Activity and safety of enobosarm, a novel, oral, selective androgen receptor modulator, in androgen receptor-positive, oestrogen receptor-positive, and HER2-negative advanced breast cancer (Study G200802): a randomised, open-label, multicentre, multinational, parallel design, phase 2 trial.

BACKGROUND: The androgen receptor is a tumour suppressor in oestrogen receptor-positive breast cancer. The activity and safety of enobosarm, an oral selective androgen receptor modulator, was evaluated in women with oestrogen receptor (ER)-positive, HER2-negative, and androgen receptor (AR)-positive disease. METHODS: Women who were postmenopausal (aged ≥18 years) with previously treated ER-positive, HER2-negative, locally advanced or metastatic breast cancer with an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled in a randomised, open-label, multicentre, multinational, parallel design, phase 2 trial done at 35 cancer treatment centres in nine countries. Participants were stratified on the setting of immediately preceding endocrine therapy and the presence of bone-only metastasis and randomly assigned (1:1) to 9 mg or 18 mg oral enobosarm daily using an interactive web response system. The primary endpoint was clinical benefit rate at 24 weeks in those with centrally confirmed AR-positive disease (ie, the evaluable population). This trial is registered with ClinicalTrials.gov (NCT02463032). FINDINGS: Between Sept 10, 2015, and Nov 28, 2017, 136 (79%) of 172 patients deemed eligible were randomly assigned to 9 mg (n=72) or 18 mg (n=64) oral enobosarm daily. Of these 136 patients, 102 (75%) patients formed the evaluable population (9 mg, n=50; 18 mg, n=52). The median age was 60·5 years (IQR 52·3-69·3) in the 9 mg group and 62·5 years (54·0-69·3) in the 18 mg group. The median follow-up was 7·5 months (IQR 2·9-14·1). At 24 weeks, 16 (32%, 95% CI 20-47) of 50 in the 9 mg group and 15 (29%, 17-43) of 52 in the 18 mg group had clinical benefit. Six (8%) of 75 patients who received 9 mg and ten (16%) of 61 patients who received 18 mg had grade 3 or grade 4 drug-related adverse events, most frequently increased hepatic transaminases (three [4%] of 75 in the 9 mg group and two [3%] of 61 in the 18 mg group), hypercalcaemia (two [3%] and two [3%]), and fatigue (one [1%] and two [3%]). Four deaths (one in the 9 mg group and three in the 18 mg group) were deemed unrelated to the study drug. INTERPRETATION: Enobosarm has anti-tumour activity in patients with ER-positive, HER2-negative advanced breast cancer, showing that AR activation can result in clinical benefit, supporting further clinical investigation of selective AR activation strategies for the treatment of AR-positive, ER-positive, HER2-negative advanced breast cancer. FUNDING: GTx.

TBCRC 039: a phase II study of preoperative ruxolitinib with or without paclitaxel for triple-negative inflammatory breast cancer.

BACKGROUND: Patients with inflammatory breast cancer (IBC) have overall poor clinical outcomes, with triple-negative IBC (TN-IBC) being associated with the worst survival, warranting the investigation of novel therapies. Preclinical studies implied that ruxolitinib (RUX), a JAK1/2 inhibitor, may be an effective therapy for TN-IBC. METHODS: We conducted a randomized phase II study with nested window-of-opportunity in TN-IBC. Treatment-naïve patients received a 7-day run-in of RUX alone or RUX plus paclitaxel (PAC). After the run-in, those who received RUX alone proceeded to neoadjuvant therapy with either RUX + PAC or PAC alone for 12 weeks; those who had received RUX + PAC continued treatment for 12 weeks. All patients subsequently received 4 cycles of doxorubicin plus cyclophosphamide prior to surgery. Research tumor biopsies were performed at baseline (pre-run-in) and after run-in therapy. Tumors were evaluated for phosphorylated STAT3 (pSTAT3) by immunostaining, and a subset was also analyzed by RNA-seq. The primary endpoint was the percent of pSTAT3-positive pre-run-in tumors that became pSTAT3-negative. Secondary endpoints included pathologic complete response (pCR). RESULTS: Overall, 23 patients were enrolled, of whom 21 completed preoperative therapy. Two patients achieved pCR (8.7%). pSTAT3 and IL-6/JAK/STAT3 signaling decreased in post-run-in biopsies of RUX-treated samples, while sustained treatment with RUX + PAC upregulated IL-6/JAK/STAT3 signaling compared to RUX alone. Both treatments decreased GZMB+ T cells implying immune suppression. RUX alone effectively inhibited JAK/STAT3 signaling but its combination with PAC led to incomplete inhibition. The immune suppressive effects of RUX alone and in combination may negate its growth inhibitory effects on cancer cells. CONCLUSION: In summary, the use of RUX in TN-IBC was associated with a decrease in pSTAT3 levels despite lack of clinical benefit. Cancer cell-specific-targeting of JAK2/STAT3 or combinations with immunotherapy may be required for further evaluation of JAK2/STAT3 signaling as a cancer therapeutic target. TRIAL REGISTRATION: www. CLINICALTRIALS: gov , NCT02876302. Registered 23 August 2016.

Clinical outcomes after 1 versus 2-3 lines of neoadjuvant therapy in stage III inflammatory breast cancer.

PURPOSE: Many stage III inflammatory breast cancer (IBC) patients experience a sufficient response to first-line (1L) neoadjuvant chemotherapy (NAC) to allow surgery, while some require additional NAC. We evaluated the pathologic complete response (pCR), breast cancer-free survival (BCFS) and overall survival (OS) among patients requiring 1 vs. 2-3 lines (L) of NAC prior to surgery. METHODS: Stage III IBC patients from 2 institutions who received 1L or 2-3L of NAC prior to surgery were identified. Hormone receptor and HER2 status, grade, and pCR were evaluated. BCFS and OS were evaluated by the Kaplan-Meier method. Multivariable Cox models were utilized to estimate the hazard ratio (HR). RESULTS: 808 eligible patients (1997-2020) were identified (median age 51 years, median follow-up 69 months). 733 (91%) had 1L and 75 (9%) had 2-3L of NAC. Grade III, triple-negative and HER2-positive disease were more prevalent in 2-3L patients. 178 (24%) 1L and 14 (19%) 2-3L patients had pCR. 376 1L patients and 41 2-3L patients had recurrences. The 5-year BCFS was worse for the 2-3L group (33 vs. 46%, HR = 1.37; 95% CI 0.99-1.91). However, in 192 patients with a pCR, BCFS was similar (76 vs. 83% in 1L vs. 2-3L, respectively). There were 308 deaths (276 among 1L and 32 among 2-3L patients). The 5-year OS in 1L vs. 2-3L was 60 vs. 53% (HR = 1.32, 95% CI 0.91-1.93). CONCLUSIONS: Among stage III IBC patients, pCR rates were similar, irrespective of the NAC lines number, and BCFS and OS were comparable with pCR after 1L and 2-3L.

Incidence, characteristics, and management of central nervous system metastases in patients with inflammatory breast cancer.

BACKGROUND: Patients with inflammatory breast cancer (IBC) have a high risk of central nervous system metastasis (mCNS). The purpose of this study was to quantify the incidence of and identify risk factors for mCNS in patients with IBC. METHODS: The authors retrospectively reviewed patients diagnosed with IBC between 1997 and 2019. mCNS-free survival time was defined as the date from the diagnosis of IBC to the date of diagnosis of mCNS or the date of death, whichever occurred first. A competing risks hazard model was used to evaluate risk factors for mCNS. RESULTS: A total of 531 patients were identified; 372 patients with stage III and 159 patients with de novo stage IV disease. During the study, there were a total of 124 patients who had mCNS. The 1-, 2-, and 5-year incidence of mCNS was 5%, 9%, and 18% in stage III patients (median follow-up: 5.6 years) and 17%, 30%, and 42% in stage IV patients (1.8 years). Multivariate analysis identified triple-negative tumor subtype as a significant risk factor for mCNS for stage III patients. For patients diagnosed with metastatic disease, visceral metastasis as first metastatic site, triple-negative subtype, and younger age at diagnosis of metastases were risk factors for mCNS. CONCLUSIONS: Patients with IBC, particularly those with triple-negative IBC, visceral metastasis, and those at a younger age at diagnosis of metastatic disease, are at significant risk of developing mCNS. Further investigation into prevention of mCNS and whether early detection of mCNS is associated with improved IBC patient outcomes is warranted.

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).

Phase II trial of veliparib and temozolomide in metastatic breast cancer patients with and without BRCA1/2 mutations.

PURPOSE: We evaluated the efficacy and safety of poly-(adenosine diphosphate-ribose) polymerase (PARP) 1 and 2 inhibitor veliparib and temozolomide in metastatic breast cancer patients with and without germline BRCA1/2 mutations. METHODS: In this single-arm phase II trial, patients with metastatic breast cancer received veliparib 30 to 40 mg twice daily on days 1 to 7 with concurrent temozolomide 150 mg/m2 on days 1 to 5 of a 28-day cycle. The primary cohort was unselected for BRCA mutation status, and an expansion cohort enrolled only BRCA1/2 carriers. The primary endpoint was objective response rate (ORR) in each cohort. Secondary endpoints included progression-free survival (PFS), clinical benefit rate (CBR), and evaluation of safety and tolerability. RESULTS: In the primary cohort of 41 unselected patients, which included 9 BRCA mutation carriers, the ORR was 10% and clinical benefit rate at 4 months (CBR) was 27%. In the expansion cohort of 21 BRCA1/2 carriers, the ORR was 14% and CBR was 43%. Among all 30 BRCA1/2 carriers, the ORR was 23% versus 0% among non-carriers. In the subset of BRCA1/2 carriers, the ORR was 32% among platinum-naïve patients versus 9% among platinum-exposed patients. The median PFS was 3.3 months among BRCA1/2 carriers compared to 1.8 months among non-carriers (HR: 0.48, p = 0.006). A longer median PFS of 6.2 months was observed among BRCA1/2 carriers who had no prior platinum therapy. The most common grade 3 and 4 toxicities were thrombocytopenia (32%) and neutropenia (21%) that generally improved with dose modifications. CONCLUSION: Veliparib and temozolomide demonstrated clinical activity in platinum-naïve BRCA-associated metastatic breast cancer with manageable toxicity at doses of veliparib well below the single-agent active dose. Although the study did not meet its primary endpoint in unselected nor BRCA-associated breast cancer, this regimen was further evaluated in the BROCADE 2 study. TRIAL REGISTRATION: NCT01009788 (ClinicalTrials.gov), November 9, 2009.

Discrepancy between FDG-PET/CT and contrast-enhanced CT in the staging of patients with inflammatory breast cancer: implications for treatment planning.

PURPOSE: Optimizing treatment strategies for patients with inflammatory breast cancer (IBC) relies on accurate initial staging. This study compared contrast-enhanced computed tomography (ce-CT) and FDG-PET/CT for initial staging of IBC to determine the frequency of discordance between the two imaging modalities and potential impact on management. METHODS: 81 patients with IBC underwent FDG-PET/CT and ce-CT prior to starting treatment. FDG-PET/CT and ce-CT scans were independently reviewed for locoregional and distant metastases and findings recorded by anatomic site as negative, equivocal, or positive for breast cancer involvement. Each paired ce-CT and FDG-PET/CT case was classified as concordant or discordant for findings. Discordant findings were subclassified as (a) related to the presence or absence of distant metastases; (b) affecting the locoregional radiation therapy plan; or (c) due to incidental findings not related to IBC. RESULTS: There were 47 discordant findings between ce-CT and FDG-PET/CT in 41 of 81 patients (50.6%). Thirty (63.8%) were related to the presence or absence of distant metastases; most commonly disease detection on FDG-PET/CT but not ce-CT (n = 12). FDG-PET/CT suggested alterations of the locoregional radiation therapy plan designed by CT alone in 15 patients. FDG-PET/CT correctly characterized 5 of 7 findings equivocal for metastatic IBC on ce-CT. CONCLUSIONS: This study demonstrates differences between ce-CT and FDG-PET/CT for initial staging of IBC and how these differences potentially affect patient management. Preliminary data suggest that FDG-PET/CT may be the imaging modality of choice for initial staging of IBC. Prospective trials testing initial staging with FDG-PET/CT versus important clinical end-points in IBC are warranted.

Characteristics associated with inflammatory breast cancer (IBC): An epidemiologic study from a dedicated IBC program.

There are scant data identifying epidemiologic characteristics among individuals diagnosed with inflammatory breast cancer (IBC), which is considered the most aggressive subtype of breast cancer. The purpose of this study was to evaluate the epidemiologic features among patients seen at a dedicated IBC program, to elucidate the potential causes of this disease and guide prevention strategies. We reviewed retrospective data from 447 patients enrolled in an IRB-approved IBC registry through Dana-Farber Cancer Institute from 1997 to 2016. The data examined included the following: demographics, medical, reproductive and family history, duration of symptoms prior to the diagnosis of IBC, pathologic characteristics, and clinical outcome. JMP statistical software was used to compile the data. Descriptive statistics were used to evaluate the data. The majority of patients (66.0%) were overweight or obese (body mass index [BMI] ≥25) at the time of diagnosis. Fifty patients (11.1%) had "secondary" IBC, defined as developing IBC after a previous history of non-IBC breast cancer in an ipsilateral breast. Of those patients with secondary IBC, 60% were also overweight or obese at the time of IBC diagnosis. Approximately 58% of IBC patients had a family history of breast or ovarian cancer, including first- and second-degree relatives. This analysis suggested a high frequency of familial breast/ovarian cancer among IBC patients which supports further evaluating genetic risks. This may have implications for screening and prevention strategies as well as insight into additional contributing risk factors. The prevalence of a high BMI among both pre- and postmenopausal women with IBC, including those diagnosed with secondary IBC, warrants focusing on strategies targeting the obesity crisis as a potential means of reducing the risk of developing this disease.

Patterns of breast reconstruction in patients diagnosed with inflammatory breast cancer: The Dana-Farber Cancer Institute's Inflammatory Breast Cancer Program experience.

Inflammatory breast cancer (IBC) exhibits dermal lymphatic involvement at presentation, and thus, the standard surgical approach is a nonskin-sparing modified radical mastectomy (MRM) without breast reconstruction (BR). In this study, we evaluated immediate and delayed BR receipt and its outcomes in IBC. Using an IRB-approved database, we retrospectively evaluated stage III IBC patients who received trimodality therapy (preoperative systemic therapy, followed by MRM and postmastectomy chest wall/regional nodal radiation). Patients with an insufficient response to preoperative systemic therapy and/or who required preoperative radiotherapy were excluded. BR receipt, timing, and morbidity were evaluated. Among 240 stage III IBC patients diagnosed between 1997 and 2016, 40 (17%) underwent BR. Thirteen (33%) had immediate, and 27 (67%) had delayed BR. Four patients had complications (1 [8%] immediate BR and 3 [11%] delayed BR); only 1 BR (delayed) was unsuccessful. From the MRM date, the median time to recurrence was 35 months (<1-212) and median overall survival was 87 months (<1-212). In this cohort of stage III IBC patients, only 11% pursued delayed BR following trimodality therapy, possibly attributable to the observed high recurrence rates hindering BR. Further studies addressing BR outcomes in IBC are needed for better counseling patients regarding their reconstructive options.

Prevalence of germline variants in inflammatory breast cancer.

BACKGROUND: Inflammatory breast cancer (IBC) is an uncommon and aggressive subtype of breast cancer associated with early disease recurrence and short survival. The prevalence of germline variants in cancer predisposition genes has not been systematically evaluated in women with IBC. METHODS: Among 301 women enrolled in the clinical IBC registry at a single institution between 2010 and 2017, 168 had documented genetic testing. A second cohort of 200 IBC cases who had panel-based germline testing performed through a commercial testing laboratory from 2012 to 2017 was added to the analyses. Personal and family cancer histories and genetic testing results were evaluated when they were available for both cohorts. RESULTS: Among 501 IBC cases, 368 had documented genetic testing. Germline mutations (56 total) were identified in 53 cases (14.4%). BRCA1 or BRCA2 mutations were found in 7.3% of the subjects, 6.3% had a mutation in other breast cancer genes (PALB2, CHEK2, ATM, and BARD1), and 1.6% had mutations in genes not associated with breast cancer. The prevalence of mutations was 24% (22 of 92) among women with triple-negative IBC, 13% (13 of 99) among women with estrogen receptor- and/or progesterone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative disease, and 9.3% (10 of 108) among women with HER2-positive IBC. CONCLUSIONS: The prevalence and diversity of germline genetic mutations among patients with IBC suggest that further studies should be performed to assess the role of inherited mutations in IBC carcinogenesis in comparison with non-IBC breast cancer. Since IBC has a high metastatic potential associated with poor prognostic outcomes, proposed future studies may also inform targeted treatment options.

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.

Inflammatory Breast Cancer: a Separate Entity.

PURPOSE OF REVIEW: Inflammatory breast cancer (IBC) is an uncommon but highly aggressive subtype of breast cancer that contributes significantly to breast cancer-related mortality. In this review, we provide an overview of the clinical and molecular characteristics of IBC, and highlight some areas of need for ongoing research. RECENT FINDINGS: The disease is characterized by florid tumor emboli that obstruct dermal lymphatics, leading to swelling and inflammation of the affected breast. Recent studies have focused on tumor cell intrinsic features, such as signaling through pathways involved in growth and stem-like behavior, as well as extrinsic features, such as the immune system, that can be leveraged to develop new potential therapies. Key efforts have led to an increase in awareness of the disease as well as new insights into IBC pathogenesis. However, there is a strong need for new therapies designed specifically for IBC, and many unanswered questions remain.

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.).

Phase II and Biomarker Study of Cabozantinib in Metastatic Triple-Negative Breast Cancer Patients.

Currently, no targeted therapies are available for metastatic triplenegative breast cancer (mTNBC). We evaluated the safety, efficacy, and biomarkers of response to cabozantinib, a multikinase inhibitor, in patients with mTNBC. We conducted a single arm phase II and biomarker study that enrolled patients with measurable mTNBC. Patients received cabozantinib (60 mg daily) on a 3-week cycle and were restaged after 6 weeks and then every 9 weeks. The primary endpoint was objective response rate. Predefined secondary endpoints included progression-free survival (PFS), toxicity, and tissue and blood circulating cell and protein biomarkers. Of 35 patients who initiated protocol therapy, 3 (9% [95% confidence interval (CI): 2, 26]) achieved a partial response (PR). Nine patients achieved stable disease (SD) for at least 15 weeks, and thus the clinical benefit rate (PR+SD) was 34% [95% CI: 19, 52]. Median PFS was 2.0 months [95% CI: 1.3, 3.3]. The most common toxicities were fatigue, diarrhea, mucositis, and palmar-plantar erythrodysesthesia. There were no grade 4 toxicities, but 12 patients (34%) required dose reduction. Two patients had TNBCs with MET amplification. During cabozantinib therapy, there were significant and durable increases in plasma placental growth factor, vascular endothelial growth factor (VEGF), VEGF-D, stromal cell-derived factor 1a, and carbonic anhydrase IX, and circulating CD3 + cells and CD8 + T lymphocytes, and decreases in plasma soluble VEGF receptor 2 and CD14+ monocytes (all p < .05). Higher baseline concentrations of soluble MET (sMET) associated with longer PFS (p = .03). In conclusion, cabozantinib showed encouraging safety and efficacy signals but did not meet the primary endpoint in pretreated mTNBC. Exploratory analyses of circulating biomarkers showed that cabozantinib induces systemic changes consistent with activation of the immune system and antiangiogenic activity, and that sMET should be further evaluated a potential biomarker of response. IMPLICATIONS FOR PRACTICE: Triple-negative breast cancer (TNBC)-a disease with a dearth of effective therapies-often overexpress MET, which is associated with poor clinical outcomes. However, clinical studies of agents targeting MET and VEGF pathways-alone or in combination-have shown disappointing results. This study of cabozantinib (a dual VEGFR2/MET) in metastatic TNBC, while not meeting its prespecified endpoint, showed that treatment is associated with circulating biomarker changes, and is active in a subset of patients. Furthermore, this study demonstrates that cabozantinib therapy induces a systemic increase in cytotoxic lymphocyte populations and a decrease in immunosuppressive myeloid populations. This supports the testing of combinations of cabozantinib with immunotherapy in future studies in breast cancer patients.

The Impact of Residual Disease After Preoperative Systemic Therapy on Clinical Outcomes in Patients with Inflammatory Breast Cancer.

BACKGROUND: Inflammatory breast cancer (IBC) is a rare and aggressive disease treated with multimodality therapy: preoperative systemic therapy (PST) followed by modified radical mastectomy (MRM), chest wall and regional nodal radiotherapy, and adjuvant biologic therapy and/or endocrine therapy when appropriate. In non-IBC, the degree of pathologic response to PST has been shown to correlate with time to recurrence (TTR) and overall survival (OS). We sought to determine if pathologic response correlates with oncologic outcomes of IBC patients. METHODS: Following review of IBC patients' records (1997-2014), we identified 258 stage III IBC patients; 181 received PST followed by MRM and radiotherapy and were subsequently analyzed. Pathologic complete response (pCR) to PST, hormone receptor and human epidermal growth factor receptor 2 (HER2) status, grade, and histology were evaluated as predictors of TTR and OS by Cox model. RESULTS: Overall, 95/181 (52%) patients experienced recurrence; 93/95 (98%) were distant metastases (median TTR 3.2 years). Seventy-three patients (40%) died (median OS 6.9 years). pCR was associated with improved TTR (hazard ratio [HR] 0.20, 95% confidence interval [CI] 0.09-0.46, p < 0.01, univariate; HR 0.17, 95% CI 0.07-0.41, p < 0.0001, multivariate) and improved OS (HR 0.26, 95% CI 0.11-0.65, p < 0.01, univariate). In patients with pCR, grade III (HR 1.91, 95% CI 1.16-3.13, p = 0.01), and triple-negative phenotype (HR 3.54, 95% CI 1.79-6.98, p = 0.0003) were associated with shorter TTR, while residual ductal carcinoma in situ was not (HR 0.85, 95% CI 0.53-1.35, p = 0.48, multivariate). CONCLUSIONS: In stage III IBC, pCR was associated with prognosis, further influenced by grade, hormone receptor, and HER2 status. Investigating mechanisms that contribute to better response to PST could help improve oncologic outcomes in IBC.

Impact of neoadjuvant therapy on eligibility for and frequency of breast conservation in stage II-III HER2-positive breast cancer: surgical results of CALGB 40601 (Alliance).

OBJECTIVE: It had been previously shown that patients who receive neoadjuvant systemic therapy (NST) are more likely to undergo breast-conserving therapy (BCT) than those who have primary surgery. However, the frequency with which patients who are not BCT-eligible prior to NST convert to BCT-eligible with treatment is unknown. To document this conversion rate in a subset of patients expected to have a high clinical response rate to NST, we studied surgical assessment and management of patients enrolled on a randomized neoadjuvant trial for stage II-III HER2-positive breast cancer (HER2 + BC)(CALGB 40601). METHODS: The treating surgeon assessed BCT candidacy based on clinico-radiographic criteria both before and after NST. Definitive breast surgical management was at surgeon and patient discretion. We sought to determine (1) the conversion rate from BCT-ineligible to BCT-eligible (2) the percentage of BCT-eligible patients who chose breast conservation, and (3) the rate of successful BCT. We also evaluated surgeon-determined factors for BCT-ineligibility and the correlation between BCT eligibility and pathologic complete response (pCR). RESULTS: Of 292 patients with pre- and post-NST surgical assessments, 59 % were non-BCT candidates at baseline. Of the 43 % of these patients who converted with NST, 67 % opted for BCT, with an 80 % success rate. NST increased the BCT-eligible rate from 41 to 64 %. Common factors cited for BCT-ineligibility prior to NST including tumor size (56 %) and probable poor cosmetic outcome (26 %) were reduced by 67 and 75 %, respectively, with treatment, while multicentricity, the second most common factor (33 %), fell by only 16 %. Since 23 % of the BCT-eligible patients chose mastectomy, BCT was the final surgical procedure in just 40 % of the patients. Patients considered BCT-eligible both at baseline and after NST had a pCR rate of 55 %, while patients who were BCT-ineligible prior to NST had the same pCR rate (44 %) whether they converted to BCT-eligible or not. CONCLUSIONS: Many patients with HER2 + BC deemed ineligible for BCT at baseline can be converted to BCT-eligible with NST; excluding patients with multicentric disease substantially increases that percentage. In converted patients who opt for BCT, the success rate is similar to that of patients considered BCT-eligible at baseline. Whether a BCT-ineligible patient converts to BCT eligibility or not does not appear to affect the likelihood of achieving a pCR. Despite the efficacy of NST in this patient cohort, only 40 % of patients had successful BCT; further research into why BCT-eligible patients often opt for mastectomy is needed.

Inflammatory breast cancer and development of brain metastases: risk factors and outcomes.

Brain metastases are associated with significant morbidity. Minimal research has been conducted on the risk factors for and incidence of brain metastases in women with inflammatory breast cancer (IBC). 210 women with Stage III or IV IBC diagnosed from 1997-2011 were identified. Competing risk analysis and competing risks regression were used to calculate the incidence of brain metastases and identify significant risk factors. After a median follow-up in surviving patients of 2.8 years (range 0.6-7.6) and 3.3 years (range 0.2-14.5) in the 47 and 163 patients with (MET) and without (non-MET) metastatic disease at diagnosis, 17 (36 %) and 30 (18 %) developed brain metastases, respectively. The cumulative incidence at 1, 2, and 3 years was 17 % [95 % confidence interval (CI), 8-30], 34 % (95 % CI, 20-48), and 37 % (95 % CI, 22-51) for the MET cohort. The corresponding non-MET values were 4 % (95 % CI, 2-8), 8 % (95 % CI 5-13), and 15 % (95 % CI, 10-22). Once non-MET patients developed extracranial distant metastases, the subsequent 1, 2, and 3 years cumulative incidence of brain metastases was 18 % (95 % CI, 10-28), 25 % (95 % CI, 15-36), and 31 % (95 % CI, 20-43). On multivariate analysis, brain metastases were associated with younger age [hazard ratio (HR), 0.73; 95 % CI, 0.53-1.00; P = 0.05] and distant metastases at diagnosis (HR, 2.33; 95 % CI, 1.11-4.89; P = 0.03). The incidence of brain metastases is high in women with IBC. Particularly for patients with extracranial distant metastases, routine screening with magnetic resonance imaging should be considered.

Chemotherapy-related amenorrhea after adjuvant paclitaxel-trastuzumab (APT trial).

Chemotherapy-related amenorrhea (CRA) is associated with infertility and menopausal symptoms. Learning how frequently paclitaxel and trastuzumab cause amenorrhea is important. Most other adjuvant breast cancer therapies induce CRA in approximately 50 % of all premenopausal recipients [1]. 410 patients enrolled on the APT Trial, a single-arm phase 2 adjuvant study of 12 weeks of paclitaxel and trastuzumab followed by nine months of trastuzumab monotherapy. Eligible patients had ≤3 cm node-negative HER2 + breast cancers. Premenopausal enrollees were asked to complete menstrual surveys every 3-12 months for 72 months. Women who responded to at least one survey at least 15 months after chemotherapy initiation (and who did not undergo hysterectomy and/or bilateral oophorectomy or receive ovarian suppressing medications prior to 15 months) were included in this analysis. A participant was defined as having amenorrhea in follow-up if her self-reported last menstrual period at last follow-up was greater than 12 months prior to the survey. Among the 64 women in the evaluable population (median age at study entry 44 years, range 27-52 years), the median time between chemotherapy initiation and last menstrual survey was 51 months (range 16-79). 18 of 64 women (28 %, 95 % CI 18-41 %) were amenorrheic at that time point. Amenorrhea rates among premenopausal women treated with adjuvant paclitaxel and trastuzumab for early stage breast cancer appear lower than those seen historically with standard alkylator-based breast cancer regimens. Future studies are needed to understand the impact of this regimen on related issues of fertility and menopausal symptoms.

Inflammatory Breast Cancer: Patterns of Failure and the Case for Aggressive Locoregional Management.

BACKGROUND: Inflammatory breast cancer (IBC) is a rare and aggressive subtype. This study analyzes the patterns of failure in patients with IBC treated at our institution. METHODS: We retrospectively analyzed the records of 227 women with IBC presenting between 1997 and 2011. Survival analysis was used to calculate overall survival (OS) and disease-free survival. Competing risk analysis was used to calculate locoregional recurrence (LRR). RESULTS: A total of 173 patients had locoregional-only disease at presentation (non-MET). Median follow-up in the surviving patients was 3.3 years. Overall, 132 (76.3 %) patients received trimodality therapy with chemotherapy, surgery, and radiotherapy. Three-year OS was 73.1 % [95 % confidence interval (CI) 64.9-82.4]. Cumulative LRR was 10.1, 16.9, and 21.3 % at 1, 2, and 3 years, respectively. No variable was significantly associated with LRR. Fifty-four patients had metastatic disease at presentation (MET). Median follow-up in the surviving patients was 2.6 years. Three-year OS was 44.3 % (95 % CI 31.4-62.5). Twenty-four (44.4 %) patients received non-palliative local therapy (radiotherapy and/or surgery). For these patients, median OS after local therapy was 2 years. Excluding six patients who received local therapy for symptom palliation, the crude incidence of locoregional progression or recurrence (LRPR) was 17 % (4/24) for those who received local therapy compared with 57 % (13/23) for those who did not. CONCLUSIONS: For non-MET patients, LRR remains a problem despite trimodality therapy. More aggressive treatment is warranted. For MET patients, nearly 60 % have LRPR with systemic therapy alone. Local therapy should be considered in the setting of metastatic disease to prevent potential morbidity of progressive local disease.