A New Method of Identifying Pathologic Complete Response After Neoadjuvant Chemotherapy for Breast Cancer Patients Using a Population-Based Electronic Medical Record System.

BACKGROUND: Accurate identification of pathologic complete response (pCR) from population-based electronic narrative data in a timely and cost-efficient manner is critical. This study aimed to derive and validate a set of natural language processing (NLP)-based machine-learning algorithms to capture pCR from surgical pathology reports of breast cancer patients who underwent neoadjuvant chemotherapy (NAC). METHODS: This retrospective cohort study included all invasive breast cancer patients who underwent NAC and subsequent curative-intent surgery during their admission at all four tertiary acute care hospitals in Calgary, Alberta, Canada, between 1 January 2010 and 31 December 2017. Surgical pathology reports were extracted and processed with NLP. Decision tree classifiers were constructed and validated against chart review results. Machine-learning algorithms were evaluated with a performance matrix including sensitivity, specificity, positive predictive value (PPV), negative predictive value [NPV], accuracy, area under the receiver operating characteristic curve [AUC], and F1 score. RESULTS: The study included 351 female patients. Of these patients, 102 (29%) achieved pCR after NAC. The high-sensitivity model achieved a sensitivity of 90.5% (95% confidence interval [CI], 69.6-98.9%), a PPV of 76% (95% CI, 59.6-87.2), an accuracy of 88.6% (95% CI, 78.7-94.9%), an AUC of 0.891 (95% CI, 0.795-0.987), and an F1 score of 82.61. The high-PPV algorithm reached a sensitivity of 85.7% (95% CI, 63.7-97%), a PPV of 81.8% (95% CI, 63.4-92.1%), an accuracy of 90% (95% CI, 80.5-95.9%), an AUC of 0.888 (95% CI, 0.790-0.985), and an F1 score of 83.72. The high-F1 score algorithm obtained a performance equivalent to that of the high-PPV algorithm. CONCLUSION: The developed algorithms demonstrated excellent accuracy in identifying pCR from surgical pathology reports of breast cancer patients who received NAC treatment.

Improvement in patient-reported pain among patients with metastatic cancer and its association with opioid prescribing.

PURPOSE: Opioids are a mainstay of cancer pain management; however, patients with metastatic cancer are often excluded from studies, leading to a lack of evidence on whether increased prescribing (dosage and/or duration) results in improved outcomes for this population. This study aimed to investigate whether increased opioid prescribing is associated with an improvement in patient-reported pain among patients with metastatic cancer. PATIENTS AND METHODS: A retrospective cohort of all adult patients diagnosed with stage IV cancers, who completed at least two patient-reported outcomes (PROs) within 30 days of each other, was identified from administrative data. Opioid prescriptions were categorized by dosage level and number of prescription days. Multivariable logistic regression was used to investigate the association between opioid prescribing and clinically important improvement in pain score (≥ 1 point change on the Edmonton Symptom Assessment System). RESULTS: A total of 2169 patients were included, 770 (35.5%) of whom had active opioid prescription between PROs, with an average daily dosage of 86.1 mg of oral morphine equivalent. Active prescription was associated with improvement in pain (OR = 2.17, P < 0.001). However, among patients with active prescription, neither dosage nor number of prescription days was significantly associated with pain improvement. CONCLUSION: Opioid prescription is important for treating cancer-related pain; however, increased dosage or duration may not be leading to greater improvements in pain. Patients with metastatic cancer who are receiving increased opioid prescribing may have difficult-to-treat pain and may benefit from multidisciplinary pain management strategies to supplement opioid prescription and improve outcomes.

No evidence of disease versus residual disease in long-term responders to first-line HER2-targeted therapy for metastatic breast cancer.

BACKGROUND: Long-term response to HER2-targeted therapies is infrequent in metastatic breast cancer (MBC). We evaluated clinical characteristics of HER2-positive MBC patients with no evidence of disease (NED) vs residual disease (RES) experiencing long-term response to first-line HER2-targeted therapy. METHODS: Patients receiving first-line chemotherapy-trastuzumab (CT) or taxane-trastuzumab-pertuzumab (THP) with response duration ≥2-fold higher than in phase II/III trials (CT [18.2 months]; THP [40.4 months]) were included. Clinical characteristics and radiographic review for NED or RES was evaluated by Cox-regression (hazard ratio; HR) or Kaplan-Meier (log-rank). Characteristics associated with NED were evaluated by logistic regression (Odds; OR). RESULTS: From 01/2005-01/2016, N = 103 (4.6%) patients were identified. In multivariate analyses, NED (N = 46) showed improved progression-free (PFS) and overall survival (OS) [p < 0.001] versus RES (N = 57), with high 5-year PFS/OS for NED (93.2%/97.4%) relative to RES (10.6%/61.3%). Premenopausal status (p = 0.006), de-novo metastases (p = 0.002), and no palliative radiotherapy (p = 0.01) were associated with NED. Overall, 6/7 (85.7%) patients with NED were alive and disease-free after discontinuing HER2 treatment (≥1 year) versus 1/17 (5.9%) with RES. CONCLUSIONS: Long-term responders with NED have better survival compared to RES. Premenopausal status and de novo metastatic disease are associated with NED. Prospective studies of HER2 therapy discontinuation with NED in MBC are warranted.

New method for determining breast cancer recurrence-free survival using routinely collected real-world health data.

BACKGROUND: In cancer survival analyses using population-based data, researchers face the challenge of ascertaining the timing of recurrence. We previously developed algorithms to identify recurrence of breast cancer. This is a follow-up study to detect the timing of recurrence. METHODS: Health events that signified recurrence and timing were obtained from routinely collected administrative data. The timing of recurrence was estimated by finding the timing of key indicator events using three different algorithms, respectively. For validation, we compared algorithm-estimated timing of recurrence with that obtained from chart-reviewed data. We further compared the results of cox regressions models (modeling recurrence-free survival) based on the algorithms versus chart review. RESULTS: In total, 598 breast cancer patients were included. 121 (20.2%) had recurrence after a median follow-up of 4 years. Based on the high accuracy algorithm for identifying the presence of recurrence (with 94.2% sensitivity and 79.2% positive predictive value), the majority (64.5%) of the algorithm-estimated recurrence dates fell within 3 months of the corresponding chart review determined recurrence dates. The algorithm estimated and chart-reviewed data generated Kaplan-Meier (K-M) curves and Cox regression results for recurrence-free survival (hazard ratios and P-values) were very similar. CONCLUSION: The proposed algorithms for identifying the timing of breast cancer recurrence achieved similar results to the chart review data and were potentially useful in survival analysis.

Documenting patients' and providers' preferences when proposing a randomized controlled trial: a qualitative exploration.

BACKGROUND: With advances in cancer diagnosis and treatment, women with early-stage breast cancer (ESBC) are living longer, increasing the number of patients receiving post-treatment follow-up care. Best-practice survivorship models recommend transitioning ESBC patients from oncology-provider (OP) care to community-based care. While developing materials for a future randomized controlled trial (RCT) to test the feasibility of a nurse-led Telephone Survivorship Clinic (TSC) for a smooth transition of ESBC survivors to follow-up care, we explored patients' and OPs' reactions to several of our proposed methods. METHODS: We used a qualitative study design with thematic analysis and a two-pronged approach. We interviewed OPs, seeking feedback on ways to recruit their ESBC patients for the trial, and ESBC patients, seeking input on a questionnaire package assessing outcomes and processes in the trial. RESULTS: OPs identified facilitators and barriers and offered suggestions for study design and recruitment process improvement. Facilitators included the novelty and utility of the study and simplicity of methods; barriers included lack of coordination between treating and discharging clinicians, time constraints, language barriers, motivation, and using a paper-based referral letter. OPs suggested using a combination of electronic and paper referral letters and supporting clinicians to help with recruitment. Patient advisors reported satisfaction with the content and length of the assessment package. However, they questioned the relevance of some questions (childhood trauma) while adding questions about trust in physicians and proximity to primary-care providers. CONCLUSIONS: OPs and patient advisors rated our methods for the proposed trial highly for their simplicity and relevance then suggested changes. These findings document processes that could be effective for cancer-patient recruitment in survivorship clinical trials.

Unwarranted imaging for distant metastases in patients with newly diagnosed ductal carcinoma in situ and stage I and II breast cancer

Background: In 2012, the American Society of Clinical Oncology (ASCO) released a Choosing Wisely Top Five list that included a recommendation against ordering advanced imaging tests to screen for metastases among asymptomatic patients with early breast cancer. Our provincial breast cancer staging guideline was subsequently updated. We report on the use of unwarranted bone scanning (BS), computed tomography (CT), nonbreast magnetic resonance imaging (MRI) and positron emission tomography (PET) among women diagnosed with stage 0­II breast cancer in Alberta in 2011­2015. Methods: The cohort was retrospectively ascertained from the Alberta Cancer Registry. We used additional provincial data sources to obtain information about diagnostic imaging tests completed from biopsy to surgical date plus 4 months. The reason for each BS, CT, MRI and PET was abstracted. We calculated the frequency of advanced imaging tests completed for routine metastatic screening. Results: Of 10 142 patients included, 2887 (28.5%) had at least 1 advanced imaging test completed for routine metastatic screening. Of these 2887 patients, 438 (15.2%) had a follow-up BS, CT, MRI or PET, and 28 patients (1.0%) had a nonbreast imageguided biopsy. Use of routine advanced imaging tests did not change clearly over time. Conclusion: Our results demonstrate persistent use of advanced imaging tests for routine metastatic screening among patients with stage 0­II breast cancer despite the release of the ASCO Choosing Wisely recommendations and the update of our provincial breast cancer staging guideline. Investigation of strategies for guideline translation to improve upon value-based care of patients with early breast cancer is warranted.

Contexte: En 2012, l'American Society of Clinical Oncology (ASCO) a publié sa liste de 5 interventions à « Choisir avec soin ¼, dans laquelle elle recommandait notamment de ne pas recourir aux techniques d'imagerie de pointe pour le dépistage des métastases chez les patientes atteintes d'un cancer du sein peu avancé et asymptomatique. Nos lignes directrices provinciales pour la stadification du cancer du sein ont été mises à jour en conséquence. Nous faisons aujourd'hui état de l'utilisation injustifiée de la scintigraphie osseuse (SO), de la tomodensitométrie (TDM), de l'imagerie par résonnance magnétique (IRM) non mammaire et de la tomographie par émission de positrons (TEP) chez les femmes ayant reçu un diagnostic de cancer du sein peu avancé (stade 0-II) en Alberta entre 2011 et 2015. Méthodes: La cohorte a été réunie de manière rétrospective à partir du registre albertain du cancer. Nous avons utilisé d'autres sources de données provinciales pour obtenir des renseignements sur les épreuves d'imagerie diagnostique effectuées entre les dates de la biopsie et les dates de la chirurgie plus 4 mois. Le motif invoqué pour recourir à chaque SO, TDM, IRM et TEP a été recueilli. Nous avons calculé la fréquence des épreuves d'imagerie de pointe effectuées pour un dépistage de routine des métastases. Résultats: Sur les 10 142 patientes incluses, 2887 (28,5 %) avaient subi au moins 1 épreuve d'imagerie de pointe pour le dépistage de routine des métastases. Parmi ces 2887 patientes, 438 (15,2 %) ont subi une SO, une TDM, une IRM ou une TEP de suivi et 28 patientes (1,0 %) ont subi une biopsie non mammaire guidée par l'imagerie. L'utilisation de routine des épreuves d'imagerie de pointe n'a pas nettement changé avec le temps. Conclusion: Selon nos résultats, l'utilisation des épreuves d'imagerie de pointe pour le dépistage de routine des métastases persiste chez les patientes atteintes d'un cancer du sein de stade 0­II, malgré la publication des recommandations Choisir avec soin de l'ASCO et la mise à jour de nos lignes directrices provinciales concernant la stadification du cancer du sein. Il faudra se pencher sur des stratégies pour améliorer l'adoption de lignes directrices relatives aux soins véritablement utiles pour les patientes atteintes d'un cancer du sein peu avancé.

Impact of Cumulative Chemotherapy Dose on Survival With Adjuvant FEC-D Chemotherapy for Breast Cancer.

BACKGROUND: Reductions in adjuvant chemotherapy dose <85% for historical regimens (ie, cyclophosphamide/methotrexate/fluorouracil) are known to affect breast cancer survival. This threshold, in addition to early versus late dose reductions, are poorly defined for third-generation anthracycline/taxane-based chemotherapy. In patients with breast cancer receiving adjuvant 5-fluorouracil/epirubicin/cyclophosphamide followed by docetaxel (FEC-D), we evaluated the impact of chemotherapy total cumulative dose (TCD), and early (FEC) versus late (D only) dose reductions, on survival outcomes. PATIENTS AND METHODS: Women with stage I-III, hormone receptor-positive/negative, HER2-negative breast cancer treated with adjuvant FEC-D chemotherapy from 2007 through 2014 in Alberta, Canada, were included. TCD for cycles 1 to 6 of <85% or ≥85% was calculated. Average cumulative dose was also calculated for early (cycles 1-3) and late (cycles 4-6) chemotherapy. Survival outcomes (disease-free survival [DFS] and overall survival [OS]) were estimated using Kaplan-Meier and multivariate analysis. Cohorts were evaluated for uniformity. RESULTS: Characteristics were reasonably balanced for all cohorts. Overall, 1,302 patients were evaluated for dose reductions, with 16% being reduced <85% (n=202) relative to ≥85% (n=1,100; 84%). Patients who received TCD ≥85% relative to <85% had superior 5-year DFS (P=.025) and OS (P<.001) according to Kaplan-Meier analysis, which remained significant on univariate and multivariate analyses. In stratified late and early dose reduction cohorts, DFS and OS showed a significant inferior survival trend for dose reduction early in treatment administration in 5-year Kaplan-Meier (P=.002 and P<.001, respectively) and multivariate analyses (hazard ratio [HR], 1.46; P=.073, and HR, 1.77; P=.011, respectively). Dose delays of <14 or ≥14 days and granulocyte colony-stimulating factor use did not affect outcomes. CONCLUSIONS: Chemotherapy TCD <85% for adjuvant FEC-D affects breast cancer survival. Late reductions (D only) were not shown to adversely affect DFS or OS. Conversely, early reductions (FEC±D) negatively affected patient outcomes.

Real-World Outcomes of Adjuvant Chemotherapy for Node-Negative and Node-Positive HER2-Positive Breast Cancer.

Background: Comparative real-world outcomes for patients with HER2-positive (HER2+) breast cancer receiving adjuvant trastuzumab outside of clinical trials are lacking. This study sought to retrospectively characterize outcomes for patients with node-negative and node-positive breast cancer receiving adjuvant trastuzumab in combination with docetaxel/cyclophosphamide (DCH), docetaxel/carboplatin/trastuzumab (TCH), or fluorouracil/epirubicin/cyclophosphamide followed by docetaxel/trastuzumab (FEC-DH) chemotherapy in Alberta, Canada, from 2007 through 2014. Methods: Disease-free survival and overall survival (OS) analyses for node-negative cohorts receiving DCH (n=111) or TCH (n=371) and node-positive cohorts receiving FEC-DH (n=146) or TCH (n=315) were compared using chi-square, Kaplan-Meier, or Cox multivariable analysis where appropriate. Results: Median follow-up was similar in node-negative (63.9 months) and node-positive (69.0 months) cohorts. The 5-year OS rates in patients with node-negative disease receiving DCH or TCH were similar (95.2% vs 96.9%; P=.268), whereas 5-year OS rates were higher but nonsignificant for patients with node-positive disease treated with FEC-DH compared with TCH (95.2% vs 91.4%; P=.160). Subgroup analysis of node-positive cohorts showed significantly improved OS with FEC-DH versus TCH in patients with estrogen receptor (ER)/progesterone receptor (PR)-positive breast cancer (98.3% vs 91.6%, respectively; P=.014). Conversely, patients with ER/PR-negative disease showed a nonsignificant trend toward higher OS rates with TCH versus FEC-DH (91.6% vs 83.3%, respectively; P=.298). Given the retrospective design, we were unable to capture all potential covariates that may have impacted treatment assignment and/or outcomes. Furthermore, cardiac toxicity data were unavailable. Conclusions: Survival rates of patients with HER2+ breast cancer in our study are comparable to those seen in clinical trials. Our findings support chemotherapy de-escalation in patients with node-negative disease and validate the efficacy of FEC-DH in those with node-positive disease.

The ONE-MIND Study: Rationale and protocol for assessing the effects of ONlinE MINDfulness-based cancer recovery for the prevention of fatigue and other common side effects during chemotherapy.

Cancer patients often experience poor quality of life (QoL) during chemotherapy (CT) treatments due to side effects including fatigue, insomnia, pain and nausea/vomiting. Mindfulness-based cancer recovery (MBCR) is an evidence-based intervention for treating such symptoms, but has not been investigated as an adjunctive treatment during CT. This study aims to determine the efficacy of an online group MBCR programme delivered during CT in 12 real-time interactive weekly sessions for managing fatigue (primary outcome). Secondary outcomes include sleep disturbance, pain, nausea/vomiting, mood, stress and QoL. Exploratory outcomes include cognitive function, white blood cell counts and return to work. The study is a two-armed randomised controlled waitlist trial with 2:1 allocation to treatment (online group MBCR during CT) or control (waitlist usual care; online MBCR following CT completion) with a target sample size of N = 178. Participants are breast or colorectal cancer patients undergoing common CT regimens in Calgary, Canada. Online assessments using validated self-reported instruments will take place at baseline, post-MBCR, post-CT and 12 months' post-baseline. If online MBCR delivered during CT significantly reduces fatigue in cancer patients' post-CT and also impacts secondary symptoms, this would provide evidence for including mindfulness training as an adjunctive symptom management therapy during CT.

Premature mortality due to breast cancer among Canadian women: an analysis of a 30-year period from 1980 through 2010.

Background: Breast cancer is the most commonly diagnosed cancer and the second most common cause of cancer deaths for women. In the present study, we examined the trend of premature mortality due to breast cancer among Canadian women from 1980 through 2010 and proposed a new measure of lifespan shortening. Methods: Mortality data for female breast cancer was obtained from the World Health Organization mortality database. Years of life lost (YLL) was estimated using Canadian life tables. Average lifespan shortened (ALSS) that is calculated and expressed by a ratio of YLL relative to expected lifespan. Results: Over this study period, age-standardized rates of breast cancer mortality adjusted to World Standard Population decreased by 40% from 23.2 to 14.2 per 100 000 women. The adjusted YLL rates fell from 5.3 years per 1000 women to 3.3 years. On average women with breast cancer died 20.8 years prior to expected death in 1980 and 18.3 years early in 2010. A novel measure of lifespan shortening, the ALSS decreased from one-fourth of the lifespan in 1980 to one-fifth in 2010. Conclusions: Our study reports that among Canadian women with breast cancer, a smaller proportion of life was lost on average at the end of the study period. The 'life lost' measures presented in this study would be useful tools to monitor the pattern of premature mortality for chronic conditions. These measures gauge the effectiveness of the health system with respect to early detection and treatment.

Canadian Cancer Trials Group IND197: a phase II study of foretinib in patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-negative recurrent or metastatic breast cancer.

In murine models, overexpression of the MET receptor transgene induces tumors with human basal gene expression characteristics supporting MET inhibition as a treatment strategy for triple-negative breast cancer (TNBC). Foretinib is an oral multi-kinase inhibitor of MET, RON, AXL, TIE-2, and VEGF receptors with anti-tumor activity in advanced HCC and papillary renal cell cancer. Patients with centrally reviewed primary TNBC and 0-1 prior regimens for metastatic disease received daily foretinib 60 mg po in a 2-stage single-arm trial. Primary endpoints were objective response and early progression rates per RECIST 1.1. In stage 2, correlative studies of MET, PTEN, EGFR, and p53 on archival and fresh tumor specimens were performed along with enumeration of CTCs. 45 patients were enrolled with 37 patients having response evaluable and centrally confirmed primary TNBC (cTNBC). There were 2 partial responses (ITT 4.7 % response evaluable cTNBC 5.4 %) with a median duration of 4.4 months (range 3.7-5 m) and 15 patients had stable disease (ITT 33 %, response evaluable cTNBC 40.5 %) with a median duration of 5.4 months (range 2.3-9.7 m). The most common toxicities (all grades/grade 3) were nausea (64/4 %), fatigue (60/4 %), hypertension (58/49 %), and diarrhea (40/7 %). Six serious adverse events were considered possibly related to foretinib and 4 patients went off study due to adverse events. There was no correlation between MET positivity and response nor between response and PTEN, EGFR, p53, or MET expression in CTCs. Although CCTG IND 197 did not meet its primary endpoint, the observation of a clinical benefit rate of 46 % in this cTNBC population suggests that foretinib may have clinical activity as a single, non-cytotoxic agent in TNBC (ClinicalTrials.gov number, NCT01147484).

Discharge to Primary Care for Survivorship Follow-Up: How Are Patients With Early-Stage Breast Cancer Faring?

PURPOSE: Oncology centers in public health systems often transfer routine follow-up of patients with early-stage breast cancer (BC) to primary care physicians because of the increasing numbers of survivors and evidence supporting the safety of this practice. After transfer of care, it is unknown how BC survivors fare with treatment and surveillance goals, and whether they have unmet needs for access to specialist care. This study conducted in a sample of women in Alberta, Canada, examined adherence with follow-up guidelines, symptoms, and need for a telephone-based survivorship clinic. METHODS: Through the Alberta Cancer Registry, we randomly invited women with stage I-III invasive BC (N=960) to participate. Of those, 272 responded, and 240 consented to a structured telephone interview and chart review. RESULTS: Women adhered well to follow-up guidelines for mammogram, but less so for clinical examination and endocrine therapy (ET). However, most patients reported ongoing bothersome symptoms, which tended to be higher in those not on ET. More than one-third of patients reported ongoing needs (managing weight, side effects, exercise adherence, and psychosocial health). Younger, fatigued or depressed, nonurban women not on ET reported the most need for a telephone clinic. CONCLUSIONS: Adherence with follow-up goals (examination, mammography, ET) was better than expected. Despite this, interest in a telephone survivorship clinic was high. Perceived needs included symptom management plus support for lifestyle behavior change. Medical follow-up needs might be well-met by discharge to primary care. However, high levels of ongoing symptoms and psychosocial needs would suggest that telephone-based survivorship clinics, psychosocial and exercise interventions, or transition programs might benefit the survivorship experience of patients with BC.

Adjuvant Ovarian Function Suppression in Premenopausal Hormone Receptor-Positive Breast Cancer.

Importance: Few oncology studies have assessed the effectiveness of adjuvant ovarian function suppression (OFS) in observational settings for premenopausal hormone receptor-positive breast cancer. Target trial emulation is increasingly used for estimating treatment outcomes in observational cohorts. Objectives: To describe hormone therapy and OFS treatment patterns (aim 1), examine the association between adding OFS to tamoxifen (TAM) or aromatase inhibitor (AI) and survival (aim 2), and examine the association between duration of hormone treatment (TAM or AI) plus OFS (H-OFS) and survival (aim 3). Design, Setting, and Participants: This population-based cohort study included all premenopausal, early-stage breast cancer diagnoses between 2010 and 2020 in Alberta, Canada. Target trial emulation was conducted. Eligibility criteria were directly modeled after the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT). Participants were followed up for a maximum of 5 years. Data were analyzed from July 2022 through March 2023. Exposures: For aim 2, exposures were receiving the following baseline treatments for 2 years: AI + OFS (AI-OFS), TAM + OFS (T-OFS), and TAM alone. For aim 3, exposures were a 2-year or greater and a less than 2-year duration of H-OFS. Main Outcomes and Measures: Recurrence-free survival was the primary outcome of interest. Marginal structural Cox models with inverse probability treatment and censoring weights were used to estimate hazard ratios (HRs), adjusted for baseline and time-varying confounding variables. Results: Among 3434 female patients with premenopausal, early-stage breast cancer diagnoses (median [IQR] age, 45 [40-48] years), 2647 individuals satisfied SOFT and TEXT eligibility criteria. There were 2260 patients who initiated TAM, 232 patients who initiated T-OFS, and 155 patients who initiated AI-OFS; 192 patients received H-OFS for 2 or more years, and 195 patients received H-OFS for less than 2 years. The 5-year recurrence risks were not significantly lower in AI-OFS vs TAM (HR, 0.76; 95% CI, 0.38-1.33) or T-OFS vs TAM (HR, 0.87; 95% CI, 0.50-1.45) groups. Patients receiving H-OFS for 2 or more years had significantly better 5-year recurrence-free survival compared with those receiving H-OFS for less than 2 years (HR, 0.69; 95% CI, 0.54-0.90). Conclusions and Relevance: This study found no significant reductions in recurrence risk for AI-OFS and T-OFS compared with TAM alone. H-OFS duration for at least 2 years was associated with significantly improved recurrence-free survival.

The Association between Mutational Signatures and Clinical Outcomes among Patients with Early-Onset Breast Cancer.

Early-onset breast cancer (EoBC), defined by a diagnosis <40 years of age, is associated with poor prognosis. This study investigated the mutational landscape of non-metastatic EoBC and the prognostic relevance of mutational signatures using 100 tumour samples from Alberta, Canada. The MutationalPatterns package in R/Bioconductor was used to extract de novo single-base substitution (SBS) and insertion-deletion (indel) mutational signatures and to fit COSMIC SBS and indel signatures. We assessed associations between these signatures and clinical characteristics of disease, in addition to recurrence-free (RFS) and overall survival (OS). Five SBS and two indel signatures were extracted. The SBS13-like signature had higher relative contributions in the HER2-enriched subtype. Patients with higher than median contribution tended to have better RFS after adjustment for other prognostic factors (HR = 0.29; 95% CI: 0.08-1.06). An unsupervised clustering algorithm based on absolute contribution revealed three clusters of fitted COSMIC SBS signatures, but cluster membership was not associated with clinical variables or survival outcomes. The results of this exploratory study reveal various SBS and indel signatures may be associated with clinical features of disease and prognosis. Future studies with larger samples are required to better understand the mechanistic underpinnings of disease progression and treatment response in EoBC.

The Association between Early-Onset Diagnosis and Clinical Outcomes in Triple-Negative Breast Cancer: A Systematic Review and Meta-Analysis.

Early-onset diagnosis, defined by age <40 years, has historically been associated with inferior outcomes in breast cancer. Recent evidence suggests that this association is modified by molecular subtype. We performed a systematic review and meta-analysis of the literature to synthesize evidence on the association between early-onset diagnosis and clinical outcomes in triple-negative breast cancer (TNBC). Studies comparing the risk of clinical outcomes in non-metastatic TNBC between early-onset patients and later-onset patients (≥40 years) were queried in Medline and EMBASE from inception to February 2023. Separate meta-analyses were performed for breast cancer specific survival (BCSS), overall survival (OS), and disease-free survival (DFS), locoregional recurrence-free survival (LRRFS), distant recurrence-free survival (DRFS), and pathological complete response (pCR). In total, 7581 unique records were identified, and 36 studies satisfied inclusion criteria. The pooled risk of any recurrence was significantly greater in early-onset patients compared to later-onset patients. Better BCSS and OS were observed in early-onset patients relative to later-onset patients aged >60 years. The pooled odds of achieving pCR were significantly higher in early-onset patients. Future studies should evaluate the role of locoregional management of TNBC and the implementation of novel therapies such as PARP inhibitors in real-world settings, and whether they improve outcomes.

Survival in Women with De Novo Metastatic Breast Cancer: A Comparison of Real-World Evidence from a Publicly-Funded Canadian Province and the United States by Insurance Status.

Metastatic breast cancer (MBC) patient outcomes may vary according to distinct health care payers and different countries. We compared 291 Alberta (AB), Canada and 9429 US patients < 65 with de novo MBC diagnosed from 2010 through 2014. Data were extracted from the provincial Breast Data Mart and from the National Cancer Institute's SEER program. US patients were divided by insurance status (US privately insured, US Medicaid or US uninsured). Kaplan-Meier and log-rank analyses were used to assess differences in OS and hazard ratios (HR) were estimated using Cox models. Multivariate models were adjusted for age, surgical status, and biomarker profile. No difference in OS was noted between AB and US patients (HR = 0.92 (0.77-1.10), p = 0.365). Median OS was not reached for the US privately insured and AB groups, and was 11 months and 8 months for the US Medicaid and US uninsured groups, respectively. The 3-year OS rates were comparable between US privately insured and AB groups (53.28% (51.95-54.59) and 55.54% (49.49-61.16), respectively). Both groups had improved survival (p < 0.001) relative to the US Medicaid and US uninsured groups [39.32% (37.25-41.37) and 40.53% (36.20-44.81)]. Our study suggests that a universal health care system is not inferior to a private insurance-based model for de novo MBC.

A Review of Trastuzumab Biosimilars in Early Breast Cancer and Real World Outcomes of Neoadjuvant MYL-1401O versus Reference Trastuzumab.

The reduced cost of trastuzumab biosimilars has led to increased adoption for HER2-positive breast cancer. This review of trastuzumab biosimilars encompasses this development and real world clinical data in early breast cancer. In addition, we present a retrospective study evaluating the total pathological complete response (tpCR) rates (lack of residual invasive cancer in resected breast tissue and axillary nodes), of MYL-1401O to reference trastuzumab (TRZ) in the neoadjuvant setting for HER2+ early breast cancer (EBC) in Alberta, Canada. Neoadjuvant patients with HER2+ EBC treated with TRZ from November 2018-October 2019 and MYL-1401O from December 2019-September 2020 were identified. Logistic regression was used to control for variables potentially associated with tpCR: trastuzumab product, age, pre-operative T- and N-stage, grade, hormone receptor (HR)-status, HER2-status, chemotherapy regimen, and chemotherapy completion. tpCR was 35.6% in the MYL-1401O group (n = 59) and 40.3% in the TRZ (n = 77) group, p = 0.598. After controlling for clinically relevant variables, there was no significant difference in the odds of achieving tpCR in patients treated with TRZ versus MYL-1401O (OR 1.1, 95% CI 0.5-2.4, p = 0.850). tpCR rates were similar for patients treated with MYL-1401O compared to trastuzumab in our real world study of HER2+ neoadjuvant EBC and comparable to pivotal phase 3 trials.

Radiation Therapy With Cyclin-Dependent Kinase 4/6 Inhibitors: A Multi-institutional Safety and Toxicity Study.

PURPOSE: Our purpose was to investigate radiation therapy (RT) toxicity when given with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) compared with RT alone. METHODS AND MATERIALS: We conducted a retrospective cohort study of patients with hormonal receptor-positive and human epidermal growth factor-2 negative metastatic breast cancer treated with RT at 4 cancer centers in Alberta, Canada, between 2016 and 2020. Toxicity in patients treated with RT within 30 days of initiating to discontinuing CDK4/6i (RT + CDK4/6i) was compared with toxicity of RT in CDK4/6i-naïve patients (RT alone). The primary outcome was acute grade (G) 2 or higher, nonhematological toxicity within 30 days of RT. We also explored toxicity based on the timing of RT (prior, concurrent, post) in relation to CDK4/6i. Propensity score matching was applied to create comparable cohorts. A generalized linear mixed model was used to evaluate factors associated with acute toxicity. RESULTS: One hundred thirty-two patients (220 RT sites) in the RT + CDK4/6i and 53 patients (93 RT sites) in RT alone were eligible. The rate of acute G2 or higher nonhematological toxicity was 11.5% versus 7%, respectively (P = .439), and acute G3 or higher nonhematological toxicity was 3.7% versus 0%, respectively (P = .151). Acute toxicity in RT + CDK4/6i group was mainly observed when RT was given concurrently (67%), with most of the G3 toxicity recorded. After propensity score matching, the association of acute toxicity with RT + CDK4/6i versus RT alone was not significant on multivariable analysis (odds ratio, 3.13; 95% confidence interval, 0.74-13.2; P = .121). CONCLUSIONS: We did not observe a significant association between CDK4/6i use and acute G2 or higher nonhematological toxicity in women with metastatic breast cancer receiving palliative RT. Given the findings of G3 toxicity, caution is advised whenever CDK4/6i is given concurrently with RT.

Developing a Prediction Model for Pathologic Complete Response Following Neoadjuvant Chemotherapy in Breast Cancer: A Comparison of Model Building Approaches.

PURPOSE: The optimal characteristics among patients with breast cancer to recommend neoadjuvant chemotherapy is an active area of clinical research. We developed and compared several approaches to developing prediction models for pathologic complete response (pCR) among patients with breast cancer in Alberta. METHODS: The study included all patients with breast cancer who received neoadjuvant chemotherapy in Alberta between 2012 and 2014 identified from the Alberta Cancer Registry. Patient, tumor, and treatment data were obtained through primary chart review. pCR was defined as no residual invasive tumor at surgical excision in breast or axilla. Two types of prediction models for pCR were built: (1) expert model: variables selected on the basis of oncologists' opinions and (2) data-driven model: variables selected by trained machine. These model types were fit using logistic regression (LR), random forests (RF), and gradient-boosted trees (GBT). We compared the models using area under the receiver operating characteristic curve and integrated calibration index, and internally validated using bootstrap resampling. RESULTS: A total of 363 cases were included in the analyses, of which 86 experienced pCR. The RF and GBT fits yielded higher optimism-corrected area under the receiver operating characteristic curves compared with LR for the expert (RF: 0.70; GBT: 0.69; LR: 0.65) and data-driven models (RF: 0.71; GBT: 0.68; LR: 0.64). The LR fit yielded the lowest integrated calibration indices for the expert (LR: 0.037; GBT: 0.05; RF: 0.10) and data-driven models (LR: 0.026; GBT: 0.06; RF: 0.099). CONCLUSION: Our models demonstrated predictive ability for pCR using routinely collected clinical and demographic variables. We show that machine learning fit methods can be used to optimize models for pCR prediction. We also show that additional variables beyond clinical expertise do not considerably improve predictive ability and may not be of value on the basis of the burden of data collection.