Third-line treatment patterns in HER2-positive metastatic breast cancer: a retrospective analysis of real-world data in Canada.

There is an increasing demand for real-world data pertaining to the usage of cancer treatments, especially in settings where no standard treatment is specifically recommended. This study presents the first real-world analysis of third-line treatment patterns in HER2-positive metastatic breast cancer (mBC) patients in Canada. The purpose was to assess evolution of clinical practice and identify unmet needs in post-second-line therapy. Retrospective data from medical records of 66 patients who received third-line treatment before 31st October 2018, and data from 56 patients who received third-line treatment after this date, extracted from the Personalize My Treatment (PMT) cancer patient registry, were analyzed. In the first cohort, the study revealed heterogeneity in the third-line setting, with trastuzumab, lapatinib, and T-DM1 being the main treatment options. Even though data were collected before the wide availability of tucatinib, neratinib and trastuzumab deruxtecan in Canada, the PMT cohort revealed the emergence of new therapeutic combinations and a shift from lapatinib usage to T-DM1 choice was observed. These findings underscore the evolving nature of third-line treatment strategies in Canada, a facet that is intrinsically tied to the availability of new drugs. The absence of a consensus on post-second-line treatment highlights the pressing need for more efficient therapeutic alternatives beyond the currently available options. This study not only offers valuable insights into the present landscape of third-line treatment in Canada but validates the significance and effectiveness of the PMT registry as a tool for generating pan-Canadian real-world evidence in oncology and its capacity to provide information on evolution of therapeutic practices.

Impact of the 21-Gene Recurrence Score Assay on Treatment Decisions and Cost in Patients with Node-Positive Breast Cancer: A Multicenter Study in Quebec.

BACKGROUND: The 21-gene Breast Recurrence Score (RS) assay, "the assay", has led to a paradigm shift for patients with hormone receptor-positive, node-negative early breast cancer and is emerging as an important tool to assist physician-patient decisions in foregoing chemotherapy in node-positive patients. We wanted to better understand the impact of the RS assay in node-positive patients upon physician treatment decisions and treatment cost in Quebec, Canada. PATIENTS AND METHODS: We conducted a multicenter, prospective observational trial for Estrogen/Progesterone Receptor (ER/PR)- positive, Human Epidermal Growth Factor Receptor 2 (HER2)-negative breast cancer patients with 1-3 positive lymph nodes. Physicians completed a questionnaire indicating treatment choice prior to and post availability of RS results. The primary endpoint was change in the physician's recommendation for chemotherapy prior to and post assay results. Secondary endpoints included change in physician's expressed level of confidence, and changes in estimated cost of recommended treatments prior to and post assay results. RESULTS: For the entire cohort, physician recommendation for chemotherapy was reduced by an absolute 67.1% by knowledge of the RS assay result (P < .0001). Physician recommendation of chemotherapy was decreased by 75.9% for patients RS result <14 (P < .0001); and 67.5% for patients with RS result 14-25 (P < .0001). Changes in treatment recommendations were associated with an overall reduction in cost by 73.7% per patient, and after incorporating the cost of the RS test, a cost benefit of $823 CAN at 6-month follow-up. CONCLUSION: Altogether, we established that the assay led to a two-third reduction in the use of chemotherapy, and was a cost-effective approach for hormone receptor-positive, node-positive breast cancer.

Behavioral and health outcomes from the NRG Oncology/NSABP B-36 trial comparing two different adjuvant therapy regimens for early-stage node-negative breast cancer.

BACKGROUND: The NSABP B-36 compared four cycles of doxorubicin and cyclophosphamide (AC) with six cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC-100) in node-negative early-stage breast cancer. A sub-study within B-36, focusing on symptoms, quality of life (QOL), menstrual history (MH), and cardiac function (CF) was conducted. PATIENTS AND METHODS: Patients completed the QOL questionnaire at baseline, during treatment, and every 6 months through 36 months. FACT-B Trial Outcome Index (TOI), symptom severity, and SF-36 Vitality and Physical Functioning (PF) scales scores were compared between the two groups using a mixed model for repeated measures analysis. MH was collected at baseline and subsequently assessed if menstrual bleeding occurred within 12 months prior to randomization. Post-chemotherapy amenorrhea outcome was examined at 18 months and was defined as lack of menses in the preceding year. Logistic regression was used to test for association of amenorrhea and treatment. CF assessment was done at baseline and 12 months. Correlation analysis was used to address associations between changes in baseline and 12-month PF and concurrent CF changes measured by LVEF. RESULTS: FEC-100 patients had statistically significantly lower TOI scores during chemotherapy (P = 0.02) and at 6 months (P < 0.001); lower Vitality score at 6 months (P < 0.01), and lower PF score during the first year than AC patients. There were no statistically significant QOL score differences between the two groups beyond 12 months. No significant differences in symptom severity between the two groups were observed. Rates of amenorrhea were significantly different between FEC-100 and AC (67.4% vs. 59.1%, P < 0.001). There was no association between changes in LVEF and PF (P = 0.38). CONCLUSIONS: Statistically significant QOL differences between the two groups favored AC; however, the magnitude was small and unlikely to be clinically meaningful. There was a clinical and statistically significant difference in risk for amenorrhea, favoring AC. TRIAL REGISTRY: NCT00087178; Date of registration: 07/08/2004.

Definitive results of a phase III adjuvant trial comparing six cycles of FEC-100 to four cycles of AC in women with operable node-negative breast cancer: the NSABP B-36 trial (NRG Oncology).

PURPOSE: Results from adjuvant trials evaluating 6 cycles of epirubicin-based chemotherapy regimens suggested these programs may be more effective than 4 cycles of doxorubicin-based chemotherapy. METHOD: NSABP B-36 was a phase III clinical trial originally designed as a 2 × 2 factorial study comparing 6 cycles of 5-FU, epirubicin, and cyclophosphamide (FEC-100) to 4 cycles of conventional doxorubicin and cyclophosphamide (AC) with celecoxib or placebo. Shortly after activation, concerns regarding increased cardiovascular risks among selective COX-2 inhibitors resulted in a decision to remove the celecoxib/placebo from the trial. Women with histologically node-negative invasive breast cancer who had undergone primary surgery with a lumpectomy or total mastectomy were eligible. Primary endpoint was disease-free survival (DFS). RESULTS: Between May 2004 and July 2008, 2722 patients were enrolled. Administration of FEC-100 did not result in improvement in DFS compared to AC (HR 1.09; 95% CI 0.92-1.29, p value = 0.31). The effect of FEC-100 compared to AC on DFS was significantly different for receptor-positive (HR 1.32, 95% CI 1.05-1.66) compared to receptor-negative patients (HR 0.86, 95% CI 0.66-1.11) (treatment-by-receptor status interaction p value = 0.02). There was no statistically significant difference in the effect of treatment on overall survival (OS) with FEC-100 compared to AC (HR 1.06; 95% CI 0.84-1.35, p value = 0.61). Overall, Grade 3 and 4 adverse events were more frequent in the FEC-100 group. CONCLUSION: The results of B-36 do not support use of six-cycle anthracycline-based regimens in node-negative breast cancer. Prolongation of anthracycline-based therapy with FEC-100 does not improve DFS or OS, relative to AC for 4 cycles, and was associated with expected increases in toxicity. A statistically significant interaction between treatment and hormone receptor status favoring AC in hormone-receptor-positive breast cancers is consistent with the hypothesis that optimal duration of chemotherapy may be four cycles in these patients. Late cardiac events and deaths prior to recurrence or second cancer were infrequent on both arms, but slightly higher with FEC-100. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00087178.

Do Preoperative Prophylactic Antibiotics Reduce Surgical Site Infection Following Wire-Localized Lumpectomy? A Single-Blind Randomized Clinical Trial.

BACKGROUND: Data on the benefits of preoperative prophylactic antibiotics for breast surgery are conflicting, and there is no specific guideline for their use in wire-localized lumpectomy. PATIENTS AND METHODS: This is a proof-of-concept, single-blind randomized controlled trial carried out from April 2018 to June 2019 at the Centre des Maladies du Sein du CHU de Québec - Université Laval. The objectives were to determine whether a single dose of preoperative antibiotics reduces surgical site infection (SSI) after wire-localized lumpectomy and to identify the risk factors for SSI. The patients were randomized to receive preoperative prophylactic antibiotics or not. SSI was defined by positive breast wound cultures, abscess drainage, and/or antibiotics given for clinical signs of breast infection within 30 days of the operation. This study was registered with ClinicalTrials.gov, NCT04818931. RESULTS: A total of 330 patients were enrolled. Eighteen patients were excluded. The SSI rate was 3.1% (5/160) in the antibiotic group versus 5.9% (9/152) in the control group (p = 0.28). Only obesity was a significant risk factor for SSI. All cases of SSI were treated routinely with antibiotics; one patient required wound re-opening. None of the SSIs delayed the adjuvant treatment. CONCLUSION: Preoperative antibiotic prophylaxis does not significantly decrease the occurrence of breast SSI. It is safe to omit prophylactic antibiotics for a wire-localized lumpectomy. This could also decrease the treatment costs and avoid unnecessary side effects.

Women with breast cancer's perceptions of nurse-led telephone-based motivational interviewing consultations to enhance adherence to adjuvant endocrine therapy: a qualitative study.

BACKGROUND: Daily adjuvant endocrine therapy (AET) for 5 or 10 years is the standard of care for women diagnosed with non-metastatic hormone receptor-positive breast cancer. However, many women experience AET-related issues that may hamper quality of life and adherence. Here, we aimed to describe women's perceptions of motivational interviewing (MI)-guided consultations delivered by a trained nurse navigator over the telephone to enhance AET adherence. METHODS: Eighteen women who were first prescribed AET for non-metastatic breast cancer in the last 5 years, who self-reported AET-related issues, and who participated in at least two MI-guided consultations over a year were interviewed about their perceptions of the intervention, using a semi-structured interview guide. Audio recordings were transcribed verbatim and analyzed using a thematic analysis approach. RESULTS: Three main themes emerged from the data about women's perceptions on MI-guided consultations. These consultations were described as (1) a person-centred experience, (2) providing key information about AET, and (3) supportive of present and future AET experience, by contributing to AET side-effect management, motivation, adherence, calming negative emotions, improving well-being and self-esteem, and making women to feel empowered. CONCLUSIONS: Nurse-led telephone-based MI-guided consultations about AET were found to respond to participants' needs and to enhance participants' perceptions of being informed and being supported in experiencing various facets of AET. Telephone-based consultations for AET are perceived as a promising strategy in an increasing virtual care world.

The efficacy and safety of enzalutamide with trastuzumab in patients with HER2+ and androgen receptor-positive metastatic or locally advanced breast cancer.

PURPOSE: Androgen receptor (AR) expression occurs in up to 86% of human epidermal growth factor receptor 2-positive (HER2+) breast cancers. In vitro, AR inhibitors enhance antitumor activity of trastuzumab, an anti-HER2 antibody, in trastuzumab-resistant HER2+ cell lines. This open-label, single-arm, phase II study evaluated the efficacy and safety of enzalutamide, an AR-signaling inhibitor, in patients with advanced HER2+ AR+ breast cancer previously treated with trastuzumab. METHODS: Eligible patients had measurable or non-measurable evaluable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Eastern Cooperative Oncology Group status ≤ 1, no history of brain metastases, and previously received ≥ 1 anti-HER2 regimen for advanced disease. Patients received 160 mg oral enzalutamide daily and 6 mg/kg intravenous trastuzumab every 21 days until disease progression or unacceptable toxicity. Primary end point was clinical benefit rate at 24 weeks (CBR24); secondary end points included progression-free survival (PFS) and safety. RESULTS: Overall, 103 women were enrolled [median age 60 years (range 34-83)]; 62% had received ≥ 3 lines of prior anti-HER2 therapy. CBR24, comprising patients with confirmed partial responses (5%) and durable stable disease at 24 weeks (19%), was 24% in the efficacy evaluable set (n = 89). CBR24 did not seem related to AR-expression levels or hormone receptor status. Median PFS was 3.4 months (95% confidence interval 2.0-3.8). Overall, 97 (94%) patients experienced treatment-emergent adverse events (TEAEs), with fatigue most common (34%). Dyspnea (4%) and malignant neoplasm progression (3%) were the only TEAEs grade ≥ 3 reported in ≥ 3 patients. 22 patients (21%) reported serious TEAEs. Four patients (4%) experienced fatal, non-drug-related TEAEs. CONCLUSIONS: Enzalutamide plus trastuzumab was well tolerated, and a subset of patients in this heavily pretreated population had durable disease control. Determination of biomarkers is needed to identify patients most likely to benefit from this combination. CLINICALTRIALS. GOV NUMBER: NCT02091960.

Wage losses among spouses of women with nonmetastatic breast cancer.

BACKGROUND: The aim of this study was to evaluate the wage losses incurred by spouses of women with nonmetastatic breast cancer in the 6 months after the diagnosis. METHODS: A prospective cohort study of spouses of women diagnosed with nonmetastatic breast cancer who were recruited in 8 hospitals in the province of Quebec (Canada) was performed. Information for estimating wage losses was collected by telephone interviews conducted 1 and 6 months after the diagnosis. Log-binomial regressions were used to identify personal, medical, and employment characteristics associated with experiencing wage losses, and generalized linear models were used to identify characteristics associated with the proportion of usual wages lost. RESULTS: Overall, 829 women (86% participation) and 406 spouses (75% participation) consented to participate. Among the 279 employed spouses, 78.5% experienced work absences because of breast cancer. Spouses were compensated for 66.3% of their salary on average during their absence. The median wage loss was $0 (mean, $1820) (2003 Canadian dollars). Spouses were more likely to experience losses if they were self-employed or lived 50 km or farther from the hospital. Among spouses who experienced wage losses, those who were self-employed or whose partners had invasive breast cancer lost a higher proportion of wages. CONCLUSIONS: Although spouses took some time off work, for many, the resulting wage losses were modest because of compensation received. Still, the types of compensation used may hide other forms of burden for families facing breast cancer.

Is contralateral breast ultrasound worthwhile in preoperative staging of breast cancer?

BACKGROUND: Women with invasive breast cancer are at higher risk of contralateral synchronous cancer. This study aimed at determining if contralateral breast ultrasound (CBUS) examination should be routinely performed in the preoperative evaluation of breast cancer patients. METHODS: This is a retrospective study of preoperative CBUS examinations performed between January 2012 and April 2015. The charts of patients presenting for biopsy of a Breast Imaging Reporting and Data System (BIRADS) 5 lesion and who had undergone a concomitant contralateral breast US examination were reviewed. Index tumor, lymph node status, American College of Radiology (ACR) breast density on mammogram, total scanning time, and results of CBUS were recorded. RESULTS: Of the 3007 patients who underwent breast biopsies during the study period, 360 patients met the inclusion criteria. Index mass size was 19 ± 10 mm. CBUS examination led to 76 biopsies, of which 12 were positive in 11 patients. Detection rate for mammographically occult contralateral invasive cancers was 3.1% (11/360). Contralateral lesion size was 13 ± 10 mm. Breast density was rated ACR C/D for nine women and ACR B for two. In the ACR C/D subgroup (82%), the contralateral cancer detection rate was 4.1%. Average additional scanning time spent required to perform CBUS examination was 3.1 ± 4.9 min. Patients diagnosed with contralateral invasive breast cancer underwent surgery and/or chemotherapy. The treatment strategy was changed in all 11 patients after the detection of a second primary cancer. CONCLUSION: Preoperative CBUS is effective and most beneficial with women presenting ACR C/D breast density. Given its impact on decreasing future morbidity, its routine use should be considered to improve quality healthcare for women diagnosed with breast cancer.

Characteristics and long-term survival of patients diagnosed with pure tubular carcinoma of the breast.

BACKGROUND AND OBJECTIVES: Pure tubular carcinomas (TC) of the breast are generally considered to have an excellent prognosis. This study aimed to analyze the characteristics and survival of patients with TC. METHODS: This was a retrospective study conducted at the CHU de Québec-Université Laval. Databases were searched for all cases treated between April 1997 and December 2010. Survival was retrieved from the Province of Quebec Ministry of Health. Follow-up was censored on December 31, 2011. Overall survival (OS) was compared to patients with invasive ductal carcinoma (ICD) matched for age, tumor size, lymph node involvement, year of diagnosis, ER, PgR, and HER2, histological grade, lymphovascular invasion, and chemotherapy. RESULTS: The frequency of TC was 2.9% (n = 223/7563). Tumors size was 7.4 ± 8.8 mm, without lymphovascular invasion (95.1%), ER-positive (98.2%), PgR-positive (69.5%), and HER2-negative (100%). Patients were followed up for 7.1 ± 2.7 years. The actuarial 13-year OS was 89.0% for TC, compared to 85.8% for IDC (P = 0.13). For TC, the 13-year OS was 95.8% in NO patients compared to 90.0% for N1-3 (P = 0.01). CONCLUSION: Despite the general popular belief that patients with TC fare better than patients with IDC, the 13-year OS of TC was similar to that of grade I IDC.

Enhancing Endocrine Therapy Combination Strategies for the Treatment of Postmenopausal HR+/HER2- Advanced Breast Cancer.

Breast cancer (BC) is the most common malignancy in women worldwide, with approximately two-thirds having hormone receptor-positive (HR+) tumors. New endocrine therapy (ET) strategies include combining ET agents as well as adding inhibitors targeting growth factors, angiogenesis, the mechanistic target of rapamycin, phosphoinositide 3-kinase (PI3K), or cyclin-dependent kinase 4/6 to ET. Level 1 evidence supports use of fulvestrant plus anastrozole or palbociclib plus letrozole as first-line therapy for HR+/HER- advanced BC with special consideration for the former in ET-naïve patients, as well as everolimus plus exemestane or palbociclib plus fulvestrant as second-line therapy with special consideration in select first-line patients. Although the safety profiles of these combinations are generally predictable and manageable, both everolimus and palbociclib are associated with an increased risk of potentially serious or early-onset toxicities requiring individualized a priori adverse event risk stratification, earlier and more rigorous agent-specific monitoring, and patient education. Although each of these combinations improves progression-free survival, none with the exception of anastrazole plus fulvestrant have demonstrated improved overall survival. PI3K catalytic-α mutations assessed from circulating tumor DNA represent the first potentially viable serum biomarker for the selection of ET combinations, and new data demonstrate the feasibility of this minimally invasive technique as an alternative to traditional tissue analysis. Therapeutic ratios of select ET combinations support their use in first- and second-line settings, but optimal sequencing has yet to be determined. THE ONCOLOGIST: 2017;22:12-24 IMPLICATIONS FOR PRACTICE: Emerging data show that new endocrine therapy (ET) combinations can improve progression-free and overall survival outcomes in patients with hormone receptor-positive, HER2-negative (HR+/HER-) advanced breast cancer. Level 1 evidence supports consideration of dual ET regimens, particularly in ET-naïve patients, or palbociclib plus letrozole as first-line therapy, as well as the addition of mTOR or CDK4/6 inhibitors to established ET in the second-line setting and in select first-line patients. Some combinations are associated with increased risk of class-specific toxicities that will require individualized risk stratification, earlier and more rigorous agent-specific monitoring, and patient education. Recent data on a noninvasive biomarker assay that predicts response to a phosphoinositide 3-kinase inhibitor demonstrates the feasibility of this minimally invasive technique as an alternative to traditional tissue analysis.

How Wide Should Margins Be for Phyllodes Tumors of the Breast?

The surgical management of phyllodes tumors (PTs) is still controversial. Some studies have suggested surgical margins ≥1 cm, but recent studies suggested that negative margins could be appropriate regardless of their width. To evaluate recurrence rates of PTs following surgery according to margins. Retrospective study of women who attended a tertiary breast cancer reference center between 1998 and 2010: 142 patients with a PT diagnosis, either at minimally invasive breast biopsy or at surgery, were identified. Clinical, pathologic and follow-up characteristics were assessed. Among 140 patients who underwent surgery, 64.3% of biopsies accurately predicted the final PT diagnosis at surgery. Forty-two (42/87, 48.3%) PTs had positive margins. Twenty-one (21/42, 50.0%) patients had a surgical revision of margins. Only one (1/42, 2.4%) had margins greater or equal to 1 cm. After a median follow-up of 1.29 years in benign PTs, 4.99 years in borderline PTs, and 5.42 years in malignant PTs, there were five local recurrences, three in originally benign PTs and two in borderline PTs. All were managed with surgery. Four had initial margins ≤1 mm. One patient with borderline PT had a local recurrence and later progressed to regional recurrence and metastasis. Free surgical margins are necessary to treat PT, and margins of at least 1 mm might be sufficient to prevent recurrence. Core needle biopsy might not be the best diagnostic tool for PTs.

Is there an Upgrading to Malignancy at Surgery of Mucocele-Like Lesions Diagnosed on Percutaneous Breast Biopsy?

Management of pure mucocele-like lesion (MLL) diagnosed on percutaneous breast biopsy (PBB) is controversial. To assess surgical upgrade rate and clinical outcome of pure MLL obtained as sole diagnosis on PBB. Patients diagnosed with a MLL as the most advanced lesion on PBB from April 1997 to December 2010 were reviewed for radiologic presentation, biopsy technique, and pathologic and clinical outcomes. Of the 21,340 image-guided PBB performed during the study period, 50 women with 51 MLL (0.24%) were identified. Mean age was 53.1 ± 7.7 years. Radiologic findings were mostly microcalcifications (n = 47, 92.2%). Stereotactic PBB was performed for 49 lesions (96.1%). Surgery was performed shortly after biopsy in 35 women, with benign final pathology in 33, and upgrade to ductal carcinoma in situ (DCIS) in two patients (2/35, 5.7%). Mean follow-up was 4.2 ± 2.5 years (3.7 ± 2.1 years for surgical patients; 5.9 ± 2.9 years for follow-up only patients); three women were lost to follow-up (3/50). Three invasive cancers (3/47, 6.4%) were diagnosed 1.2, 1.2, and 2.8 years after biopsy: two in surgical patients, and one in a follow-up only patient. No cancer occurred at the same site as the original MLL. Pure MLL lesion of the breast is a rare entity and is mostly associated with a benign outcome. We observed an upgrade to DCIS slightly superior to 5%, but no invasive cancer. It is therefore unclear if these lesions should be excised or clinically and radiologically followed up when such lesions are found at PBB.

Comparison of serious adverse events between the original and a generic docetaxel in breast cancer patients.

BACKGROUND: Generic formulations are not necessarily identical to the original in terms of efficacy and adverse events. Generic docetaxel has been available in Canada since 2011. OBJECTIVE: To compare the occurrence of grade III to IV adverse events between original docetaxel and a generic formulation in breast cancer patients. METHODS: A consecutive series of 400 patients were assessed retrospectively: 200 who received the original docetaxel and 200 who received a generic formulation. Patients who received both formulations or received their chemotherapy outside our center were excluded. The primary outcome was the occurrence of grade III to IV adverse events related to docetaxel (febrile neutropenia, hand and foot syndrome, intestinal perforation, thrombotic event, and death). RESULTS: Three hundred-sixty-four patients were available for analysis (182/group). The use of a granulocyte colony-stimulating factor (G-CSF) was more frequent in the generic group (44.5% vs 28.8%), as well as treatment discontinuation (26.4% vs 14.8%). The occurrence of grade III to IV febrile neutropenia, hand and foot syndrome, intestinal perforation, thrombotic event, and docetaxel-related deaths were similar between the 2 formulations. However, grade IV febrile neutropenia was more frequent with the generic formulation (78.8% vs 56.3%). Limitations were the retrospective nature of the study and the variety of chemotherapy regimens. CONCLUSION: Adverse events occurrence was similar between the 2 formulations. However, febrile neutropenia was more serious with generic docetaxel, despite increased G-CSF use. Results suggest that the studied generic formulation may be safe, but more caution during treatments might be warranted, especially concerning febrile neutropenia events.

Survey about the use of scalp cooling to prevent alopecia during breast cancer chemotherapy treatment in Canada.

Alopecia is a side effect of chemotherapies used in breast cancer. Scalp cooling is a technique preventing alopecia, but its use remains controversial. We conducted a survey about knowledge of scalp cooling and interest in conducting a randomized clinical trial (RCT). An invitation was sent to 1,022 participants and a total of 139 individuals responded to the survey. The majority knew about the existence of scalp cooling. Ninety per cent thought that an RCT was needed and would participate. The survey revealed different potential problems associated with the increased chair time, limited space, and safety. We concluded that an RCT is needed and that the trial must include evaluation on the impact on health care system resources and safety.

Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive breast cancer: 10-year follow-up of the phase 3 randomised BCIRG 001 trial.

BACKGROUND: We compared standard adjuvant anthracycline chemotherapy with anthracycline-taxane combination chemotherapy in women with operable node-positive breast cancer. Here we report the final, 10-year follow-up analysis of disease-free survival, overall survival, and long-term safety. METHODS: BCIRG 001 was an open label, phase 3, multicentre trial in which 1491 patients aged 18-70 years with node-positive, early breast cancer and a Karnofsky score of 80% or more were randomly assigned to adjuvant treatment with docetaxel, doxorubicin, and cyclophosphamide (TAC) or fluorouracil, doxorubicin, and cyclophosphamide (FAC) every 3 weeks for six cycles. Randomisation was stratified according to institution and number of involved axillary lymph nodes per patient (one to three vs four or more). Disease-free survival was the primary endpoint and was defined as the interval between randomisation and breast cancer relapse, second primary cancer, or death, whichever occurred first. Efficacy analyses were based on the intention-to-treat principle. BCIRG 001 is registered with ClinicalTrials.gov, number NCT00688740. FINDINGS: Enrolement took place between June 11, 1997 and June 3, 1999; 745 patients were assigned to receive TAC and 746 patients were assigned to receive FAC. After a median follow-up of 124 months (IQR 90-126), disease-free survival was 62% (95% CI 58-65) for patients in the TAC group and 55% (51-59) for patients in the FAC group (hazard ratio [HR] 0·80, 95% CI 0·68-0·93; log-rank p=0·0043). 10-year overall survival was 76% (95% CI 72-79) for patients in the TAC group and 69% (65-72) for patients in the FAC group (HR 0·74, 0·61-0·90; log-rank p=0·0020). TAC improved disease-free survival relative to FAC irrespective of nodal, hormone receptor, and HER2 status, although not all differences were significant in these subgroup analyses. Grade 3-4 heart failure occurred in 26 (3%) patients in the TAC group and 17 (2%) patients in the FAC group, and caused death in two patients in the TAC group and four patients in the FAC group. A substantial decrease in left ventricular ejection fraction (defined as a relative decrease from baseline of 20% or more) was seen in 58 (17%) patients who received TAC and 41 (15%) patients who received FAC. Six patients who received TAC developed leukaemia or myelodysplasia, as did three patients who received FAC. INTERPRETATION: Our results provide evidence that the initial therapeutic outcomes seen at the 5-year follow-up with a docetaxel-containing adjuvant regimen are maintained at 10 years. However, a substantial percentage of patients had a decrease in left ventricular ejection fraction, probably caused by anthracycline therapy, which warrants further investigation. FUNDING: Sanofi.

Pilot randomized controlled trial of a program to enhance experience and adherence with adjuvant endocrine therapy among women with non-metastatic breast cancer: 12-month quantitative results.

PURPOSE: Adjuvant endocrine therapy (AET) reduces recurrence risk after hormone receptor-positive breast cancer, but non-adherence is common. We pilot-tested SOIE, a program to enhance AET experience and adherence, to assess its acceptability, feasibility, and effects on psychosocial precursors of AET adherence. METHODS: We conducted a 12-month pilot randomized controlled trial among women who had a first AET prescription. Intervention group received SOIE while control group received usual care. Psychosocial factors from the Theory of Planned Behavior (TPB) (intention - primary outcome -, attitude, subjective norm, behavioral control), additional constructs (AET knowledge, social support, coping planning), impact of AET services received, and adherence were measured by questionnaires at baseline, 3-month, and 12-month endpoints. Group patterns were compared using repeated measures analyses with generalized estimating equations. RESULTS: A total of 106 women were randomized (participation = 54.9%; intervention n = 52; control n = 54; retention = 93.8%). Among SOIE women, ≥ 90% received the program components and were satisfied. Both groups scored high on adherence intentions and group patterns over time were not statistically different. In the intervention group, AET knowledge and coping planning with side effects increased (group-by-time p-value = .002 and .016), a higher proportion reported that AET services received helped them take their AET (p < .05) and have a consistent daily intake (p = .01). CONCLUSION: SOIE is feasible and acceptable for survivors with an AET. SOIE did not significantly impact adherence intentions but was beneficial for other program outcomes and daily intake. IMPLICATIONS FOR CANCER SURVIVORS: SOIE may represent an encouraging avenue to enhance supportive care and empower survivors with managing AET.

A Phase I/II Study of GSK525762 Combined with Fulvestrant in Patients with Hormone Receptor-positive/HER2-negative Advanced or Metastatic Breast Cancer.

PURPOSE: Endocrine-based therapy is the initial primary treatment option for hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC). However, patients eventually experience disease progression due to resistance to endocrine therapy. Molibresib (GSK525762) is a small-molecule inhibitor of bromodomain and extraterminal (BET) family proteins (BRD2, BRD3, BRD4, and BRDT). Preclinical data suggested that the combination of molibresib with endocrine therapy might overcome endocrine resistance. This study aimed to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy [objective response rate (ORR)] of molibresib combined with fulvestrant in women with HR+/HER2- mBC. PATIENTS AND METHODS: In this phase I/II dose-escalation and dose-expansion study, patients received oral molibresib 60 or 80 mg once daily in combination with intramuscular fulvestrant. Patients enrolled had relapsed/refractory, advanced/metastatic HR+/HER2- breast cancer with disease progression on prior treatment with an aromatase inhibitor, with or without a cyclin-dependent kinase 4/6 inhibitor. RESULTS: The study included 123 patients. The most common treatment-related adverse events (AE) were nausea (52%), dysgeusia (49%), and fatigue (45%). At a 60-mg dosage of molibresib, >90% of patients experienced treatment-related AE. Grade 3 or 4 treatment-related AE were observed in 47% and 48% of patients treated with molibresib 60 mg and molibresib 80 mg, respectively. The ORR was 13% [95% confidence interval (CI), 8-20], not meeting the 25% threshold for proceeding to phase II. Among 82 patients with detected circulating tumor DNA and clinical outcome at study enrollment, a strong association was observed between the detection of copy-number amplification and poor progression-free survival (HR, 2.89; 95% CI, 1.73-4.83; P < 0.0001). CONCLUSIONS: Molibresib in combination with fulvestrant did not demonstrate clinically meaningful activity in this study.