A phase 2 trial exploring the significance of homologous recombination status in patients with platinum sensitive or platinum resistant relapsed ovarian cancer receiving combination cediranib and olaparib.

OBJECTIVE: Combination cediranib/olaparib has reported activity in relapsed ovarian cancer. This phase 2 trial investigated the activity of cediranib/olaparib in relapsed ovarian cancer and its association with homologous recombination deficiency (HRD). METHODS: Seventy patients were enrolled to cohorts of either platinum-sensitive or platinum-resistant ovarian cancer and received olaparib tablets 200 mg twice daily and cediranib tablets 30 mg once daily under a continuous dosing schedule. HRD testing was performed on pre-treatment, on-treatment and archival biopsies by sequencing key homologous recombination repair (HRR) genes and by genomic LOH analysis. The primary objective for the platinum-sensitive cohort was the association of HRD, defined as presence of HRR gene mutation, with progression-free survival (PFS). The primary objective for the platinum-resistant cohort was objective response rate (ORR), with a key secondary endpoint evaluating the association of HRD status with activity. RESULTS: In platinum-sensitive ovarian cancer (N = 35), ORR was 77.1% (95% CI 59.9-89.6%) and median PFS was 16.4 months (95% CI 13.2-18.6). Median PFS in platinum-sensitive HRR-HRD cancers (N = 22) was 16.8 months (95% CI 11.3-18.6), and 16.4 months (95% CI 9.4-NA) in HRR-HR proficient cancers (N = 13; p = 0.57). In platinum-resistant ovarian cancer (N = 35), ORR was 22.9% (95% CI 10.4-40.1%) with median PFS 6.8 months (95% CI 4.2-9.1). Median PFS in platinum-resistant HRR-HRD cancers (N = 7) was 10.5 months (95% CI 3.6-NA) and 5.6 months (95% CI 3.6-7.6) in HRR-HR proficient cancers (N = 18; p = 0.23). CONCLUSIONS: Cediranib/olaparib had clinical activity in both platinum-sensitive and -resistant ovarian cancer. Presence of HRR gene mutations was not associated with cediranib/olaparib activity in either setting.

Effects of an educational physical activity intervention in young women with newly diagnosed breast cancer: Findings from the Young and Strong Study.

BACKGROUND: Obesity and inactivity are poor prognostic factors in breast cancer, but less is known regarding physical activity (PA) and weight patterns in young breast cancer survivors. METHODS: The Young and Strong Study was a cluster-randomized trial evaluating education and support interventions for young women (age <45 years) with newly diagnosed breast cancer. Sites were randomized 1:1 to a Young Women's Intervention (YWI) or a contact-time control physical activity intervention (PAI). Changes in PA and weight were compared between groups using general estimating equations to evaluate clustered binary and Gaussian data. RESULTS: A total of 467 patients enrolled between July 2012 and December 2013 across 54 sites. Median age at diagnosis was 40 years (range, 22-45). At baseline, median body mass index (BMI) was 25.4 kg/m2 (range, 16.1-61.1), and participants reported a median of 0 minutes (range, 0-2190) of moderate/vigorous PA/week. PA increased significantly over time in both groups (p < .001), with no difference between groups at any time point. BMI increased modestly but significantly (p < .001) over time in both groups. Provider attention to PA was observed in 74% of participants on PAI and 61% on YWI (p = .145) and correlated with PA at 12 months (median 100 min/week of PA in participants with provider attention to PA vs. 60 min/week in those without, p = .016). CONCLUSIONS: In a cohort of young women with breast cancer, rates of obesity and inactivity were high. PA and BMI increased over time and were not impacted by an educational PA intervention. Findings provide important information for developing lifestyle interventions for young breast cancer survivors.

The feasibility of using an autologous GM-CSF-secreting breast cancer vaccine to induce immunity in patients with stage II-III and metastatic breast cancers.

PURPOSE: The antigenic targets of immunity and the role of vaccination in breast cancer are unknown. We performed a phase I study of an autologous GM-CSF-secreting breast cancer vaccine in patients with metastatic and stage II-III breast cancer. METHODS: Tumor cells from patients with metastatic (n = 15) and stage II-III (n = 7) disease were transduced with a replication-defective adenoviral vector encoding GM-CSF, and then irradiated. Twelve and seven patients with metastatic and stage II-III disease, respectively, received weekly vaccination for three weeks, followed by every other week until disease progression or vaccine supply was exhausted (metastatic) or until six total vaccine doses were administered (stage II-III). RESULTS: Among those patients with metastatic disease who received vaccinations, eight had progressive disease at two months, three had stable disease for 4-13 months, and one has had no evidence of disease for 13 years. Of the patients with stage II-III disease, five died of metastatic disease between 1.16 and 8.49 years after the start of vaccinations (median 6.24 years) and two are alive as of September 2021. Toxicities included injection site reactions, fatigue, fever, upper respiratory symptoms, joint pain, nausea, and edema. Four of five evaluable patients with metastatic disease developed a skin reaction with immune cell infiltration after the fifth injection of unmodified, irradiated tumor cells. CONCLUSION: We conclude that tumor cells can be harvested from patients with metastatic or stage II-III breast cancer to prepare autologous GM-CSF-secreting vaccines that induce coordinated immune responses with limited toxicity. TRIAL REGISTRATION AND DATE OF REGISTRATION: clinicaltrials.gov, NCT00317603 (April 25, 2006) and NCT00880464 (April 13, 2009).

Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. BET bromodomain inhibitors, which have shown efficacy in several models of cancer, have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs. Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance.

A randomized phase II trial of bevacizumab vs. bevacizumab and erlotinib as first-line consolidation after carboplatin, paclitaxel, and bevacizumab in newly diagnosed patients with mullerian tumors.

BACKGROUND: The combination of paclitaxel to platinum remains the backbone of therapy in patients with advanced Mullerian tumors. In patients with newly diagnosed Mullerian tumors, we investigated the progression-free survival benefit of bevacizumab and bevacizumab and erlotinib as consolidation therapy post-induction therapy. METHODS: Sixty patients were enrolled in a phase II trial of carboplatin, paclitaxel, and bevacizumab (induction therapy). After the completion induction therapy, patients were stratified by response (≥ SD) and then randomized (1:1) to either bevacizumab (A) or bevacizumab and erlotinib (AE.) The primary endpoint was PFS. Secondary endpoints included the response rate of induction and consolidation therapy and toxicity profile of each consolidative arm. Each consolidative arm was compared to the historical control GOG 111. RESULTS: Forty-eight patients advanced to the consolidative phase of the trial. Twelve patients were removed in the induction phase, the majority for toxicity. The most common toxicity (grade ≥ 3) was diarrhea (20%: arm AE; 0%: arm A). One patient in the AE arm had a fatal cardiac arrest deemed unrelated to the study treatment. No gastrointestinal perforations were reported. The median PFS in the AE and A arm was 18.9 months (p < 0.0001) and 13.3 months (p: ns), respectively. The overall rate of grade 3/4 toxicities in the AE arm was 72% and in the A arm 30%. Six patients remain free of disease 10 years after enrollment. CONCLUSION: Combinatorial consolidation therapy with AE was associated with an improved progression-free survival in patients with Mullerian tumors.

Phase II, 2-stage, 2-arm, PIK3CA mutation stratified trial of MK-2206 in recurrent endometrial cancer.

Endometrial cancers have high rates of phosphoinositide 3-kinase (PI3K) pathway alterations. MK-2206 is an allosteric inhibitor of AKT, an effector kinase of PI3K signals. We hypothesized patients with tumors harboring PIK3CA mutations would be more likely to benefit from MK-2206 than those without PIK3CA mutation. A Phase II study was performed in patients with recurrent endometrial cancer; all histologies except carcinosarcoma were eligible. Up to two prior chemotherapy lines were permitted, excluding prior treatment with PI3K pathway inhibitors. The first 18 patients were treated with MK-2206 200 mg weekly. Due to unacceptable toxicity, dose was reduced to 135 mg. Co-primary endpoints were objective response rate (ORR) and progression-free survival at 6 months (6moPFS). Thirty-seven patients were enrolled (one ineligible). By somatic PIK3CA mutation analysis, nine patients were mutant (MT) [one with partial response (PR)/6moPFS, two with 6moPFS]. Twenty-seven patients were wild-type (WT) (one PR and four 6moPFS). Most common toxicities were rash (44%), fatigue (41%), nausea (42%) and hyperglycemia (31%). Grade 3 and 4 toxicities occurred in 25 and 17% of patients, respectively. Exploratory analysis found serous histology had greater 6moPFS as compared to all other histologies (5/8 vs. 2/28, p = 0.003). PTEN expression was associated with median time to progression (p = 0.04). No other significant associations with PI3K pathway alterations were identified. There is limited single agent activity of MK-2206 in PIK3CA MT and PIK3CA WT endometrial cancer populations. Activity was detected in patients with serous histology and due to their poor outcomes warrants further study (NCT01307631).

Patterns of recurrence and metastasis in BRCA1/BRCA2-associated breast cancers.

BACKGROUND: Breast cancer subtypes are associated with distinct metastatic patterns. Whether germline BRCA1/BRCA2 mutation status is independently associated with central nervous system (CNS) relapse, controlling for tumor subtype, is unknown. METHODS: Patients who were treated at Dana-Farber Cancer Institute and diagnosed with a first locoregional recurrence (LRR) or metastasis between 1981 and 2014 were identified using 2 institutional registries: 1) patients treated for recurrent breast cancer and 2) patients who underwent BRCA testing. The frequencies of LRR, sites of metastasis, and breast cancer-specific survival from LRR or metastasis were calculated, and the factors associated with CNS recurrence were evaluated using multivariable logistic regression models. RESULTS: The final study cohort included 30 BRCA1 mutation carriers, 32 BRCA2 mutation carriers, and 270 noncarriers. Most BRCA1 carriers (73%) had triple-negative breast cancer; whereas most BRCA2 carriers (72%) had hormone receptor-positive tumors. BRCA1 carriers frequently experienced lung and distant lymph node metastasis, whereas BRCA2 carriers and noncarriers most often experienced bone metastasis. Although CNS disease occurred frequently in both BRCA1 and BRCA2 carriers (53% BRCA1, 50% BRCA2, 25% noncarriers; P < .001), only BRCA2 mutation (P = .006) was significantly associated with CNS metastasis in multivariable analysis controlling for tumor subtype. BRCA2 mutation (P = .01), triple-negative subtype (P < .001), and the involvement of CNS (P < .001) and other non-CNS distant sites (relative to locoregional recurrence or contralateral disease; P < .001) at presentation of recurrent breast cancer were associated with risk for mortality. CONCLUSIONS: CNS involvement is frequent in women with germline BRCA1/BRCA2 mutations who have metastatic breast cancer. BRCA2 mutation carriers had a significantly higher frequency of CNS metastasis than noncarriers when controlling for breast cancer subtype.

A phase II study of cabozantinib alone or in combination with trastuzumab in breast cancer patients with brain metastases.

PURPOSE: To analyze the efficacy and tolerability of cabozantinib-a small molecule inhibitor of MET and VEGFR2-alone or with trastuzumab in patients with breast cancer brain metastases (BCBM). METHODS: This single-arm phase II study enrolled patients with new or progressive measurable BCBM into 3 cohorts: Cohort 1 (HER2-positive), Cohort 2 (hormone receptor-positive/HER2-negative), and Cohort 3 (triple-negative). Patients received cabozantinib 60-mg daily on a 21-day cycle. Cohort 1 added trastuzumab every 3 weeks and had a primary objective of central nervous system (CNS) objective response rate (ORR) by RECIST 1.1. Secondary objectives for all cohorts were progression-free survival, overall survival, toxicity, and changes in vascular parameters and circulating biomarkers. Cohorts 2 and 3 also had CNS ORR as a secondary objective. RESULTS: Thirty-six BCBM patients enrolled (cohort 1, n = 21; cohort 2, n = 7; cohort 3, n = 8), with a median age of 50. Patients had a median of 3 prior lines for metastatic disease (range 1-9). Treatments prior to enrollment included craniotomy (n = 4), whole brain radiation (n = 24) and stereotactic radiosurgery (n = 11). CNS ORR was 5% in cohort 1, 14% in cohort 2, and 0% in cohort 3. Most common grade 3/4 adverse events included elevations in lipase (11%), AST (8%), ALT (6%), hyponatremia (8%), and hypertension (6%). Cabozantinib increased plasma concentrations of CA-IX, soluble (s)MET, PlGF, sTIE-2, VEGF, and VEGF-D, and decreased sVEGFR2 and TNF-α and total tumor blood volume. CONCLUSIONS: Cabozantinib had insufficient activity in heavily pretreated BCBM patients. Biomarker analysis showed that cabozantinib had antiangiogenic activity and increased tissue hypoxia. TRIAL REGISTRATION: Clinicaltrial.gov registration: NCT02260531.

Combined pembrolizumab and pegylated liposomal doxorubicin in platinum resistant ovarian cancer: A phase 2 clinical trial.

OBJECTIVE: Pegylated liposomal doxorubicin (PLD) in vitro may have immunomodulatory abilities and preclinical evidence suggests it synergizes with immune checkpoint blockade. We hypothesized that combining PLD and pembrolizumab would be active in patients with platinum-resistant ovarian cancer (PROC). METHODS: This was a single-arm, multi-center phase II trial. Eligible patients had PROC with ≤2 prior lines of cytotoxic therapy for recurrent or persistent disease. Twenty-six patients were enrolled and given pembrolizumab 200 mg intravenously (IV) every 3 weeks and PLD 40 mg/m2 IV every 4 weeks. Patients were assessed radiographically every 8 weeks. The primary endpoint was clinical benefit rate (CBR), defined as complete response (CR) + partial response (PR) + stable disease (SD) ≥24 weeks. The study was powered to detect an improvement in CBR from 25% to 50%, with rejection of the null hypothesis if at least 10 patients achieved clinical benefit. T-cell inflamed gene expression profiles (GEP) and PD-L1 were assessed and correlated with clinical outcome. RESULTS: Twenty-three patients were evaluable for best overall response. The study satisfied its primary endpoint, with 12 patients achieving clinical benefit for a CBR of 52.2% (95% CI 30.6-73.2%). There were 5 PRs (21.7%) and 1 CR (4.3%), for an overall response rate (ORR) of 26.1%. Six patients had SD lasting at least 24 weeks. Combination therapy was well tolerated without unexpected toxicities. CONCLUSIONS: The combination of pembrolizumab and PLD was manageable, without unexpected toxicities, and showed preliminary evidence of clinical benefit in the treatment of platinum resistant ovarian cancer. ORR and median PFS of combination therapy in this study was higher than historical comparisons of PLD alone or anti-PD-1/PD-L1 agents alone. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02865811.

The utility of magnetic resonance imaging in early-stage breast cancer survivors-An institutional experience and literature review.

The role of breast magnetic resonance imaging (MRI) in the screening of breast cancer survivors with remaining breast tissue is not well studied. We sought to evaluate the outcomes of screening breast MRI in a cohort of breast cancer survivors. A population of patients with history of stage I-IIIa breast cancer and ≥1 MRI a year or later from diagnosis between 2006-2008 were identified using the National Comprehensive Cancer Network data base from two large Boston-area cancer centers. Patient and disease characteristics were obtained from the data base, and medical records were reviewed to identify the index MRI (first eligible), indications, and two-year outcomes. Overall, 647 patients had breast MRI scans during the study period including 342 eligible patients whose index MRIs were done for breast screening purposes. 47/342 (13.7%) were abnormal, and 3.8% (13/342) underwent biopsy, resulting in the detection of 3 cases of locoregional recurrence or new primary breast cancer (0.9%, 95% CI = 0.2%-2.5%). Of 295 patients with a normal index screening MRI, 12 had a breast cancer recurrence diagnosed within 2 years (4.1% 95%CI = 2.1%-7.0%), and 5 of these recurrences were limited to MRI-screened breast tissue. No statistically significant difference in the rate of 2-year locoregional or distant recurrence was observed between patients with an abnormal screening MRI and those with a normal scan. Adjunct single breast MRI surveillance in a general population of breast cancer survivors one year after diagnosis detected few recurrences, and its effect on short-term outcomes was unclear.

Bilateral mastectomy operations and the role for the cosurgeon technique: A Nationwide analysis of surgical practice patterns.

Traditionally, bilateral mastectomy (BM) operations are performed by a single surgeon but a two-attending co-surgeon technique (CST) has been described. A questionnaire was sent to members of the American Society of Breast Surgeons to assess national BM practices and analyze utilization and perceived benefits of the CST. Among surgeons responding, most continue to use the single-surgeon approach for BMs; however, 14.1% utilize the CST and up to 31% are interested in future CST use. Time savings, mentorship, cost savings, and opportunity to learn new techniques were identified as perceived CST advantages.

Prospective evaluation of the impact of stress, anxiety, and depression on household income among young women with early breast cancer from the Young and Strong trial.

BACKGROUND: Young women with breast cancer tend to report lower quality of life and higher levels of stress than older women with breast cancer, and this may have implications for other psychosocial factors including finances. We sought to determine if stress, anxiety, and depression at diagnosis were associated with changes in household income over 12-months in young women with breast cancer in the United States. METHODS: This study was a prospective, longitudinal cohort study comprised of women enrolled in the Young and Strong trial. Of the 467 women aged 18-45 newly diagnosed with early-stage breast cancer enrolled in the Young and Strong trial from 2012 to 2013, 356 (76%) answered income questions. Change in household income from baseline to 12 months was assessed and women were categorized as having lost, gained, maintained the same household income <$100,000, or maintained household income ≥$100,000. Patient-reported stress, anxiety, and depression were assessed close to diagnosis at trial enrollment. Adjusted multinomial logistic regression models were used to compare women who lost, gained, or maintained household income ≥$100,000 to women who maintained the same household income <$100,000. RESULTS: Although most women maintained household income ≥$100,000 (37.1%) or the same household income <$100,000 (32.3%), 15.4% lost household income and 15.2% gained household income. Stress, anxiety, and depression were not associated with gaining or losing household income compared to women maintaining household incomes <$100,000. Women with household incomes <$50,000 had a higher risk of losing household income compared to women with household incomes ≥$50,000. Women who maintained household incomes ≥$100,000 were less likely to report financial or insurance problems. Among women who lost household income, 56% reported financial problems and 20% reported insurance problems at 12 months. CONCLUSIONS: Baseline stress, anxiety, and depression were not associated with household income changes for young women with breast cancer. However, lower baseline household income was associated with losing household income. Some young survivors encounter financial and insurance problems in the first year after diagnosis, and further support for these women should be considered. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01647607 ; date registered: July 23, 2012.

Olaparib and α-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-expansion phase 1b trial.

BACKGROUND: Based on preclinical work, we found that combination of poly (ADP-ribose) polymerase (PARP) inhibitors with drugs that inhibit the homologous recombination repair (HRR) pathway (such as PI3K inhibitors) might sensitise HRR-proficient epithelial ovarian cancers to PARP inhibitors. We aimed to assess the safety and identify the recommended phase 2 dose of the PARP inhibitor olaparib in combination with the PI3K inhibitor alpelisib in patients with epithelial ovarian cancer and in patients with breast cancer. METHODS: In this multicentre, open-label, phase 1b trial following a 3 + 3 dose-escalation design, we recruited patients aged 18 years or older with the following key eligibility criteria: confirmed diagnosis of either recurrent ovarian, fallopian tube, or primary peritoneal cancer of high-grade serous histology; confirmed diagnosis of either recurrent ovarian, fallopian tube, or primary peritoneal cancer of any histology with known germline BRCA mutations; confirmed diagnosis of recurrent breast cancer of triple-negative histology; or confirmed diagnosis of recurrent breast cancer of any histology with known germline BRCA mutations. Additional patients with epithelial ovarian cancer were enrolled in a dose-expansion cohort. Four dose levels were planned: the starting dose level of alpelisib 250 mg once a day plus olaparib 100 mg twice a day (dose level 0); alpelisib 250 mg once a day plus olaparib 200 mg twice a day (dose level 1); alpelisib 300 mg once a day plus olaparib 200 mg twice a day (dose level 2); and alpelisib 200 mg once a day plus olaparib 200 mg twice a day (dose level 3). Both drugs were administered orally, in tablet formulation. The primary objective was to identify the maximum tolerated dose and the recommended phase 2 dose of the combination of alpelisib and olaparib for patients with epithelial ovarian cancer and patients with breast cancer. Analyses included all patients who received at least one dose of the study drugs. The trial is active, but closed to enrolment; follow-up for patients who completed treatment is ongoing. This trial is registered with ClinicalTrials.gov, number NCT01623349. FINDINGS: Between Oct 3, 2014, and Dec 21, 2016, we enrolled 34 patients (28 in the dose-escalation cohort and six in the dose-expansion cohort); two in the dose-escalation cohort were ineligible at the day of scheduled study initiation. Maximum tolerated dose and recommended phase 2 dose were identified as alpelisib 200 mg once a day plus olaparib 200 mg twice a day (dose level 3). Considering all dose levels, the most common treatment-related grade 3-4 adverse events were hyperglycaemia (five [16%] of 32 patients), nausea (three [9%]), and increased alanine aminotransferase concentrations (three [9%]). No treatment-related deaths occurred. Dose-limiting toxic effects included hyperglycaemia and fever with decreased neutrophil count. Of the 28 patients with epithelial ovarian cancer, ten (36%) achieved a partial response and 14 (50%) had stable disease according to Response Evaluation Criteria in Solid Tumors 1.1. INTERPRETATION: Combining alpelisib and olaparib is feasible with no unexpected toxic effects. The observed activity provides preliminary clinical evidence of synergism between olaparib and alpelisib, particularly in epithelial ovarian cancer, and warrants further investigation. FUNDING: Ovarian Cancer Dream Team (Stand Up To Cancer, Ovarian Cancer Research Alliance, National Ovarian Cancer Coalition), Breast Cancer Research Foundation, Novartis.

A randomized study to improve care for young women with breast cancer at community and academic medical oncology practices in the United States: The Young and Strong study.

BACKGROUND: The authors conducted a cluster randomized study to determine the effect of an exportable educational intervention for young women with breast cancer (YWI) on improving care. METHODS: Sites were randomized 1:1 to the YWI or a contact time control physical activity intervention (PAI) stratified by academic or community site. Up to 15 women aged ≤45 years with newly diagnosed breast cancer were enrolled at each of 14 academic sites and 10 were enrolled at each of 40 community sites. The primary endpoint, attention to fertility, was ascertained by medical record review. Statistical inferences concerning the effect of the intervention used general estimating equations for clustered data. RESULTS: A total of 467 patients across 54 sites were enrolled between July 2012 and December 2013. The median age of the patients at the time of diagnosis was 40 years (range, 22-45 years). Attention to fertility by 3 months was observed in 55% of patients in the YWI and 58% of patients in the PAI (P = .88). Rates were found to be strongly correlated with age (P < .0001), and were highest in patients aged <30 years. Attention to genetics was similar (80% in the YWI and 81% in the PAI), whereas attention to emotional health was higher in patients in the YWI (87% vs 76%; estimated odds ratio, 2.63 [95% confidence interval, 1.20-5.76; P = .016]). Patients rated both interventions as valuable in providing education (64% in the YWI and 63% in the PAI). CONCLUSIONS: The current study failed to demonstrate differences in attention to fertility with an intervention to improve care for women with breast cancer, although attention to fertility was found to be higher than expected in both groups and emotional health was improved in the YWI group. Greater attention to young women with breast cancer in general may promote more comprehensive care for this population.

Mixed Invasive Ductal and Lobular Carcinoma of the Breast: Prognosis and the Importance of Histologic Grade.

BACKGROUND: The diagnosis of mixed invasive ductal and lobular carcinoma (IDC-L) in clinical practice is often associated with uncertainty related to its prognosis and response to systemic therapies. With the increasing recognition of invasive lobular carcinoma (ILC) as a distinct disease subtype, questions surrounding IDC-L become even more relevant. In this study, we took advantage of a detailed clinical database to compare IDC-L and ILC regarding clinicopathologic and treatment characteristics, prognostic power of histologic grade, and survival outcomes. MATERIALS AND METHODS: In this retrospective cohort study, we identified 811 patients diagnosed with early-stage breast cancer with IDC-L or ILC. Descriptive statistics were performed to compare baseline clinicopathologic characteristics and treatments. Survival rates were subsequently analyzed using the Kaplan-Meier method and compared using the Cox proportional hazards model. RESULTS: Patients with ILC had more commonly multifocal disease, low to intermediate histologic grade, and HER2-negative disease. Histologic grade was prognostic for patients with IDC-L but had no significant discriminatory power in patients with ILC. Among postmenopausal women, those with IDC-L had significantly better outcomes when compared with those with ILC: disease-free survival (DFS) and overall survival (OS; adjusted hazard ratio [HR], 0.54; 95% confidence interval [CI] 0.31-0.95). Finally, postmenopausal women treated with an aromatase inhibitor had more favorable DFS and OS than those treated with tamoxifen only (OS adjusted HR, 0.50; 95% CI, 0.29-0.87), which was similar for both histologic types (p = .212). CONCLUSION: IDC-L tumors have a better prognosis than ILC tumors, particularly among postmenopausal women. Histologic grade is an important prognostic factor in IDC-L but not in ILC. IMPLICATIONS FOR PRACTICE: This study compared mixed invasive ductal and lobular carcinoma (IDC-L) with invasive lobular carcinomas (ILCs) to assess the overall prognosis, the prognostic role of histologic grade, and response to systemic therapy. It was found that patients with IDC-L tumors have a better prognosis than ILC, particularly among postmenopausal women, which may impact follow-up strategies. Moreover, although histologic grade failed to stratify the risk of ILC, it showed an important prognostic power in IDC-L, thus highlighting its clinical utility to guide treatment decisions of IDC-L. Finally, the disease-free survival advantage of adjuvant aromatase inhibitors over tamoxifen in ILC was consistent in IDC-L.

Local-regional recurrence in women with small node-negative, HER2-positive breast cancer: results from a prospective multi-institutional study (the APT trial).

PURPOSE: Women with HER2-positive breast cancer treated prior to effective anti-HER2 therapy have higher rates of local-regional recurrence (LRR) than those with HER2-negative disease. Effective systemic therapy, however, has been shown to decrease LRR. This study examines LRR in women with HER2-positive breast cancer treated on a single-arm prospective multicenter trial of adjuvant trastuzumab (H) and paclitaxel (T). METHODS: Patients with HER2-positive tumors ≤ 3.0 cm with negative axillary nodes or micrometastatic disease were eligible. Systemic therapy included weekly T and H for 12 weeks followed by continuation of H to complete 1 year. Radiation therapy (RT) was required following breast-conserving surgery (BCS), but dose and fields were not specified. Disease-free survival (DFS) and LRR-free survival were calculated using the Kaplan-Meier method. RESULTS: Of the 410 patients enrolled from September 2007 to September 2010, 406 initiated protocol therapy and formed the basis of this analysis. A total of 272 (67%) had hormone receptor-positive tumors. Of 162 patients undergoing mastectomy, local therapy records were unavailable for two. None of the 160 for whom records were available received RT. Among 244 BCS patients, detailed RT records were available for 217 (89%). With a median follow-up of 6.5 years, 7-year DFS was 93.3% (95% CI 90.4-96.2), and LRR-free survival was 98.6% (95% CI 97.4-99.8). CONCLUSION: LRR in this select group of early-stage patients with HER2-positive disease receiving effective anti-HER2 therapy is extremely low. If confirmed in additional studies, future investigational efforts should focus on de-escalating local therapy.

Impact of Residual Nodal Disease Burden on Technical Outcomes of Sentinel Lymph Node Biopsy for Node-Positive (cN1) Breast Cancer Patients Treated with Neoadjuvant Chemotherapy.

BACKGROUND: Recent trials have demonstrated the feasibility of sentinel lymph node biopsy (SLNB) for cN1 breast cancer patients after neoadjuvant chemotherapy (NAC). This study evaluated the technical outcomes of SLNB by residual nodal disease volume. METHODS: From a prospective database, cT1-3 cN1 patients receiving NAC and surgery from 2016 to 2017 were identified. Performance measures of post-NAC physical exam and imaging-based axillary assessment were compared. For the patients who converted to cN0 and underwent SLNB, adequate mapping (defined as ≥ 3 SLN) and the false-negative rate (FNR) of intraoperative SLN evaluation were assessed by residual nodal disease volume (ypN1-3 vs ypN0[i+]/ypN1mi vs ypN0). RESULTS: Of 156 cT1-3 cN1 patients, 96 converted to cN0 and underwent SLNB. Adequate mapping was achieved for 64 patients (66.7%) and was not associated with nodal volume (p = 0.12). The FNR of the intraoperative SLN evaluation was 37.8%, and smaller nodal volume was associated with FNR (p < 0.01). Of 36 patients (37.5%) who achieved an axillary pathologic complete response, 24 (66.7%) had three or more negative SLNs and were safely spared axillary lymph node dissection (ALND). The positive predictive values of physical exam versus imaging-based post-NAC nodal assessment were respectively 88% and 69.8%. CONCLUSIONS: This study showed SLNB to be an effective tool for minimizing axillary surgery in cN1 patients treated with NAC. However, important technical limitations exist, such as inability to identify three SLNs in more than two-thirds of patients and high-false negative rates for intraoperative SLN evaluation, particularly for patients with small residual nodal volumes. Preoperative counseling should include realistic assessment of the potential need for ALND in this population.

Breast cancer-specific survival by age: Worse outcomes for the oldest patients.

BACKGROUND: Although breast cancer often is perceived to be indolent in older women, breast cancer outcomes in the oldest patients are variable. In the current study, the authors examined breast cancer-specific death by age, stage, and disease subtype in a large, population-based cohort. METHODS: Using Surveillance, Epidemiology, and End Results data, a total of 486,118 women diagnosed with American Joint Committee on Cancer stage I to IV breast cancer between 2000 and 2012 were identified. Using a series of Fine and Gray regression models to account for competing risk, the authors examined the risk of breast cancer-specific death by age and stage (I-IV) for subcohorts with hormone receptor (HR)-positive, HR-negative, human epidermal growth factor receptor 2-positive, and triple-negative disease, adjusting for demographic and clinical variables. RESULTS: Overall, 18% of women were aged 65 to 74 years, 13% were aged 75 to 84 years, and 4% were aged ≥85 years. Regardless of stage of disease within the HR-positive and HR-negative cohorts, patients aged ≥75 years (vs those aged 55-64 years) experienced a higher adjusted hazard of breast cancer-specific death, which was particularly evident for those with early-stage, HR-positive disease (hazard ratio for those aged 75-84 years, 1.88 [95% confidence interval, 1.68-2.09] and hazard ratio for those aged ≥85 years, 3.59 [95% confidence interval, 3.12-4.13] [both for stage I disease]). In the cohorts with human epidermal growth factor receptor 2-positive and triple-negative disease, women aged ≥70 years had a consistently higher risk of breast cancer-specific death across disease stages (vs those aged 51-60 years), with the exception of stage IV triple-negative disease. CONCLUSIONS: Older patients experience worse breast cancer outcomes, regardless of disease subtype and stage. With an increasing number of older patients anticipated to develop breast cancer in the future, addressing disparities for older patients must emerge as a clinical and research priority. Cancer 2018;124:2184-91. © 2018 American Cancer Society.

Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer.

BACKGROUND: No single standard treatment exists for patients with small, node-negative, human epidermal growth factor receptor type 2 (HER2)-positive breast cancers, because most of these patients have been ineligible for the pivotal trials of adjuvant trastuzumab. METHODS: We performed an uncontrolled, single-group, multicenter, investigator-initiated study of adjuvant paclitaxel and trastuzumab in 406 patients with tumors measuring up to 3 cm in greatest dimension. Patients received weekly treatment with paclitaxel and trastuzumab for 12 weeks, followed by 9 months of trastuzumab monotherapy. The primary end point was survival free from invasive disease. RESULTS: The median follow-up period was 4.0 years. The 3-year rate of survival free from invasive disease was 98.7% (95% confidence interval [CI], 97.6 to 99.8). Among the 12 relapses seen, 2 were due to distant metastatic breast cancer. Excluding contralateral HER2-negative breast cancers and nonbreast cancers, 7 disease-specific events were noted. A total of 13 patients (3.2%; 95% CI, 1.7 to 5.4) reported at least one episode of grade 3 neuropathy, and 2 had symptomatic congestive heart failure (0.5%; 95% CI, 0.1 to 1.8), both of whom had normalization of the left ventricular ejection fraction after discontinuation of trastuzumab. A total of 13 patients had significant asymptomatic declines in ejection fraction (3.2%; 95% CI, 1.7 to 5.4), as defined by the study, but 11 of these patients were able to resume trastuzumab therapy after a brief interruption. CONCLUSIONS: Among women with predominantly stage I HER2-positive breast cancer, treatment with adjuvant paclitaxel plus trastuzumab was associated with a risk of early recurrence of about 2%; 6% of patients withdrew from the study because of protocol-specified adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT00542451.).

Variation in guideline-concordant care for elderly patients with metastatic breast cancer in the United States.

PURPOSE: Prior studies have identified shortcomings in the quality of care for early-stage breast cancer. Guidelines recommend systemic therapy for metastatic breast cancer (MBC), but few studies have examined guideline concordance for these patients. METHODS: We used Surveillance, Epidemiology, and End Results (SEER)-Medicare data to identify patients aged ≥ 66 diagnosed in 2010-2011 with de novo MBC who were continuously enrolled in fee-for-service Medicare. We described initial care (within 6 months of diagnosis) for hormone receptor (HR)-positive/human epidermal receptor-2 (HER2)-negative, HER2-positive, and triple-negative (TN) tumors. We identified factors independently associated with receiving no initial systemic therapy, and compared hospice and hospital utilization for treated versus untreated patients. RESULTS: Among 446 patients, 65% were HR-positive, 21% were HER2-positive, and 14% were TN. Most patients (76.9%) received initial systemic treatment. Among treated HR-positive patients, 15% received chemotherapy as initial treatment; among treated HER2-positive patients, 34% did not receive HER2-targeted initial therapy. Factors independently associated with receiving no initial systemic therapy included older age (ORage continuous/year = 1.08, 95% CI 1.04-1.11), being not married (ORnot married vs. married = 2.87, 95% CI 1.42-5.81), and subtype (ORTN vs. HR+ = 4.95, 95% CI 2.53-9.71). Of patients who did not receive initial systemic therapy, 41.1% did not receive hospice services. CONCLUSIONS: In this population-based MBC cohort, almost one quarter did not receive initial systemic therapy and a substantial proportion of treated patients did not receive guideline-concordant first-line therapy. Further research should explore underuse of chemotherapy and HER2-targeted therapies, investigate whether patterns of care are consistent with patient preferences, and identify opportunities to optimize hospice utilization for patients not receiving treatment.