addition to focusing on improving disease outcomes.

Long-Term Clinical and Cosmetic Outcomes of Once-Daily Accelerated Partial Breast Irradiation in Early Breast Cancer.

Purpose: Accelerated partial breast irradiation (APBI) is one of the standard treatment options in early-stage node negative breast cancer in selected patients. However, the optimal dose fractionation schedule still represents a challenge. We present the 12-year follow up results of clinical and cosmetic outcomes of once daily APBI with external beam radiation therapy which provides an APBI radiation dose equivalent to the whole breast radiation with a boost. Methods and Materials: From July 2008 to August 2010, we enrolled 34 patients with T1, T2 (< 3cm) N0 to receive once daily APBI with three dimensional conformal radiation therapy (3D-CRT) to a total dose of 49.95 Gy over 15 single daily fractions over 3 weeks at 3.33 Gy per fraction. Ipsilateral breast tumor recurrence (IBTR), acute toxicity, late toxicity and cosmesis was analyzed. The median follow-up for all patients is 144 months (12 years). Results: The median age of the patients was 61 years (range 46-83). Nine patients had ductal carcinoma in situ (DCIS) and 25 patients had invasive cancer. The median size of the tumor with DCIS pathology was 0.5 cm, while median size of the tumor with invasive cancer pathology was 1.0 cm. All of the patients had negative margins and negative nodes. Two IBTR was observed (5.8%). One patient had DCIS at recurrence and other had invasive recurrence. Two patients died due to non-cancer cause. The 12-year actuarial ipsilateral breast recurrence free survival was 93.5% and the 12-year actuarial overall survival was 93.2%. Late Grade 2 toxicity was observed in 6 patients and late grade 3 toxicity was seen in 1 patient. 91% of the patients had excellent to good cosmesis. Conclusions: This novel APBI dosing schema is based on an equivalent dose compared to whole breast radiation plus a tumor bed boost. This once daily APBI scheme is well-tolerated and demonstrates good to excellent cosmetic outcome and low rates of late complications on long term follow-up.

Adapting and implementing breast cancer follow-up in primary care: protocol for a mixed methods hybrid type 1 effectiveness-implementation cluster randomized study.

BACKGROUND: Advances in detection and treatment for breast cancer have led to an increase in the number of individuals managing significant late and long-term treatment effects. Primary care has a role in caring for patients with a history of cancer, yet there is little guidance on how to effectively implement survivorship care evidence into primary care delivery. METHODS: This protocol describes a multi-phase, mixed methods, stakeholder-driven research process that prioritizes actionable, evidence-based primary care improvements to enhance breast cancer survivorship care by integrating implementation and primary care transformation frameworks: the Exploration, Preparation, Implementation, and Sustainment (EPIS) framework and the Practice Change Model (PCM). Informed by depth interviews and a four round Delphi panel with diverse stakeholders from primary care and oncology, we will implement and evaluate an iterative clinical intervention in a hybrid type 1 effectiveness-implementation cluster randomized design in twenty-six primary care practices. Multi-component implementation strategies will include facilitation, audit and feedback, and learning collaboratives. Ongoing data collection and analysis will be performed to optimize adoption of the intervention. The primary clinical outcome to test effectiveness is comprehensive breast cancer follow-up care. Implementation will be assessed using mixed methods to explore how organizational and contextual variables affect adoption, implementation, and early sustainability for provision of follow-up care, symptom, and risk management activities at six- and 12-months post implementation. DISCUSSION: Study findings are poised to inform development of scalable, high impact intervention processes to enhance long-term follow-up care for patients with a history of breast cancer in primary care. If successful, next steps would include working with a national primary care practice-based research network to implement a national dissemination study. Actionable activities and processes identified could also be applied to development of organizational and care delivery interventions for follow-up care for other cancer sites. TRIAL REGISTRATION: Registered with ClinicalTrials.gov on June 2, 2022: NCT05400941.

Identifying Mediators of Intervention Effects Within a Randomized Controlled Trial to Motivate Cancer Genetic Risk Assessment Among Breast and Ovarian Cancer Survivors.

BACKGROUND: A theory-guided Tailored Counseling and Navigation (TCN) intervention successfully increased cancer genetic risk assessment (CGRA) uptake among cancer survivors at increased risk of hereditary breast and ovarian cancer (HBOC). Understanding the pathways by which interventions motivate behavior change is important for identifying the intervention's active components. PURPOSE: We examined whether the TCN intervention exerted effects on CGRA uptake through hypothesized theoretical mediators. METHODS: Cancer survivors at elevated risk for HBOC were recruited from three statewide cancer registries and were randomly assigned to three arms: TCN (n = 212), Targeted Print (TP, n = 216), and Usual Care (UC, n = 213). Theoretical mediators from the Extended Parallel Process Model, Health Action Planning Approach, and Ottawa Decision Support Framework were assessed at baseline and 1-month follow-up; CGRA uptake was assessed at 6 months. Generalized structural equation modeling was used for mediation analysis. RESULTS: The TCN effects were most strongly mediated by behavioral intention alone (ß = 0.49 and 0.31) and by serial mediation through self-efficacy and intention (ß = 0.041 and 0.10) when compared with UC and TP, respectively. In addition, compared with UC, the TCN also increased CGRA through increased perceived susceptibility, knowledge of HBOC, and response efficacy. CONCLUSIONS: Risk communication and behavioral change interventions for hereditary cancer should stress a person's increased genetic risk and the potential benefits of genetic counseling and testing, as well as bolster efficacy beliefs by helping remove barriers to CGRA. System-level and policy interventions are needed to further expand access.

It is recommended that cancer survivors at increased risk for heredity seek cancer genetic risk assessment (CGRA), which includes cancer genetic counseling and genetic testing. A Tailored Counseling and Navigation (TCN) intervention successfully increased CGRA uptake among women with a history of cancer who enrolled in a randomized controlled trial. Understanding reasons for TCN's effectiveness can guide future interventions that use risk messages and behavior change techniques. We conducted mediation analyses, which enabled identification of the TCN's active components. Eligible breast and ovarian cancer survivors (n = 641) were recruited from three statewide cancer registries and were assigned to three groups: TCN, Targeted Print, and Usual Care. Mediator variables drawn from behavioral and risk communication theories were assessed at baseline and 1-month follow-up; CGRA uptake was assessed at 6 months. The strongest mediator was intention to obtain a CGRA, followed by self-efficacy, perceived risk, knowledge of hereditary breast and ovarian cancer, and perceived CGRA benefits. Risk communication and behavioral change interventions for hereditary cancer should stress a person's increased genetic risk and the potential benefits of genetic counseling and testing, as well as bolster efficacy beliefs by helping remove CGRA barriers. System-level and policy interventions are needed to further expand access.

Clinical efficacy of PARP inhibitors in breast cancer.

BRCA1 and BRCA2 are key tumor suppressor genes that are essential for the homologous recombination DNA repair pathway. Loss of function mutations in these genes result in hereditary breast and ovarian cancer syndromes, which comprise approximately 5% of cases. BRCA1/2 mutations are associated with younger age of diagnosis and increased risk of recurrences. The concept of synthetic lethality led to the development of PARP inhibitors which cause cell cytotoxicity via the inhibition of PARP1, a key DNA repair protein, in cells with germline BRCA1/2 mutations. Although still poorly understood, the most well-acknowledged proposed mechanisms of action of PARP1 inhibition include the inhibition of single strand break repair, PARP trapping, and the upregulation of non-homologous end joining. Olaparib and talazoparib are PARP inhibitors that have been approved for the management of HER2-negative breast cancer in patients with germline BRCA1/2 mutations. This review article highlights the clinical efficacy of PARP inhibitors in patients with HER2-negative breast cancer in early and advanced settings.

Association Between Biomarkers and Clinical Outcomes of Pembrolizumab Monotherapy in Patients With Metastatic Triple-Negative Breast Cancer: KEYNOTE-086 Exploratory Analysis.

PURPOSE: In the two-cohort phase II KEYNOTE-086 study (ClinicalTrials.gov identifier: NCT02447003), first-line and second-line or later pembrolizumab monotherapy demonstrated antitumor activity in metastatic triple-negative breast cancer (mTNBC; N = 254). This exploratory analysis evaluates the association between prespecified molecular biomarkers and clinical outcomes. METHODS: Cohort A enrolled patients with disease progression after one or more systemic therapies for metastatic disease irrespective of PD-L1 status; Cohort B enrolled patients with previously untreated PD-L1-positive (combined positive score [CPS] ≥ 1) metastatic disease. The association between the following biomarkers as continuous variables and clinical outcomes (objective response rate [ORR], progression-free survival [PFS], and overall survival [OS]) was evaluated: PD-L1 CPS (immunohistochemistry), cluster of differentiation 8 (CD8; immunohistochemistry), stromal tumor-infiltrating lymphocyte (sTIL; hematoxylin and eosin staining), tumor mutational burden (TMB; whole-exome sequencing [WES]), homologous recombination deficiency-loss of heterozygosity, mutational signature 3 (WES), mutational signature 2 (apolipoprotein B mRNA editing catalytic polypeptide-like; WES), T-cell-inflamed gene expression profile (TcellinfGEP; RNA sequencing), and 10 non-TcellinfGEP signatures (RNA sequencing); Wald test P values were calculated, and significance was prespecified at α = 0.05. RESULTS: In the combined cohorts (A and B), PD-L1 (P = .040), CD8 (P < .001), sTILs (P = .012), TMB (P = .007), and TcellinfGEP (P = .011) were significantly associated with ORR; CD8 (P < .001), TMB (P = .034), Signature 3 (P = .009), and TcellinfGEP (P = .002) with PFS; and CD8 (P < .001), sTILs (P = .004), TMB (P = .025), and TcellinfGEP (P = .001) with OS. None of the non-TcellinfGEP signatures were associated with outcomes of pembrolizumab after adjusting for the TcellinfGEP. CONCLUSION: In this exploratory biomarker analysis from KEYNOTE-086, baseline tumor PD-L1, CD8, sTILs, TMB, and TcellinfGEP were associated with improved clinical outcomes of pembrolizumab and may help identify patients with mTNBC who are most likely to respond to pembrolizumab monotherapy.

Improving Uptake of Cancer Genetic Risk Assessment in a Remote Tailored Risk Communication and Navigation Intervention: Large Effect Size but Room to Grow.

PURPOSE: Cancer genetic risk assessment (CGRA) is recommended for women with ovarian cancer or high-risk breast cancer, yet fewer than 30% receive recommended genetic services, with the lowest rates among underserved populations. We hypothesized that compared with usual care (UC) and mailed targeted print (TP) education, CGRA uptake would be highest among women receiving a phone-based tailored risk counseling and navigation intervention (TCN). METHODS: In this three-arm randomized trial, women with ovarian or high-risk breast cancer were recruited from statewide cancer registries in Colorado, New Jersey, and New Mexico. Participants assigned to TP received a mailed educational brochure. Participants assigned to TCN received the mailed educational brochure, an initial phone-based psychoeducational session with a health coach, a follow-up letter, and a follow-up navigation phone call. RESULTS: Participants' average age was 61 years, 25.4% identified as Hispanic, 5.9% identified as non-Hispanic Black, and 17.5% lived in rural areas. At 6 months, more women in TCN received CGRA (18.7%) than those in TP (3%; odds ratio, 7.4; 95% CI, 3.0 to 18.3; P < .0001) or UC (2.5%; odds ratio, 8.9; 95% CI, 3.4 to 23.5; P < .0001). There were no significant differences in CGRA uptake between TP and UC. Commonly cited barriers to genetic counseling were lack of provider referral (33.7%) and cost (26.5%), whereas anticipated difficulty coping with test results (14.0%) and cost (41.2%) were barriers for genetic testing. CONCLUSION: TCN increased CGRA uptake in a group of geographically and ethnically diverse high-risk breast and ovarian cancer survivors. Remote personalized interventions that incorporate evidence-based health communication and behavior change strategies may increase CGRA among women recruited from statewide cancer registries.

Uveitis, a rare but important complication of adjuvant zoledronic acid for early-stage breast cancer.

Bisphosphonates such as zoledronic acid are an important part of adjuvant therapy to reduce the risk of recurrence in early-stage breast cancer. Uveitis remains one of the lesser-known side effects of zoledronic acid; prompt recognition is essential to ensure patients receive appropriate and timely care to help prevent permanent vision loss. We report a case of anterior uveitis in a postmenopausal woman who presented with visual symptoms after receiving the first dose of zoledronic acid. This case report serves to educate and increase awareness of the risk of uveitis in patients who are given zoledronic acid. This is the first and only reported case of zoledronic acid when used in the adjuvant setting for the treatment of breast cancer.

HLA inherence as a potential parameter in checkpoint inhibitor-associated autoimmune adverse event assessment.

Background: The success of immunotherapy has made it a lifesaving treatment, but not without side effects. Currently, the risk factors for developing immune-related adverse events (irAEs) in patients who receive immunotherapy are poorly understood, and there is no risk-stratifying mechanism for potentially fatal irAEs. It is postulated that oncology patients with preexisting autoimmune diseases are likely to have flares on immunotherapy. However, some patients develop de novo autoimmune conditions on immunotherapy without a prior history. Literature reports have postulated that human leukocyte antigen (HLA) inherence may play a role in irAEs. However, this potential remains underexplored. Methods: The oncology patients who developed autoimmune adverse events on immunotherapy for whom the continuation of treatment was prudent or lifesaving were selected. Of note, all nine patients received checkpoint inhibitors (CIs). Of the nine selected patients, only one had a prior history of an autoimmune condition. None of the nine selected patients had an active autoimmune condition at the time of CI initiation. Their HLA was typed, and the results were cross-referenced with the literature reports in PubMed and Google search with the corresponding autoimmune condition of each patient. Results: Herein, we report nine patients with irAEs for whom retrospective HLA typing revealed the inherence of multiple related HLA alleles that may correspond to the autoimmune condition that they had developed on immunotherapy. It is to be mentioned that the inherence of enriched disease-related HLA alleles was shared among patients with the same irAEs. These patients developed a range of irAEs including bullous pemphigoid, pemphigus foliaceus/vulgaris, thyroiditis, vitiligo, and hepatitis on immunotherapy. Although some combinations of disease-related HLA were well reported in otherwise idiopathic autoimmune diseases, a frequently repeated HLA allele combination in our patient population was found to be rarely seen in the general population. Conclusion: The authors suggest that an enriched inherence of disease-related HLA alleles may play a role in the genetic propensity for the development of irAEs in oncology patients, who receive immunotherapy, including CIs. Inherence of more than one or a cluster of particular autoimmune disease-related HLA alleles in patients who receive immunotherapy may unmask the corresponding autoimmune disease as the genotype inherence presents with the phenotype of the corresponding condition. It is suggested that enriched linked HLA genotypes, which are otherwise rare in the general population, may present as the corresponding phenotype of the autoimmune condition. Such clinical presentation, enhanced by immunotherapy, such as CIs, can play a role in risk stratifying patients for precision medicine and improve the outcome.

Understanding cancer genetic risk assessment motivations in a remote tailored risk communication and navigation intervention randomized controlled trial.

Background: National guidelines recommend cancer genetic risk assessment (CGRA) (i.e. genetic counseling prior to genetic testing) for women at increased risk for hereditary breast and ovarian cancer (HBOC). Less than one-half of eligible women obtain CGRA, leaving thousands of women and their family members without access to potentially life-saving cancer prevention interventions. Purpose: The Genetic Risk Assessment for Cancer Education and Empowerment Project (GRACE) addressed this translational gap, testing the efficacy of a tailored counseling and navigation (TCN) intervention vs. a targeted print brochure vs. usual care on CGRA intentions. Selected behavioral variables were theorized to mediate CGRA intentions. Methods: Breast and ovarian cancer survivors meeting criteria for guideline-based CGRA were recruited from three state cancer registries (N = 654), completed a baseline survey, and were randomized. TCN and targeted print arms received the brochure; TCN also participated in a tailored, telephone-based decision coaching and navigation session grounded in the Extended Parallel Process Model and Ottawa Decision Support Framework. Participants completed a one-month assessment. Logistic regression was used to compare the rate of CGRA intentions. CGRA intentions and theorized mediator scores (continuous level variables) were calculated using mixed model analysis. Results: CGRA intentions increased for TCN (53.2%) vs. targeted print (26.7%) (OR = 3.129; 95% CI: 2.028, 4.827, p < .0001) and TCN vs. usual care (23.1%) (OR = 3.778, CI: 2.422, 5.894, p < .0001). Perceived risk (p = 0.023) and self-efficacy (p = 0.035) mediated CGRA intentions in TCN. Conclusions: Improvements in CGRA intentions and theorized mediators support the use of a tailored communication intervention among women at increased HBOC risk. (Clinicaltrials.gov: NCT03326713.)Trial registration: ClinicalTrials.gov identifier: NCT03326713.

Immune Checkpoint Inhibitors in Triple Negative Breast Cancer: The Search for the Optimal Biomarker.

Triple negative breast cancer (TNBC) is a high-risk and aggressive malignancy characterized by the absence of estrogen receptors (ER) and progesterone receptors (PR) on the surface of malignant cells, and by the lack of overexpression of human epidermal growth factor 2 (HER2). It has limited therapeutic options compared to other subtypes of breast cancer. There is now a growing body of evidence on the role of immunotherapy in TNBC, however much of the data from clinical trials is conflicting and thus, challenging for clinicians to integrate the data into clinical practice. Landmark phase III trials using immunotherapy in the early-stage neoadjuvant setting concluded that the addition of immunotherapy to chemotherapy improved the pathologic complete response (pCR) rate compared to chemotherapy with placebo while others found no significant improvement in pCR. Phase III trials have investigated the utility of immunotherapy in previously untreated metastatic TNBC, and these studies have similarly arrived at inconsistent conclusions. Some studies showed no benefit while others demonstrated a clinically significant improvement in overall survival in the PD-L1 positive population. It is not yet clear which biomarkers are most useful, and assays for these biomarkers have not been standardized. Given the often serious and severe side effects of immunotherapy, it is important and necessary to identify predictive biomarkers of response and resistance in order to enhance patient selection. In this review, we will discuss both the challenges of traditional biomarkers and the opportunities of emerging biomarkers for patient selection.

Durable Response to PD1 Inhibitor Pembrolizumab in a Metastatic, Metaplastic Breast Cancer.

Metaplastic breast cancer (MBC) is a rare and aggressive subtype of breast cancer. Tumor characteristics typically feature estrogen receptor, progesterone receptor, and HER2-negative, triple-negative breast cancer (TNBC), with a poorer prognosis relative to pure invasive ductal or lobular disease. Resistance to chemotherapy often leads to local recurrence and distant metastasis. Genomic profiling has identified multiple molecular abnormalities that may translate to targetable therapies in MBC. These tumors are known to display higher PD-L1 expressivity than other subtypes of breast cancer, and disease control with pembrolizumab and chemotherapy has been documented. We identify a patient with metastatic, metaplastic TNBC, with mesenchymal components and osseous differentiation, who completed 2 years of pembrolizumab treatment and has remained without evidence of disease after 32 months of observation, while maintaining good quality of life. Future efforts should focus on immunotherapy response with respect to the various subtypes of MBC, and treatment should continue to be incorporated in clinical trials to maximize disease response.

Clinical and Pharmacologic Differences of CDK4/6 Inhibitors in Breast Cancer.

Targeted therapies such as Cyclin Dependent Kinase 4 and 6 (CDK 4/6) inhibitors have improved the prognosis of metastatic hormone receptor (HR) positive breast cancer by combating the resistance seen with traditional endocrine therapy. The three approved agents currently in the market are palbociclib, ribociclib and abemaciclib. Besides the overall similarities associated with CDK4/6 inhibition, there are differences between the three approved agents that may explain the differences noted in unique clinical scenarios- monotherapy, patients with brain metastases or use in the adjuvant setting. This review article will explore the preclinical and pharmacological differences between the three agents and help understand the benefits seen with these agents in certain subgroups of patients with metastatic HR positive breast cancer.

SARS-CoV-2 nosocomial infection: Real-world results of environmental surface testing from a large tertiary cancer center.

BACKGROUND: Despite consensus guidelines, concern about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission has dissuaded patients with cancer from seeking medical care. Studies have shown that contaminated surfaces may contain viable virus for up to 72 hours in laboratory settings. The purpose of this study was to investigate contamination of SARS-CoV-2 on commonly used environmental surfaces in a tertiary cancer care center. METHODS: This study evaluated the incidence of SARS-CoV-2 viral RNA in high-touch outpatient and inpatient cancer center spaces. Surfaces were tested over a 2-week period after patient or staff exposure but before scheduled disinfection services according to the World Health Organization protocols for coronavirus disease 2019 (COVID-19) surface sampling. Samples were analyzed via reverse transcriptase-polymerase chain reaction for the presence of SARS-CoV-2 RNA. RESULTS: Two hundred four environmental samples were obtained from inpatient and outpatient oncology clinics and infusion suites, and they were categorized as 1) public areas, 2) staff areas, or 3) medical equipment. One hundred thirty surfaces from 2 outpatient hematology and oncology clinics and 36 surfaces from an inpatient leukemia/lymphoma/chimeric antigen receptor T-cell unit were examined, and all 166 samples were negative for SARS-CoV-2. One of 38 samples (2.6%) from COVID-19+ inpatient units was positive. Altogether, the positive test rate for SARS-CoV-2 RNA across all surfaces was 0.5% (1 of 204). CONCLUSIONS: This prospective, systematic quality assurance investigation of real-world environmental surfaces, performed in inpatient and outpatient hematology/oncology units, revealed overall negligible detection of SARS-CoV-2 RNA when strict mitigation strategies against COVID-19 transmission were instituted. LAY SUMMARY: The potential risks of nosocomial infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have deterred patients with cancer from seeking timely care despite consensus guidelines. This study has found negligible rates of environmental contamination with SARS-CoV-2 across a multitude of commonly used surfaces in outpatient and inpatient hematology/oncology settings with adherence to strict infection control protocols.

Serial Analysis of Circulating Tumor Cells in Metastatic Breast Cancer Receiving First-Line Chemotherapy.

BACKGROUND: We examined the prognostic significance of circulating tumor cell (CTC) dynamics during treatment in metastatic breast cancer (MBC) patients receiving first-line chemotherapy. METHODS: Serial CTC data from 469 patients (2202 samples) were used to build a novel latent mixture model to identify groups with similar CTC trajectory (tCTC) patterns during the course of treatment. Cox regression was used to estimate hazard ratios for progression-free survival (PFS) and overall survival (OS) in groups based on baseline CTCs, combined CTC status at baseline to the end of cycle 1, and tCTC. Akaike information criterion was used to select the model that best predicted PFS and OS. RESULTS: Latent mixture modeling revealed 4 distinct tCTC patterns: undetectable CTCs (56.9% ), low (23.7%), intermediate (14.5%), or high (4.9%). Patients with low, intermediate, and high tCTC patterns had statistically significant inferior PFS and OS compared with those with undetectable CTCs (P < .001). Akaike Information Criterion indicated that the tCTC model best predicted PFS and OS compared with baseline CTCs and combined CTC status at baseline to the end of cycle 1 models. Validation studies in an independent cohort of 1856 MBC patients confirmed these findings. Further validation using only a single pretreatment CTC measurement confirmed prognostic performance of the tCTC model. CONCLUSIONS: We identified 4 novel prognostic groups in MBC based on similarities in tCTC patterns during chemotherapy. Prognostic groups included patients with very poor outcome (intermediate + high CTCs, 19.4%) who could benefit from more effective treatment. Our novel prognostic classification approach may be used for fine-tuning of CTC-based risk stratification strategies to guide future prospective clinical trials in MBC.

Race, Ethnicity, and Clinical Outcomes in Hormone Receptor-Positive, HER2-Negative, Node-Negative Breast Cancer in the Randomized TAILORx Trial.

BACKGROUND: Black race is associated with worse outcomes in early breast cancer. We evaluated clinicopathologic characteristics, the 21-gene recurrence score (RS), treatment delivered, and clinical outcomes by race and ethnicity among women who participated in the Trial Assigning Individualized Options for Treatment. METHODS: The association between clinical outcomes and race (White, Black, Asian, other or unknown) and ethnicity (Hispanic vs non-Hispanic) was examined using proportional hazards models. All P values are 2-sided. RESULTS: Of 9719 eligible women with hormone receptor-positive, HER2-negative, node-negative breast cancer, there were 8189 (84.3%) Whites, 693 (7.1%) Blacks, 405 (4.2%) Asians, and 432 (4.4%) with other or unknown race. Regarding ethnicity, 889 (9.1%) were Hispanic. There were no substantial differences in RS or ESR1, PGR, or HER2 RNA expression by race or ethnicity. After adjustment for other covariates, compared with White race, Black race was associated with higher distant recurrence rates (hazard ratio [HR] = 1.60, 95% confidence intervals [CI] = 1.07 to 2.41) and worse overall survival in the RS 11-25 cohort (HR = 1.51, 95% CI = 1.06 to 2.15) and entire population (HR = 1.41, 95% CI = 1.05 to 1.90). Hispanic ethnicity and Asian race were associated with better outcomes. There was no evidence of chemotherapy benefit for any racial or ethnic group in those with a RS of 11-25. CONCLUSIONS: Black women had worse clinical outcomes despite similar 21-gene assay RS results and comparable systemic therapy in the Trial Assigning Individualized Options for Treatment. Similar to Whites, Black women did not benefit from adjuvant chemotherapy if the 21-gene RS was 11-25. Further research is required to elucidate the basis for this racial disparity in prognosis.

Utilization of Hypofractionated Whole-Breast Radiotherapy With Concurrent Anti-Human Epidermal Growth Factor Receptor 2 (HER2) Therapy.

INTRODUCTION: Hypofractionated radiotherapy (Hypo-RT) is now considered the standard of care for the majority of patients receiving whole-breast irradiation (WBI). However, there are few data on the use of Hypo-RT in human epidermal growth factor receptor 2 (HER2)-positive patients receiving concurrent anti-HER2 therapy. In this study, we sought to examine patterns of WBI in HER2-positive patients. PATIENTS AND METHODS: Using the National Cancer Data Base, we identified women with nonmetastatic HER2-positive breast cancer diagnosed between 2010 and 2015 who received WBI. The Hypo-RT group was defined as those receiving 21 or fewer fractions. All other patients were in the conventional radiotherapy (RT) group. Multivariate logistic regression was used to identify predictors of Hypo-RT utilization. Five-year overall survival was estimated by the Kaplan-Meier method. RESULTS: The study included 15,776 patients, of whom 17.7% received Hypo-RT. The rate of Hypo-RT utilization increased from 7.4% in 2010 to 29.3% in 2015 (P = .004). Predictors of Hypo-RT use included older age (≥60 vs. < 60 years), higher median income quartile, further distance from the treatment facility (>50 vs. ≤50 miles), treatment at an academic facility, and later year of diagnosis. Unadjusted 5-year overall survival rates were similar among patients who received Hypo-RT and conventional RT (93.9% vs. 95.2%, P = .26). After adjusting for patient, facility, and tumor variables, Hypo-RT was not significantly associated with survival. CONCLUSION: Although Hypo-RT was not commonly delivered in patients with HER2-positive breast cancer, the utilization rate quadrupled over the study period. Multiple socioeconomic and clinical predictors of Hypo-RT receipt were identified. Adjuvant RT regimen was not significantly associated with overall survival.

Testing considerations for phosphatidylinositol-3-kinase catalytic subunit alpha as an emerging biomarker in advanced breast cancer.

Breast cancer is the most common cancer in women, and approximately 71% of carcinomas are hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-not-amplified (HER2-negative). Pathogenesis of breast cancer is associated with dysregulation of several signaling pathways, including the phosphatidylinositol-3-kinase (PI3K) pathway. PIK3CA, the gene encoding PI3K catalytic subunit p110α, is mutated in 20%-40% of breast cancer patients. Several PI3K inhibitors have been developed and one, alpelisib, was recently approved for use in PIK3CA-mutated, HR+, HER2-negative advanced breast cancer. There are numerous types of assays and methods used in clinical studies to determine PIK3CA status in cancers. Additionally, there are several factors to consider for PIK3CA testing in clinical practice, including choice of assay, source of sample, and test timing. In this review, we discuss the use of PIK3CA as a biomarker to guide treatment decisions in patients with HR+, HER2-negative advanced breast cancer, as well as practical considerations and recommendations for testing.

5-Year Update of a Multi-Institution, Prospective Phase 2 Hypofractionated Postmastectomy Radiation Therapy Trial.

PURPOSE: Hypofractionation in the setting of postmastectomy radiation (PMRT) is not currently the standard of care in most countries. Here we present a 5-year update of our multi-institutional, phase 2 prospective trial evaluating a novel 15-day hypofractionated PMRT regimen. METHODS AND MATERIALS: Patients were enrolled to receive 3.33 Gy daily to the chest wall (or reconstructed breast) and regional lymphatics in 11 fractions with an optional 4-fraction mastectomy scar boost. The primary endpoint was freedom from grade 3 or higher late non-reconstruction-related radiation toxicities. Toxicities were scored using Common Terminology Criteria for Adverse Events v4.0. Secondary endpoints included local and locoregional recurrence rates, cosmesis, and reconstruction complications. RESULTS: After enrolling 69 patients with stage II-IIIa breast cancer, 67 women were eligible for analysis. At a median follow up of 54 months, there were no acute or late grade 3 and 4 nonreconstruction reported toxicities. The grade 2 or greater late toxicity rate was only 12% and comprised grade 2 pain, fatigue, and lymphedema that persisted beyond 6 months after completion of radiation therapy. Only 3 women (4.6%) experienced a chest wall or nodal recurrence as a first site of relapse. Freedom from local failure, including local failure after distant relapse, was 92% at 5 years, and the 5-year overall survival was 90%. CONCLUSIONS: This is the first prospective trial conducted in the United States to demonstrate the safe and effective use of hypofractionated PMRT. We have demonstrated a low complication rate while achieving excellent local control. Toxicity was better than anticipated based on previously published series of PMRT toxicities. Although our fractionation was novel, the radiobiological equivalent dose is similar to other hypofractionation schedules. This trial was the basis for the creation of Alliance A221505 (RT CHARM), which is currently accruing patients in a phase 3 randomized design.