Nikita Shah

Efficacy and Safety of Anti-Trop-2 Antibody Drug Conjugate Sacituzumab Govitecan (IMMU-132) in Heavily Pretreated Patients With Metastatic Triple-Negative Breast Cancer

Purpose Trop-2, expressed in most triple-negative breast cancers (TNBCs), may be a potential target for antibody-drug conjugates. Sacituzumab govitecan, an antibody-drug conjugate, targets Trop-2 for the selective delivery of SN-38, the active metabolite of irinotecan. Patients and Methods We evaluated sacituzumab govitecan in a single-arm, multicenter trial in patients with relapsed/refractory metastatic TNBC who received a 10 mg/kg starting dose on days 1 and 8 of 21-day repeated cycles. The primary end points were safety and objective response rate; secondary end points were progression-free survival and overall survival. Results In 69 patients who received a median of five prior therapies (range, one to 12) since diagnosis, the confirmed objective response rate was 30% (partial response, n = 19; complete response, n = 2), the median response duration was 8.9 (95% CI, 6.1 to 11.3) months, and the clinical benefit rate (complete response + partial response + stable disease ≥ 6 months) was 46%. These responses occurred early, with a median onset of 1.9 months. Median progression-free survival was 6.0 (95% CI, 5.0 to 7.3) months, and median overall survival was 16.6 (95% CI, 11.1 to 20.6) months. Grade ≥ 3 adverse events included neutropenia (39%), leukopenia (16%), anemia (14%), and diarrhea (13%); the incidence of febrile neutropenia was 7%. The majority of archival tumor specimens (88%) were moderately to strongly positive for Trop-2 by immunohistochemistry. No neutralizing antibodies to the ADC or antibody were detected, despite repeated cycles developed. Conclusion Sacituzumab govitecan was well tolerated and induced early and durable responses in heavily pretreated patients with metastatic TNBC. As a therapeutic target and predictive biomarker, Trop-2 warrants further research.

Lifestyle Interventions in the Prevention and Treatment of Cancer

Despite evidence that cancer death rates in the United States are declining, the absolute number of new cancers and cancer deaths continues to increase, and there is clear evidence that certain human behaviors are influencing these increases. The 4 major factors of lifestyle that continue to be causally related to certain cancers—tobacco use, an unhealthy diet, inadequate exercise, and excessive exposure to ultraviolet radiation—are each independently important in their effects on the genetic and molecular processes that result in the malignant transformation of human cells. There is both irrefutable and otherwise strong evidence that 4 common cancers that occur in the United States—lung cancer, colon/rectal cancer, breast cancer, and prostate cancer—and a less common cancer, malignant melanoma, have etiologic factors that are lifestyle based and therefore controllable through alterations in human behavior. These cancers and the evidence that lifestyle is important in the causation and/or prevention of the disease are the subjects of this review.

MGMT Inhibition Restores ERα Functional Sensitivity to Antiestrogen Therapy

Antiestrogen therapy resistance remains a huge stumbling block in the treatment of breast cancer. We have found significant elevation of O6 methylguanine DNA methyl transferase (MGMT) expression in a small sample of consecutive patients who have failed tamoxifen treatment. Here, we show that tamoxifen resistance is accompanied by upregulation of MGMT. Further we show that administration of the MGMT inhibitor, O6-benzylguanine (BG), at nontoxic doses, leads to restoration of a favorable estrogen receptor alpha (ERα) phosphorylation phenotype (high p-ERα Ser167/low p-ERα Ser118), which has been reported to correlate with sensitivity to endocrine therapy and improved survival. We also show BG to be a dual inhibitor of MGMT and ERα. In tamoxifen-resistant breast cancer cells, BG alone or in combination with antiestrogen (tamoxifen [TAM]/ICI 182,780 [fulvestrant, Faslodex]) therapy enhances p53 upregulated modulator of apoptosis (PUMA) expression, cytochrome C release and poly (ADP-ribose) polymerase (PARP) cleavage, all indicative of apoptosis. In addition, BG increases the expression of p21cip1/waf1. We also show that BG, alone or in combination therapy, curtails the growth of tamoxifen-resistant breast cancer in vitro and in vivo. In tamoxifen-resistant MCF7 breast cancer xenografts, BG alone or in combination treatment causes significant delay in tumor growth. Immunohisto-chemistry confirms that BG increases p21cip1/waf1 and p-ERα Ser167 expression and inhibits MGMT, ERα, p-ERα Ser118 and ki-67 expression. Collectively, our results suggest that MGMT inhibition leads to growth inhibition of tamoxifen-resistant breast cancer in vitro and in vivo and resensitizes tamoxifen-resistant breast cancer cells to antiestrogen therapy. These findings suggest that MGMT inhibition may provide a novel therapeutic strategy for overcoming antiestrogen resistance. Online address:http://www.molmed.org

LCCC 1025: a phase II study of everolimus, trastuzumab, and vinorelbine to treat progressive HER2-positive breast cancer brain metastases

PurposeHER2 + breast cancer (BC) is an aggressive subtype with high rates of brain metastases (BCBM). Two-thirds of HER2 + BCBM demonstrate activation of the PI3K/mTOR pathway driving resistance to anti-HER2 therapy. This phase II study evaluated everolimus (E), a brain-permeable mTOR inhibitor, trastuzumab (T), and vinorelbine (V) in patients with HER2 + BCBM.Patients and methodsEligible patients had progressive HER2 + BCBM. The primary endpoint was intracranial response rate (RR); secondary objectives were CNS clinical benefit rate (CBR), extracranial RR, time to progression (TTP), overall survival (OS), and targeted sequencing of tumors from enrolled patients. A two-stage design distinguished intracranial RR of 5% versus 20%.Results32 patients were evaluable for toxicity, 26 for efficacy. Intracranial RR was 4% (1 PR). CNS CBR at 6 mos was 27%; at 3 mos 65%. Median intracranial TTP was 3.9 mos (95% CI 2.2–5). OS was 12.2 mos (95% CI 0.6–20.2). Grade 3–4 toxicities included neutropenia (41%), anemia (16%), and stomatitis (16%). Mutations in TP53 and PIK3CA were common in BCBM. Mutations in the PI3K/mTOR pathway were not associated with response. ERBB2 amplification was higher in BCBM compared to primary BC; ERBB2 amplification in the primary BC trended toward worse OS.ConclusionWhile intracranial RR to ETV was low in HER2 + BCBM patients, one-third achieved CNS CBR; TTP/OS was similar to historical control. No new toxicity signals were observed. Further analysis of the genomic underpinnings of BCBM to identify tractable prognostic and/or predictive biomarkers is warranted. Clinical Trial: (NCT01305941).

Patterns of Progression in Metastatic Estrogen Receptor Positive Breast Cancer: An Argument for Local Therapy

Purpose Despite advances in endocrine therapy (ET), metastatic estrogen receptor positive breast cancer (BrCA) remains incurable. Though the mechanisms of resistance to ET have been studied extensively, the anatomic pattern of disease progression remains poorly characterized. The purpose of this study was to characterize the pattern of progression for patients receiving ET for metastatic BrCA. Methods The records of 108 patients with metastatic BrCA who progressed on ET were reviewed. Progression was characterized as follows: diffuse progression, progression in greater than 3 sites; oligoprogression, progression in fewer than 3 sites with prior diffuse metastases; and oligometastatic disease with progression, progression in 3 or fewer sites with prior limited metastases. Results Seventy-four patients (69%) displayed only diffuse disease progression. Conversely, 23 patients (21%) displayed oligoprogression and 11 patients (10%) displayed oligometastases with progression at least once in their disease course. Further analysis of the patients with oligoprogression suggested that in 14 patients the sites of progression would have been amenable to local therapy. Conclusion Oligoprogressive disease occurs in a significant subset of patients with metastatic BrCA treated with ET. These patients with oligoprogressive disease may be eligible for local therapy, potentially obviating the need to change of systemic therapy.

Abstract P5-16-28: A single-institution clinical experience with neoadjuvant docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP): A safety and efficacy analysis

Background: Pertuzumab, a monoclonal antibody targeting subdomain II of HER2 and blocking dimerization , was approved by the FDA in 2013 for use in combination with trastuzumab and docetaxel as neoadjuvant therapy for pts with HER2+, locally advanced, inflammatory or early-stage breast cancer (>2cm and/or node-positive). This accelerated approval was based on results from the NeoSphere and the TRYPHAENA trials. In NeoSphere, pathologic complete response in the breast and nodes [pCR] was 39.3% after 4 cycles of neoadjuvant pertuzumab/trastuzumab/docetaxel. In TRYPHAENA, pCR was 63.6% among 76 patients treated with 6 cycles of neoadjuvant TCHP(47.5% in pts with ER+and/or PR+/HER2+ tumors and 81.1% in those with ER-/PR-/HER2+ tumors). Aside from TRYPHAENA, we have limited information on clinical outcomes, with neoadjuvant TCHP. Here we report our institutional experience at UF Health Cancer Center, Orlando (UFHCC) with Neoadjuvant TCHP in patients with operable or locally advanced breast cancer. Patients and Methods: After IRB approval, electronic medical record search was performed in order to identify HER2+ patients with tumors T2-T4/N0-3 or Tany/N1-3, treated with neoadjuvant TCHP between 10/13 and 5/16. Information from chart review included patient and tumor characteristics at the time of diagnosis , details of neoadjuvant chemotherapy plus anti-HER2 therapy, clinical, radiologic and pathologic assessment of tumor response to neoadjuvant TCHP, type of breast and axillary nodal surgery, surgical outcomes as well as disease outcomes. Results: 76 patients (75 female, 1 male) met the inclusion criteria; median age: 52 yrs; 83% of pts presented with clinical stage II and 17% with clinical stage III; 62% were ER+ and/or PR+ and 38% were ER-/PR-negative. 49 patients received all planned 6 cycles without dose reduction. The remaining 27 patients required dose reduction due to rash, diarrhea, nausea, vomiting, neuropathy or neutropenia; 5 patients requested dose reduction due to poor quality of life and fatigue; 2 patients required dose delay due to asymptomatic cardio-toxicity with ≥ 10% drop in EF. None had symptomatic CHF; 37% of patients underwent breast conserving surgery, 7% unilateral mastectomy and 55% bilateral mastectomy. Surgical lymph node assessment was performed after neoadjuvant chemotherapy and included sentinel lymph node biopsy (SLNB) in 74%, axillary dissection (ALND) in 8% or both in 18% of pts. Overall pCR rate (ypT0/is, ypN0) was 63.2%. pCR rate was 53.1% in pts with ER+ and/or PR+ tumors and 79.3% in those with ER-/PR- tumors. pCR by stage was 61% for Stage IIA, 65% for Stage IIB, 67% for Stage IIIA and 71% for Stage IIIC. Toxicity profile was consistent with what has been observed in the TRYPHAENA trial with fatigue, nausea, vomiting and neuropathy being the more commonly noted grade 3/4 toxicities. With median follow up of 18 months, all patients are disease-free with no documented recurrences observed. Conclusion: Our clinical experience with neoadjuvant TCHP confirms the efficacy and safety data from the TRYPHAENA trial in a single-institution, tertiary care center setting. Citation Format: Tariq R, Ajaz B, Shah N, Mamounas E, Moroose R. A single-institution clinical experience with neoadjuvant docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP): A safety and efficacy analysis [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 P5-16-28.

Abstract P4-22-15: Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate (ADC) for the treatment of relapsed/refractory, metastatic triple-negative breast cancer (mTNBC): Updated results

Background . mTNBC has an aggressive course with limited effective therapy options and a median progression-free survival (PFS) of 2-4 months (mos) with standard therapy. Sacituzumab govitecan (IMMU-132) is an ADC targeting Trop-2, an antigen present in many epithelial cancers, including TNBC, and delivering SN-38, a topoisomerase I inhibitor as its therapeutic moiety. IMMU-132 was awarded Breakthrough Therapy designation by FDA based on its previously reported activity in relapsed/refractory mTNBC patients. Here we present updated results from the mTNBC cohort of an ongoing phase I/II study (ClinicalTrials.gov, NCT01631552). Methods . mTNBC patients (pts) received IMMU-132 10 mg/kg on days 1 and 8 every 21 days. Trop-2 expression was not required for enrollment, but available tumor specimens underwent immunohistological (IHC) testing. Efficacy was assessed locally by RECIST 1.1; ORR, PFS and overall survival (OS) were determined for all pts. Pharmacokinetic parameters were estimated in select pts with adequate blood sampling. Immunogenicity to IMMU-132 was examined in all pts. Results . We previously reported preliminary efficacy results in 51 mTNBC patients. Here we present data on 69 patients with data cutoff June 5, 2016. Median age was 56 years (31-81) and a median of 5 prior therapies (range 1-12), with 66 evaluable for response; ORR was 29% (19/66) 2 confirmed complete (CR) and 17 confirmed partial responses (PR). The median intention-to-treat PFS is 5.6 mos (95% CI, 3.6-7.1 mos) and median OS is 14.3 mos (95% CI, 10.5-18.8 mos). PRs included 2 pts whose tumors did not respond to anti-PD-L1 therapy. The duration of response in the 19 confirmed responders (8 continuing therapy) is 11.5 mos (95% CI = 7.6 to 12.7). The clinical benefit rate (CR+PR+SD>6 mos) for the 66 assessable patients is currently 45.5%. The majority (88%) of archival tumor specimens were moderately (2+) to strongly (3+) positive by IHC for Trop-2, precluding using Trop-2 expression as a selection criterion. Among current adverse events, grade >3 drug-related toxicities included neutropenia (35%), leukopenia (16%), anemia (13%), vomiting (9%), diarrhea (10%), and febrile neutropenia (4%). Clearance kinetics in 8 pts showed IMMU-132 and IgG had a terminal half-life of 15.3 ± 2.7 h and 86.5 ± 40.5 h, respectively, with area under the curve for free SN-38 (unbound) only 3% of the total amount of SN-38 (e.g., IgG bound). Thus, most SN-38 remains bound to the conjugate, and is released at a rate predicted from in vitro serum stability studies. No pt developed anti-IMMU-132 antibodies. Conclusion The Trop-2-targeting ADC, IMMU-132, delivering cytotoxic doses of SN-38, shows high objective and durable tumor responses with manageable toxicity in heavily-pretreated pts with mTNBC in this updated cohort, supporting further development in this population with an unmet medical need. Citation Format: Bardia A, Diamond JR, Mayer IA, Isakoff SJ, Abramson V, Starodub AN, O9Shaughnessy J, Kalinsky K, Moroose R, Shah N, Juric D, Shapiro GI, Guarino M, Ocean AJ, Messersmith WA, Berlin JD, Wegener WA, Sharkey RM, Goldenberg DM, Vahdat LT. Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate (ADC) for the treatment of relapsed/refractory, metastatic triple-negative breast cancer (mTNBC): Updated results [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 P4-22-15.

Study comparing the concordance between PET/CT and bone scan in detecting skeletal metastasis in breast cancer patients.

e11122 Background: Bone metastasis is the most common site of metastases from breast cancer. Bone scan using technetium-99m is widely used for the detection of bony metastasis in patients with breast cancer but specificity is lowered by benign processes and sensitivity is lessened by poor detection of osteolytic metastasis. Positron emission tomography (PET) using 2-[18F] - fluoro-2-deoxy-D-glucose is a useful tool for the detection of metastatic disease in patients with breast cancer. It is unclear whether one or both modalities should be used to detect bone metastasis. METHODS Within our institution, we reviewed PET/CT scans and bone scans from 97 female patients with breast cancer whose scans were within a 4 -week period between June 2007 and March 2010 (109 studies of each, PET scan and bone scan). Data was divided into three sites: spine, pelvis+ribs, extremities. All scans were reviewed by 2 independent expert nuclear medicine physicians. Utilizing bone scan as the standard, McNemars test was performed to examine the marginal homogeneity of diagnoses for each of the three locations. The sensitivity, specificity, and accuracy of PET scan as opposed to bone scan were compared. RESULTS See table. CONCLUSIONS There is no statistical difference between PET/CT scan compared with bone scan when bone scan is utilized as the standard test for detection of skeletal metastasis. In addition, using bone scan as a standard, PET scan has higher sensitivity (lower false-positive rates) in detecting spine metastasis, higher specificity (lower false-negative rates), and accuracy in detecting extremity metastasis. [Table: see text].

Abstract 716: O6-Methylguanine DNA methyl transferase (MGMT) and tamoxifen resistance in patients with breast cancer

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Tamoxifen is an estrogen receptor antagonist in breast tissue. It has been used as a hormonal therapy for early and advanced breast cancer both in premenopausal and postmenopausal patients with estrogen receptor positive breast cancer. Acquired resistance to tamoxifen therapy is a common therapeutic encounter. Different mechanisms for Tamoxifen resistance have been postulated. In the present study we investigated if over expression of MGMT causes tamoxifen resistance in breast cancer patients. Purpose: We sought to determine MGMT expression levels in various breast cancer cell lines as well as in breast cancer patients samples before and after treatment with tamoxifen. Experimental Design: MGMT expression levels were compared in breast cancer tissue samples obtained from patients before starting treatment with Tamoxifen and after tumor progression due to development of Tamoxifen resistance. MGMT expression level was evaluated using western blot and immunohistochemical assays. Several commercial breast cell lines were evaluated for expression of MGMT. Results: We found that MGMT is over expressed in the majority of breast cancer cell lines compared to normal breast epithelial cells. Compared to pre Tamoxifen treatment, post Tamoxifen treated breast cancer patient samples have significantly higher levels of MGMT expression. Conclusion: Collectively, our results demonstrate that breast cancer cells showed significantly higher levels of MGMT expression and furthermore, Tamoxifen treatment induces further MGMT over expression in breast cancer patients. According to our results over expression of MGMT is a possible cause for Tamoxifen resistance. Inhibition of MGMT might overcome Tamoxifen resistance and restore breast cancer sensitivity to Tamoxifen treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 716. doi:10.1158/1538-7445.AM2011-716