Effects of Adjuvant Endocrine Therapy-Specific Perceptions on Response to a Behavioral Intervention for Adjuvant Endocrine Therapy Adherence in Patients With Breast Cancer.

PURPOSE: Adjuvant endocrine therapy (AET) is a life-saving medication for patients with hormone-sensitive breast cancer, yet many struggle with adherence, warranting behavioral intervention. In our recent trial, participation in a group cognitive behavioral intervention (STRIDE) for symptom management and adherence was associated with improvements in symptom distress, coping, quality of life, and mood. We now explore whether baseline patient- and medication-specific factors-which may be modifiable by clinician-led discussions-moderated the effect of STRIDE on adherence rates. METHODS: From October 2019 to June 2021, 100 patients with early-stage breast cancer reporting AET-related distress were enrolled and randomly assigned to STRIDE or a medication monitoring (MM) control group. All patients stored their AET in electronic pill bottles to track objective adherence. Patients also self-reported their adherence on the Medication Adherence Report Scale-5 and their perceptions of AET on the Cancer Therapy Satisfaction Questionnaire at baseline. We conducted hierarchical linear modeling to test moderators of intervention effects on objective adherence rates. We report the time × group × moderator effects. RESULTS: Among patients reporting greater perceived difficulties with AET adherence at baseline, STRIDE participants had higher adherence rates over time compared with MM (b = -13.80; SE = 4.56; P < .01). Patients with greater expectations of therapeutic benefit from AET also had improved adherence rates if they were assigned to STRIDE, versus MM (b = 0.25; SE = 0.10; P = .01). Patients who perceived taking AET as convenient and had been taking their AET for less time had higher adherence rates in STRIDE, versus MM. CONCLUSION: The current study identified patient- and medication-specific factors that may augment AET adherence interventions and may be modifiable through clinician-led discussions, such as perceptions of adherence problems, therapeutic efficacy, and convenience of AET.

Estrogen levels in young women with hormone receptor-positive breast cancer on ovarian function suppression therapy.

Ovarian function suppression (OFS) benefits young women with hormone receptor (HR)-positive breast cancer but they are at risk for ovarian function breakthrough. We assessed endocrine effects of gonadotropin-releasing hormone agonist (GnRHa) treatment in a prospective cohort of patients aged ≤ 40 years with HR-positive breast cancer. Plasma estradiol (E2), estrone, and follicule-stimulating hormone (FSH) levels were measured from blood samples drawn 1 and 4 years after diagnosis. Patient characteristics, invasive breast cancer-free survival (iBCFS), and overall survival (OS) were compared between those with and without E2 > 2.72 pg/mL during GnRHa treatment. Among eligible patients, 54.7% (46/84) and 60% (15/25) had E2 > 2.72 pg/mL at 1 and 4 years, respectively. Factors associated with E2 > 2.72 pg/mL at 1 year were no prior chemotherapy (P = 0.045) and tamoxifen use (P = 0.009). After a median follow-up of 7 years, among patients with stage I-III breast cancer (N = 74), iBCFS events were seen in 6 (8.1%) with E2 > 2.72 pg/mL and 5 (6.8%) with E2 ≤ 2.72 pg/mL (P = 0.893). Among patients with de novo metastatic breast cancer (N = 12), 6 (50%) with E2 > 2.72 pg/mL and 3 (25%) with E2 ≤ 2.72 pg/mL died during follow-up (P = 0.052). Larger studies exploring the clinical implications of incomplete E2 suppression by GnRHa are needed to ensure optimal OFS treatment strategies are being employed for this population.

Association of cancer treatment with excess heart age among five-year young breast cancer survivors.

PURPOSE: Data evaluating cardiovascular disease (CVD) risk by cancer treatment among young women (≤ 40 years) with breast cancer are limited. METHODS: Among 372 five-year breast cancer survivors aged 30-40 years from the Young Women's Breast Cancer Study, we assessed the association of cancer treatments (anthracyclines, trastuzumab, radiation/laterality, endocrine therapy) and excess heart age (difference between predicted 10-year CVD risk as assessed by adapted Framingham Risk Score and chronological age), prevalent elevated excess heart age (≥ 2 years), and worsening excess heart age (change of ≥ 2 excess heart age years) at breast cancer diagnosis and two- and five-year follow-up using multivariable linear and logistic regressions. RESULTS: Most women had stage I or II (79%), ER + (71%), or PR + (65%) breast cancer. At diagnosis, women had little excess heart age by treatment receipt (range of means = -0.52,0.91 years). Left-sided radiation (ß = 2.49,SE = 0.96,p = 0.01) was associated with higher excess heart age at five-year follow-up. For prevalent elevated excess heart age (two-year = 26%;five-year = 27%), women treated with right-sided radiation had increased risk at two-years (OR = 2.17,95%CI = 1.12-4.19), yet at five-years, associations were observed after any radiation (OR = 1.92,95%CI = 1.09-3.41), especially after left-sided (OR = 2.13,95%CI = 1.09-3.41) radiation. No associations were observed between systemic treatments and prevalent elevated excess heart age or any treatments with worsening excess heart age. CONCLUSIONS: Among young breast cancer survivors, radiation, but not other cancer treatments, was associated with elevated excess heart age. IMPLICATIONS FOR CANCER SURVIVORS: CVD risk tools that incorporate cancer treatment, such as radiation, are needed to identify high risk young breast cancer survivors given the long survivorship and long latency of cardiovascular disease.

Helping ourselves, helping others: the Young Women's Breast Cancer Study (YWS) - a multisite prospective cohort study to advance the understanding of breast cancer diagnosed in women aged 40 years and younger.

PURPOSE: Compared with older women diagnosed with breast cancer, younger women are more likely to die of breast cancer and more likely to suffer psychosocially in both the short-term and long term. The Young Women's Breast Cancer Study (YWS) is a multisite prospective cohort study established to address gaps in our knowledge about this vulnerable and understudied population. PARTICIPANTS: The YWS enrolled 1302 women newly diagnosed with stages 0-IV breast cancer at age 40 years or younger at 13 academic and community sites in North America between 2006 and 2016. Longitudinal patient-reported outcome data are complemented by clinical data abstraction and biospecimen collection at multiple timepoints. FINDINGS TO DATE: Key findings related to fertility include that nearly 40% of participants were interested in pregnancy following diagnosis; of those who reported interest, 10% pursued fertility preservation. Overall, approximately 10% of YWS participants became pregnant in the first 5 years after diagnosis; follow-up is ongoing for pregnancies after 5 years. Studies focused on psychosocial outcomes have characterised quality of life, post-traumatic stress and fear of recurrence, with findings detailing the factors associated with the substantial psychosocial burden many young women face during and following active treatment. Multiple studies have leveraged YWS biospecimens, including whole-exome sequencing of tumour analyses that revealed that select somatic alterations occur at different frequencies in young (age≤35) versus older women with luminal A breast cancer, and a study that explored clonal hematopoiesis of indeterminate potential found it to be rare in young survivors. FUTURE PLANS: With a median follow-up of approximately 10 years, the cohort is just maturing for many relevant long-term outcomes and provides outstanding opportunities to further study and build collaborations to address gaps in our knowledge, with the ultimate objective to improve care and outcomes for young women with breast cancer. TRIAL REGISTRATION NUMBER: NCT01468246.

National survey of patient perspectives on cost discussions among recipients of copay assistance.

BACKGROUND: Individuals with cancer and other medical conditions often experience financial concerns from high costs-of-care and may utilize copay assistance programs (CAP). We sought to describe CAP recipients' experiences/preferences for cost discussions with clinicians. METHODS: We conducted a national, cross-sectional electronic-survey from 10/2022 to 11/2022 of CAP recipients with cancer or autoimmune conditions to assess patient perspectives on cost discussions. We used multivariable logistic regression models to explore associations of patient perspectives on cost discussions with patient characteristics and patient-reported outcomes (eg, financial toxicity, depression/anxiety, and health literacy). RESULTS: Among 1,566 participants, 71% had cancer and 29% had autoimmune conditions. Although 62% of respondents desired cost discussions, only 32% reported discussions took place. Additionally, 52% of respondents wanted their doctor to consider out-of-pocket costs when deciding the best treatment, and 61% of respondents felt doctors should ensure patients can afford treatment prescribed. Participants with depression symptoms were more likely to want doctors to consider out-of-pocket costs (OR = 1.54, P = .005) and to believe doctors should ensure patients can afford treatment (OR = 1.60, P = .005). Those with severe financial toxicity were more likely to desire cost discussions (OR = 1.65, P < .001) and want doctors to consider out-of-pocket costs (OR = 1.52, P = .001). Participants with marginal/inadequate health literacy were more likely to desire cost discussions (OR = 1.37, P = .01) and believe doctors should ensure patients can afford treatment (OR = 1.30, P = .036). CONCLUSIONS: In this large sample of CAP recipients with cancer and autoimmune conditions, most reported a desire for cost discussions, but under one-third reported such discussions took place.

Sticking to the script: Breast cancer patients' decision making regarding oral endocrine therapy.

OBJECTIVES: We sought to understand why some women with early-stage breast cancer decide to forgo or discontinue endocrine therapy (ET), and to identify factors that might lead to greater acceptance of, and long-term adherence to, this treatment. METHODS: We conducted in-depth interviews with N = 53 stage I-III HR+ women who were either non-initiators of ET, initiators who discontinued or initiators who continued with variable daily patterns of adherence. An inductive content analysis was performed to explore the decision-making process of women prescribed ET. RESULTS: Qualitative analyses revealed 55 themes that drove complex decision making. The initiators generally trusted their physicians and did little research before starting the medication. Non-initiators were more suspicious of the medical system, believing that ET presented more risks than benefits. Most discontinuers stopped ET because of side effects. Both non-initiators and discontinuers indicated that push-back from their physicians could have changed their decision. Stories and social support were important in decision making. CONCLUSIONS: Although ET can significantly reduce the risk of breast cancer recurrence, substantial barriers prevent many women from initiating or continuing it. PRACTICE IMPLICATIONS: Physicians have powerful influence over patients' decisions to initiate ET and can be important levers for motivating patients to persist.

Race and Ethnicity Representation in Phase 2/3 Oncology Clinical Trial Publications: A Systematic Review.

Importance: The five 1997 Office of Management and Budget races in the US include American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, and White, with Hispanic ethnicity. Despite the Affordable Care Act mandating Office of Management and Budget-based collecting and reporting standards, race and ethnicity publishing in medical journals is inconsistent, despite being necessary to achieve health equity. Objective: To quantify race and ethnicity reporting rates and calculate representation quotients (RQs) in published oncology clinical trials. Evidence Review: In this systematic review, PubMed and Embase were queried for phase 2/3 clinical trials of the 6 most common noncutaneous solid cancers, published between January 1, 2012, and December 31, 2022, in 4 high-impact journals. Trial characteristics were recorded. The RQs for each race and ethnicity were calculated by dividing the percent of representation in each clinical trial publication by the percent of year-matched, site-specific incident cancers in the US, compared with Kruskal-Wallis tests with Bonferroni correction (BC). Reporting was compared between journal publications and ClinicalTrials.gov. Findings: Among 1202 publications evaluated, 364 met inclusion criteria: 16 JAMA, 241 Journal of Clinical Oncology, 19 Lancet, and 88 New England Journal of Medicine. Publications included 268 209 patients (171 132 women [64%]), with a median of 356 (IQR, 131-800) patients per publication. Reported race and ethnicity included American Indian or Alaska Native in 52 (14%) publications, Asian in 196 (54%), Black or African American in 215 (59%), Hispanic in 67 (18%), Native Hawaiian or Other Pacific Islander in 28 (8%), and White in 254 (70%). Median RQ varied across race (P < .001 BC), with 1.04 (IQR, 0.09-4.77) for Asian, 0.98 (IQR, 0.86-1.06) for White, 0.42 (IQR, 0.12-0.75) for Black or African American, and 0.00 (IQR, 0.00-0.00) for both American Indian or Alaska Native and Native Hawaiian or Other Pacific Islander patients. Sensitivity analyses showed similar findings on subset analysis for US-only clinical trials. There was significantly less race and ethnicity reporting in the clinical trial publications compared with ClinicalTrials.gov documentation for American Indian or Alaska Native (14% vs 45%; P < .001 per McNemar χ2 test with continuity correction [MC]) and Native Hawaiian or Other Pacific Islander (8% vs 43%; P < .001 MC). Conclusions and Relevance: While most phase 2/3 oncology clinical trials published in high-impact journals report race and ethnicity, most did not report American Indian or Alaska Native and Native Hawaiian or Other Pacific Islander racial categories. Our findings support a call to action for consistent journal policies and transparent race and ethnicity reporting, in alignment with Affordable Care Act-concordant race and ethnicity federal reporting requirements.

Antibody-Drug Conjugate Sacituzumab Govitecan Enables a Sequential TOP1/PARP Inhibitor Therapy Strategy in Patients with Breast Cancer.

PURPOSE: The antibody-drug conjugate (ADC) sacituzumab govitecan (SG) comprises the topoisomerase 1 (TOP1) inhibitor (TOP1i) SN-38, coupled to a monoclonal antibody targeting trophoblast cell surface antigen 2 (TROP-2). Poly(ADP-ribose) polymerase (PARP) inhibition may synergize with TOP1i and SG, but previous studies combining systemic PARP and TOP1 inhibitors failed due to dose-limiting myelosuppression. Here, we assess the proof-of-mechanism and clinical feasibility for SG and talazoparib (TZP) employing an innovative sequential dosing schedule. PATIENTS AND METHODS: In vitro models tested pharmacodynamic endpoints, and in a phase 1b clinical trial (NCT04039230), 30 patients with metastatic triple-negative breast cancer (mTNBC) received SG and TZP in a concurrent (N = 7) or sequential (N = 23) schedule. Outcome measures included safety, tolerability, preliminary efficacy, and establishment of a recommended phase 2 dose. RESULTS: We hypothesized that tumor-selective delivery of TOP1i via SG would reduce nontumor toxicity and create a temporal window, enabling sequential dosing of SG and PARP inhibition. In vitro, sequential SG followed by TZP delayed TOP1 cleavage complex clearance, increased DNA damage, and promoted apoptosis. In the clinical trial, sequential SG/TZP successfully met primary objectives and demonstrated median progression-free survival (PFS) of 7.6 months without dose-limiting toxicities (DLT), while concurrent dosing yielded 2.3 months PFS and multiple DLTs including severe myelosuppression. CONCLUSIONS: While SG dosed concurrently with TZP is not tolerated clinically due to an insufficient therapeutic window, sequential dosing of SG followed by TZP proved a viable strategy. These findings support further clinical development of the combination and suggest that ADC-based therapy may facilitate novel, mechanism-based dosing strategies.

Critical importance of correctly defining and reporting secondary endpoints when assessing the ethics of research biopsies.

This article reviews the implementation challenges to the American Society of Clinical Oncology's ethical framework for including research biopsies in oncology clinical trials. The primary challenges to implementation relate to the definitions of secondary endpoints, the scientific and regulatory framework, and the incentive structure that encourages inclusion of biopsies. Principles of research stewardship require that the clinical trials community correctly articulate the scientific goals of any research biopsies, especially those that are required for the patient to enroll on a trial and receive an investigational agent. Furthermore, it is important to sufficiently justify the characterization of secondary (as distinguished from exploratory) endpoints, protect the interest of research participants, and report accurate and complete information to ClinicalTrials.gov and the published literature.

The Right Dose: Results of a Patient Advocate-Led Survey of Individuals With Metastatic Breast Cancer Regarding Treatment-Related Side Effects and Views About Dosage Assessment to Optimize Quality of Life.

PURPOSE: Although patients with metastatic breast cancer (MBC) have been living longer with the advent of more effective treatments such as targeted therapy and immunotherapy, the disease remains incurable, and most patients will undergo therapy indefinitely. When beginning therapy, patients are typically prescribed dose often based upon the maximum tolerated dose identified in phase I clinical trials. However, patients' perspectives about tolerability and willingness to discuss individualized dosing of drugs upon initiation of a new regimen and throughout the course of treatment have not been comprehensively evaluated. METHODS: Patient advocates and medical oncologists from the Patient-Centered Dosing Initiative (PCDI) developed a survey to ascertain the prevalence and severity of MBC patients' treatment-related side effects, the level of patient-physician communication, mitigation strategies, perception about the relative efficacy of higher versus lower doses, and willingness to discuss alternative dosing. The PCDI distributed the anonymous confidential online survey in August 2020 to individuals with self-reported MBC. RESULTS: One thousand and two hundred twenty-one patients with MBC completed the survey. 86.1% (n = 1,051) reported experiencing at least one significant treatment-related side effect, and of these, 20.3% (n = 213) visited the emergency room/hospital and 43.2% (n = 454) missed at least one treatment. Nearly all patients with side effects (97.6%, n = 1,026) informed their doctor and 81.7% (n = 838) received assistance. Of the 556 patients given a dose reduction for side-effect mitigation, 82.6% (n = 459) reported relief. Notably, majority of patients (53.3%, n = 651) do not believe that higher dose is always more effective than lower dose, and 92.3% (n = 1,127) would be willing to discuss flexible dosing options with their physicians based upon personal characteristics to optimize quality of life. CONCLUSION: Given that the majority of patients with MBC experienced at least one substantial treatment-related side effect and most patients given a dose reduction reported improvement, innovative dosage-related strategies are warranted to sustain and improve patients' well-being. Patient-physician discussions in which the patient's unique attributes and circumstances are assessed upon initiation of new treatment and throughout the course of therapy may facilitate the identification of the most favorable dose for each patient, and the majority of patients would be receptive to this approach.

Shifting from Equality toward Equity: Addressing Disparities in Research Participation for Clinical Cancer Research.

AbstractThere is societal consensus that cancer clinical trial participation is unjust because some sociodemographic groups have been systematically underrepresented. Despite this, neither a definition nor an ethical explication for the justice norm of equity has been clearly articulated in this setting, leading to confusion over its application and goals. Herein we define equity as acknowledging sociodemographic circumstances and apportioning resource and opportunity allocation to eliminate disparities in outcomes, and we explore the issues and tensions this norm generates through practical examples. We assess how equality-based enrollment structures in clinical cancer research have perpetuated historical disparities and what equity-based alternatives are necessary to achieve representativeness and an expansive conception of participatory justice in clinical cancer research. This framework addresses the breadth from normative to applied by defining the justice norm of equity and translating it into practical strategies for addressing participation disparities in clinical cancer research.

Searching for the "Holy Grail" of breast cancer recurrence risk: a narrative review of the hunt for a better biomarker and the promise of circulating tumor DNA (ctDNA).

BACKGROUND: This paper is a narrative review of a major clinical challenge at the heart of breast cancer care: determining which patients are at risk of recurrence, which require systemic therapy, and which remain at risk in the survivorship phase of care despite initial therapy. METHODS: We review the literature on prognostic and predictive biomarkers in breast cancer with a focus on detection of minimal residual disease. RESULTS: While we have many tools to estimate and refine risk that are used to individualize local and systemic therapy, we know that we continue to over treat many patients and undertreat others. Many patients also experience what is, at least in hindsight, needless fear of recurrence. In this review, we frame this dilemma for the practicing breast oncologist and discuss the search for what we term the "holy grail" of breast cancer evaluation: the ideal biomarker of residual distant disease. We review the history of attempts to address this problem and the up-to-date science on biomarkers, circulating tumor cells and circulating tumor DNA (ctDNA). CONCLUSION: This review suggests that the emerging promise of ctDNA may help resolve a crticical dilemma at the heart of breast cancer care, and improve prognostication, treatment selection, and outcomes for patients with breast cancer.

Identification of patient subgroups who benefit from a behavioral intervention to improve adjuvant endocrine therapy adherence: a randomized-controlled trial.

PURPOSE: Adjuvant endocrine therapy (AET) reduces breast cancer morbidity and mortality; however, adherence is suboptimal. Interventions exist, yet few have improved adherence. Patient characteristics may alter uptake of an intervention to boost adherence. We examined moderators of the effect of a virtual intervention (STRIDE; #NCT03837496) on AET adherence after breast cancer. METHODS: At a large academic medical center, patients taking AET (N = 100; Mage = 56.1, 91% White) were randomized to receive STRIDE versus medication monitoring. All stored their medication in digital pill bottles (MEMS Caps) which captured objective adherence. Participants self-reported adherence (Medication Adherence Report Scale) at 12 weeks post-baseline. Moderators included age, anxiety, and depressive symptoms (Hospital Anxiety and Depression Scale), AET-related symptom distress (Breast Cancer Prevention Trial Symptom Scale), and AET-specific concerns (Beliefs about Medications Questionnaire). We used hierarchical linear modeling (time × condition × moderator) and multiple regression (condition × moderator) to test the interaction effects on adherence. RESULTS: Age (B = 0.05, SE = 0.02, p = 0.003) and AET-related symptom distress (B = -0.04, SE = 0.02, p = 0.02) moderated condition effect on self-reported adherence while anxiety (B = -1.20, SE = 0.53, p = 0.03) and depressive symptoms (B = -1.65, SE = 0.65, p = 0.01) moderated objective adherence effects. AET-specific concerns approached significance (B = 0.91, SE = 0.57, p = 0.12). Participants who received STRIDE and were older or presented with lower anxiety and depressive symptoms or AET-related symptom distress exhibited improved adherence. Post hoc analyses revealed high correlations among most moderators. CONCLUSIONS: A subgroup of patients who received STRIDE exhibited improvements in AET adherence. The interrelatedness of moderators suggests an underlying profile of patients with lower symptom burden who benefitted most from the intervention. STUDY REGISTRATION: NCT03837496.

Conception and pregnancy among women with a live birth after breast cancer treatment: A survey study of young breast cancer survivors.

BACKGROUND: Breast cancer (BC) is the most common malignancy in women of reproductive age. This study sought to explore the postcancer conception and pregnancy experience of young BC survivors to inform counseling. METHODS: In the Young Women's Breast Cancer Study (NCT01468246), a multicenter, prospective cohort, participants diagnosed at age ≤40 years with stage 0-III BC who reported ≥1 postdiagnosis live birth were sent an investigator-developed survey. RESULTS: Of 119 eligible women, 94 (79%) completed the survey. Median age at diagnosis was 32 years (range, 17-40) and at first postdiagnosis delivery was 38 years (range, 29-47). Most had stage I or II (77%) and HR+ (78%) BC; 51% were nulligravida at diagnosis. After BC treatment, most (62%) conceived naturally, though 38% used assisted reproductive technology, 74% of whom first attempted natural conception for a median of 9 months (range, 2-48). Among women with a known inherited pathogenic variant (n = 20), two underwent preimplantation genetic testing. Of 59 women on endocrine therapy before pregnancy, 26% did not resume treatment. Hypertensive disorders of pregnancy (20%) was the most common obstetrical condition. Nine percent of newborns required neonatal intensive care unit admission and 9% had low birth weight. CONCLUSION: Among women with live births after BC treatment, most conceived naturally and having a history of BC did not appear to negatively impact pregnancy complications, though the high rate of hypertensive disorders of pregnancy warrants further investigation. The prolonged period of attempting natural conception for some survivors suggests the potential need for improved understanding and counseling surrounding family planning goals after BC.

The impact of feedback training on prediction of cancer clinical trial results.

INTRODUCTION: Funders must make difficult decisions about which squared treatments to prioritize for randomized trials. Earlier research suggests that experts have no ability to predict which treatments will vindicate their promise. We tested whether a brief training module could improve experts' trial predictions. METHODS: We randomized a sample of breast cancer and hematology-oncology experts to the presence or absence of a feedback training module where experts predicted outcomes for five recently completed randomized controlled trials and received feedback on accuracy. Experts then predicted primary outcome attainment for a sample of ongoing randomized controlled trials. Prediction skill was assessed by Brier scores, which measure the average deviation between their predictions and actual outcomes. Secondary outcomes were discrimination (ability to distinguish between positive and non-positive trials) and calibration (higher predictions reflecting higher probability of trials being positive). RESULTS: A total of 148 experts (46 for breast cancer, 54 for leukemia, and 48 for lymphoma) were randomized between May and December 2017 and included in the analysis (1217 forecasts for 25 trials). Feedback did not improve prediction skill (mean Brier score for control: 0.22, 95% confidence interval = 0.20-0.24 vs feedback arm: 0.21, 95% confidence interval = 0.20-0.23; p = 0.51). Control and feedback arms showed similar discrimination (area under the curve = 0.70 vs 0.73, p = 0.24) and calibration (calibration index = 0.01 vs 0.01, p = 0.81). However, experts in both arms offered predictions that were significantly more accurate than uninformative forecasts of 50% (Brier score = 0.25). DISCUSSION: A short training module did not improve predictions for cancer trial results. However, expert communities showed unexpected ability to anticipate positive trials.Pre-registration record: https://aspredicted.org/4ka6r.pdf.