Miller, Kathy D.

Abstract Background: Pre-clinical data and results from early phase clinical trials point to synergistic antitumor activity and potential efficacy of palbociclib when given in combination with anti-HER2 therapy (tx). The aim of PATINA is to determine the effect of adding palbociclib to anti-HER2 and ET maintenance after induction tx in the 1st line setting for HR+/HER2+ MBC. Trial Design: The PATINA trial (AFT-38/NCT02947685) is a pivotal, open-label, international, phase III study. Following 6-8 cycles of chemotherapy (taxane or vinorelbine) with anti-HER2 tx for MBC participants will be randomized 1:1 to standard anti-HER2 tx (trastuzumab +/- pertuzumab) in combination with ET with or without palbociclib until disease progression. ET options are either an aromatase inhibitor or fulvestrant. Premenopausal patients (pts) must receive ovarian suppression. The trial is open to men or women with histologically confirmed HR+/HER2+ MBC provided they are without evidence of disease progression by local assessment after induction tx. Total planned accrual is 496 pts. Primary objective is to demonstrate that the combination of palbociclib with anti-HER2 tx plus ET is superior to anti-HER2 tx plus ET alone in prolonging progression-free survival (PFS). Key secondary objectives are measures of tumor control, overall survival, safety and Quality of Life. The main translational science objective is to compare PFS estimates according to PIK3CA mutation status. The study has a 90% power to detect a hazard ratio of 0.667 in favor of the palbociclib arm. All pts approached to participate in PATINA will be asked to share remaining biospecimens and clinical data with the Mastering Breast Cancer Initiative. This initiative was created in order to understand the natural history of MBC and how it envolves over time with the aim to develop new treatments for this patient population. Recruitment has started in 07/2017 and is planned for approximately 22 months in 140 sites in Australia, Germany, Italy, France, New Zealand, Spain, and the US. 69 pts have been recruited so far. The study is sponsored by Alliance Foundation Trials (AFT) and financially supported by Pfizer Citation Format: Metzger O, Mandrekar S, Loibl S, Mundhenke C, Seiler S, Valagussa P, Lim E, Tripathy D, Winer EP, Huang C, Carey L, Francis P, Miller K, Goetz MP, Prat A, Loi S, Krop I, Gianni L, Delalogue S, Vaz-Luis I, Dockter T, Lanzillotti J, Ciruelos E, DeMichele AM. PATINA: A randomized, open label, phase III trial to evaluate the efficacy and safety of palbociclib + anti-HER2 therapy + endocrine therapy (ET) vs. anti-HER2 therapy + ET after induction treatment for hormone receptor positive (HR+)/HER2-positive metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-02-07.

PurposeBevacizumab improves progression-free survival but not overall survival in patients with metastatic breast cancer. E5103 tested the effect of bevacizumab in the adjuvant setting in patients with human epidermal growth factor receptor 2–negative disease.Patients and MethodsPatients were assigned 1:2:2 to receive placebo with doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (arm A), bevacizumab only during AC and paclitaxel (arm B), or bevacizumab during AC and paclitaxel followed by bevacizumab monotherapy for 10 cycles (arm C). Random assignment was stratified and bevacizumab dose adjusted for choice of AC schedule. Radiation and hormonal therapy were administered concurrently with bevacizumab in arm C. The primary end point was invasive disease–free survival (IDFS).ResultsFour thousand nine hundred ninety-four patients were enrolled. Median age was 52 years; 64% of patients were estrogen receptor positive, 27% were lymph node negative, and 78% received dose-dense AC. Chemotherapy-associated adverse events including myelosuppression and neuropathy were similar across all arms. Grade ≥ 3 hypertension was more common in bevacizumab-treated patients, but thrombosis, proteinuria, and hemorrhage were not. The cumulative incidence of clinical congestive heart failure at 15 months was 1.0%, 1.9%, and 3.0% in arms A, B, and C, respectively. Bevacizumab exposure was less than anticipated, with approximately 24% of patients in arm B and approximately 55% of patients in arm C discontinuing bevacizumab before completing planned therapy. Five-year IDFS was 77% (95% CI, 71% to 81%) in arm A, 76% (95% CI, 72% to 80%) in arm B, and 80% (95% CI, 77% to 83%) in arm C.ConclusionIncorporation of bevacizumab into sequential anthracycline- and taxane-containing adjuvant therapy does not improve IDFS or overall survival in patients with high-risk human epidermal growth factor receptor 2–negative breast cancer. Longer duration bevacizumab therapy is unlikely to be feasible given the high rate of early discontinuation.

BACKGROUNDPublished studies have suggested that most patients with early stage breast cancer are willing, for modest survival benefits, to receive 6 months of adjuvant cyclophosphamide, methotrexate, and 5‐fluorouracil, an older regimen that is used infrequently today. We examined preferences regarding the survival benefit needed to justify 6 months of a contemporary chemotherapy regimen.METHODSThe Eastern Cooperative Oncology Group Protocol 5103 was a phase 3 trial that randomized breast cancer patients to receive standard adjuvant doxorubicin, cyclophosphamide, and paclitaxel with either bevacizumab or placebo. Serial surveys to assess quality of life were administered to patients enrolled between January 1, 2010, and June 8, 2010. Survival benefit needed to justify 6 months of chemotherapy by patients was collected at the 18‐month assessment. A parallel survey was sent to physicians who had enrolled patients in the study.RESULTSOf 519 patients who had not withdrawn at a time point earlier than 18 months, 87.8% responded to this survey. A total of 175 physicians participated. We found considerable variation in patient preferences, particularly for modest survival benefits: for 2 months of benefit, 57% would consider 6 months of chemotherapy, whereas 96% of patients would consider 6 months of chemotherapy for 24 months. Race and education were associated with the choices. Physicians who responded were less likely to accept chemotherapy for modest benefit.CONCLUSIONSAmong patients who received contemporary adjuvant chemotherapy in a randomized controlled trial, we found substantial variation in preferences regarding benefits that justified undergoing chemotherapy. Differences between patients' and physicians' choices were also apparent. Eliciting preferences regarding risks and benefits of adjuvant chemotherapy is critical. Cancer 2017;123:2821–28. © 2017 American Cancer Society.

Abstract Background LIV-1, a transmembrane protein and downstream target of STAT3, is highly expressed in breast cancer cells. It is associated with lymph node involvement and metastatic progression. SGN-LIV1A is an anti-LIV-1 antibody conjugated via a protease-cleavable linker to monomethyl auristatin E (MMAE). Upon binding to cell-surface LIV-1, SGN-LIV1A is internalized and releases MMAE, which binds to tubulin and induces G2/M arrest and apoptosis. Methods This is an ongoing, phase 1 dose-escalation study evaluating safety, tolerability, pharmacokinetics, and antitumor activity of SGN-LIV1A (q3 wks IV) in women with LIV-1-positive, unresectable, locally advanced or metastatic breast cancer (LA/MBC) (NCT01969643). Patients (pts) with measurable disease and ≥2 prior cytotoxic regimens for LA/MBC were eligible. Pts with ≥Grade 2 neuropathy were excluded. Response was assessed per RECIST v1.1; pts with stable disease (SD) or better could continue treatment until disease progression or intolerable toxicity. At completion of dose escalation in hormone receptor-positive/HER2-negative (HR+/HER2–) and triple-negative (TN) pts, expansion cohorts were opened to further evaluate safety and antitumor activity of monotherapy in TN pts and combination therapy with trastuzumab (Tz) in HER2-positive (HER2+) pts. Pre- and post-treatment tumor biopsies were done to evaluate LIV-1 expression and other correlative endpoints. Results To date, 39 pts (18 HR+/HER2–, 21 TN) have received a median of 3 cycles (range, 1–10) of SGN-LIV1A monotherapy at doses of 0.5–2.8 mg/kg. Median age was 57 yrs (range, 33–79). At baseline, pts had a median of 4 prior cytotoxic regimens for LA/MBC (range, 2–8); 36 had visceral disease and 25 had bone involvement. No dose-limiting toxicities (DLT) occurred in 19 DLT-evaluable pts; maximum tolerated dose was not exceeded at 2.8 mg/kg. Treatment-emergent adverse events (AEs) reported in ≥30% of pts were: fatigue (64%), nausea (54%), alopecia (46%), decreased appetite (41%), constipation (39%), neutropenia (33%), and vomiting (31%). Peripheral neuropathy was reported in 9 pts (23%). Most AEs were Grade 1/2, except neutropenia (all ≥Grade 3). Four pts discontinued treatment due to AEs (acute respiratory distress syndrome, nausea, pneumonia, tachycardia). In dose escalation, modest activity was observed in 17 efficacy evaluable (EE) HR+/HER2- pts, with a disease control rate (DCR) of 59% (10 SD), including 1 pt with SD≥24 wks. Among the 17 EE TN pts (dose escalation plus cohort expansion), the overall response rate (ORR) was 41% (7 PR), DCR was 82% (7 PR, 7 SD) and clinical benefit rate (CBR=OR+SD≥24 wks) was 53% (9 pts). For TN pts, median PFS was 17.1 wks (95% CI: 6.0, 18.4); 6 pts remain on treatment. Of 281 MBC tumor samples evaluated for LIV-1, 93% were positive; 81% had moderate-to-high expression (H-score ≥100). Conclusions LIV-1 is expressed in almost all MBC tumors. SGN-LIV1A monotherapy has been generally well tolerated and shown encouraging antitumor activity in heavily pretreated TN MBC, with a PR rate of 41% and a CBR at ≥24 wks of 53%. Response duration data continue to evolve. Enrollment continues in the TN monotherapy expansion cohort and the HER2+ combination cohort with Tz. Citation Format: Forero-Torres A, Modi S, Specht J, Miller K, Weise A, Burris III H, Liu M, Krop I, Pusztai L, Kostic A, Li M, Mita M. Phase 1 study of the antibody-drug conjugate (ADC) SGN-LIV1A in patients with heavily pretreated metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-12-04.

PURPOSE: Hot flashes represent a significant clinical problem for some breast cancer survivors. Safe, effective treatment is needed for this prominent clinical problem. Although it has been shown that estrogen or progesterone replacement therapy can alleviate this problem, there are continued safety concerns regarding the use of hormonal therapies in these women. Based on anecdotal information, we hypothesized that soy-derived phytoestrogens, weak estrogen-like substances in the soybean that demonstrate estrogen agonist and/or antagonist effects when they bind to estrogen receptors, could alleviate hot flashes. This current trial was designed to investigate this hypothesis.PATIENTS AND METHODS: This double-blind clinical trial involved breast cancer survivors with substantial hot flashes. After randomization, patients underwent a 1-week baseline period with no therapy. This was followed by 4 weeks of either soy tablets or placebo. The patients then crossed over to the opposite arm in a double-blind manner for the last 4 weeks. Patients completed a daily questionnaire documenting hot flash frequency, intensity, and perceived side effects.RESULTS: Of the 177 women who were randomized and started the study substance, 155 (88%) provided useable data over the first 5 weeks; 149 provided usable data over the entire 9 weeks. There was no suggestion that the soy product was more effective in reducing hot flashes than the placebo. At study completion, patients preferred the soy product 33% of the time, the placebo 37% of the time, and neither substance 31% of the time. No toxicity was observed.CONCLUSION: The soy product did not alleviate hot flashes in breast cancer survivors.

Abstract Background: The ECOG E5194 study was a prospective trial designed to evaluate surgical excision (lumpectomy) without radiation for selected women with ductal carcinoma in situ (DCIS) of the breast with low risk clinical and pathologic features. Methods: Eligible patients were enrolled on two study cohorts (not randomized): (1) low or intermediate grade DCIS, tumor size < 2.5 cm; or (2) high grade DCIS, tumor size < 1.0 cm. Cohort assignment was based on pathology assessment from the treating institution. Protocol specifications included surgical excision of the DCIS tumor with a minimum negative margin width of at least 3 mm or no tumor on re-excision. Radiation treatment was not allowed. From April 1997 to October 2002, 665 evaluable patients were enrolled through ECOG or NCCTG (561 in Cohort 1; 104 in Cohort 2). Tamoxifen was optional (not randomized) beginning in May 2000, and was given to 30% of the patients. The primary study endpoint was the rate of developing an ipsilateral breast event (IBE), defined as local recurrence of DCIS or invasive carcinoma in the treated breast. The median follow-up was 12.3 years. We have previously reported 7-year results (L. Hughes, J Clin Oncol 27:5319, 2009; median follow-up 6.3 years; 66 IBE’s), and we herein provide 12-year results. Results: Median patient age was 60 years and 58 years for Cohort 1 and Cohort 2, respectively. Tumor size was < 10 mm for 79% and 80% of patients, respectively. The minimum negative margin width was > 5 mm for 64% and 69% of patients, respectively. There were 99 IBE’s, of which 51 (52%) were an invasive IBE. The IBE and invasive IBE rates increased over time in both cohorts (see Table). The 12-year rates of an IBE were 14.4% for Cohort 1 and 24.6% for Cohort 2 (p = 0.003), and for an invasive IBE, 7.5% and 13.4%, respectively (p = 0.08). No difference was seen for the 12-year rates of overall survival (84.0% vs 82.8%; p = .96) or contralateral breast events (6.7% vs 12.0%; p = 0.16). On multivariate analysis, study cohort (hazard ratio = 1.81; p = 0.01) and tumor size (p = 0.01) were statistically significant for an IBE, and study cohort was borderline statistically significant for an invasive IBE (p = 0.08). On central pathology review (75% of cases), neither grade nor comedo necrosis was associated with the risk of an IBE or invasive IBE (all p > 0.15). Salvage treatment at the time of an IBE included mastectomy for 42% (31/74) and 64% (16/25) of the patients, respectively. Conclusions: For these selected patients with favorable DCIS based on clinical and pathologic characteristics treated with surgical excision without radiation, the rates of an IBE and an invasive IBE continued to increase through at least 12 years of follow-up. IBE Rates According To Study Cohort. Cohort 1 (Low or Intermediate Grade)Cohort 2 (High Grade)TimeIBEInvasive IBEIBEInvasive IBEAt 5 years6.0% (4.0%, 8.1%)2.7% (1.3%, 4.1%)15.0% (7.7%, 21.7%)5.3% (0.8%, 9.7%)At 7 years9.5% (7.0%, 12.0%)4.8% (2.9%, 6.6%)18.2% (10.6%, 25.8%)7.6% (2.2%, 13.0%)At 10 years12.5% (9.5%, 15.4%)6.4% (4.2%, 8.6%)24.6% (15.7%, 33.4%)13.4% (5.9%, 20.9%)At 12 years14.4% (11.2%, 17.6%)7.5% (5.1%, 10.0%)24.6% (15.7%, 33.4%)13.4% (5.9%, 20.9%) Citation Format: Lawrence J Solin, Robert Gray, Lorie L Hughes, William C Wood, Mary Ann Lowen, Sunil Badve, Frederick L Baehner, James N Ingle, Edith A Perez, Abram Recht, Joseph Sparano, Kathy Miller, Nancy E Davidson. Local excision without radiation for ductal carcinoma in situ: 12-year results from the ECOG E5194 study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-13-01.

Abstract Background First identified as an estrogen-inducible gene in a breast cancer cell line, LIV-1 is a multispan transmembrane protein of the solute-carrier family 39 with putative zinc transporter and metalloproteinase activity. As a downstream target of STAT3, it promotes the epithelial-to-mesenchymal transition that is important in the malignant progression to metastasis. LIV-1 is expressed in a number of cancers with the highest prevalence and level of expression in breast, prostate, and melanoma. Additionally, LIV-1 has been linked with malignant progression to metastasis and associated with lymph node involvement in breast cancer. Normal tissue expression is predominantly limited to hormonally regulated tissues, including breast and prostate. In metastatic breast cancer tissue samples, the current validated immunohistochemistry assay for LIV-1 has detected moderate to high expression in 82% of samples tested, with 88% positivity in hormone receptor-positive tumors and 73% in triple-negative tumors. SGN-LIV1A is an antibody-drug conjugate (ADC) composed of a humanized anti-LIV-1 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. In vitro, SGN-LIV1A shows target-specific internalization and cytotoxic activity against LIV-1-positive neoplastic cell lines. Significant dose-dependent tumor regression was demonstrated in mouse xenograft models. Methods The primary objective of this first-in-human phase 1, open label, multicenter study is to evaluate the safety and tolerability, and to identify the maximum tolerated dose of SGN-LIV1A using a 3+3 dose-escalation study design. Pharmacokinetics, immunogenicity, and antitumor activity will also be evaluated (ClinicalTrials.gov #NCT01969643). Enrollment to this US-based trial began in late 2013. Eligible patients are adult females who have hormone receptor-positive/HER2-negative or triple-negative metastatic breast cancer. Tumor tissue must be positive for expression of LIV-1 per central assessment. Patients must have received at least 2 prior cytotoxic regimens in the metastatic setting and have measurable disease per RECIST v1.1. Pre-existing neuropathy ≥ Grade 2 is not permitted. SGN-LIV1A is administered intravenously every 3 weeks at protocol-defined doses starting at 0.5 mg/kg. Patients who achieve an objective response or stable disease per RECIST v1.1 are eligible to continue treatment until disease progression. At the completion of dose escalation, expansion cohorts may be opened to enroll patients with specific breast cancer subtypes to further define safety and antitumor activity. Tumor biopsies are being obtained at baseline and after one cycle of treatment to evaluate the role of LIV-1 expression, target saturation, and other tumor-specific measurements in the antitumor activity of SGN-LIV1A. Citation Format: Andres Forero, Howard Burris III, Patricia LoRusso, Jennifer Specht, Kathy Miller, Monica Mita, Minetta C Liu, Shanu Modi, Lajos Pusztai, Django Sussman, Ana Kostic. SGN-LIV1A: A phase 1 trial evaluating a novel antibody-drug conjugate in patients with LIV-1-positive breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-3-01.