Paula Klein

Vitamin D and Breast Cancer

In addition to its role in calcium homeostasis and bone health, vitamin D has also been reported to have anticancer activities against many cancer types, including breast cancer. The discovery that breast epithelial cells possess the same enzymatic system as the kidney, allowing local manufacture of active vitamin D from circulating precursors, makes the effect of vitamin D in breast cancer biologically plausible. Preclinical and ecologic studies have suggested a role for vitamin D in breast cancer prevention. Inverse associations have also been shown between serum 25-hydroxyvitamin D level (25(OH)D) and breast cancer development, risk for breast cancer recurrence, and mortality in women with early-stage breast cancer. Clinical trials of vitamin D supplementation, however, have yielded inconsistent results. Regardless of whether or not vitamin D helps prevent breast cancer or its recurrence, vitamin D deficiency in the U.S. population is very common, and the adverse impact on bone health, a particular concern for breast cancer survivors, makes it important to understand vitamin D physiology and to recognize and treat vitamin D deficiency. In this review, we discuss vitamin D metabolism and its mechanism of action. We summarize the current evidence of the relationship between vitamin D and breast cancer, highlight ongoing research in this area, and discuss optimal dosing of vitamin D for breast cancer prevention.

Breast cancer in female-to-male transsexuals: two cases with a review of physiology and management.

Testosterone is important for the development of secondary sexual characteristics in female-to-male (FtM) transsexuals, but it may increase breast cancer risk. To date, only one breast cancer case has been reported in the literature in a FtM transsexual after 10 years of testosterone therapy. We describe 2 cases of breast cancers diagnosed in FtM transsexuals who have been treated with supraphysiological doses of testosterone. Our 2 cases demonstrate the unique issues that concern the management of FtM transsexuals with breast cancer and examine possible roles of testosterone in the development of breast cancer.

Abstract S1-02: PrECOG 0102: A randomized, double-blind, phase II trial of fulvestrant plus everolimus or placebo in post-menopausal women with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC) resistant to aromatase inhibitor (AI) therapy

Background: Although AIs are an effective treatment for HR-positive MBC, whether used alone or in combination with CDK4/6 inhibitors, resistance to therapy and disease progression invariably develops. Therapeutic options for AI-resistant disease include the m-TOR inhibitor everolimus in combination with the steroidal AI exemestane, or the selective estrogen receptor downregulator (SERD) fulvestrant alone. We hypothesized that the combination of fulvestrant and everolimus would be more effective than fulvestrant alone in AI-resistant MBC. Methods: Major eligibility criteria included post-menopausal women with HR-positive, HER2-negative MBC, recurrence or progression while receiving prior non-steroidal or steroidal AI therapy, ECOG PS 0-1, and ≤1 prior chemotherapy regimen for metastases. All patients received fulvestrant (500mg IM q2 weeks for 3 doses, then q4 weeks) plus oral everolimus (10mg) or placebo (1:1 randomization). Prophylactic corticosteroid mouthwash was not used. Tumor assessment was performed at baseline and every 12 weeks. Treatment continued until progressive disease (PD) by RECIST 1.1 criteria. Patients who discontinued everolimus/placebo due to toxicity continued fulvestrant until PD. The primary endpoint was progression-free survival (PFS), defined as time from start of treatment until progression or death. With accrual of 130 patients (120 eligible), the trial had 90% power to detect an improvement in median PFS from 5.4 months to 9.2 months (1-sided stratified log-rank test, type I error rate10%), with analysis planned after 98 PFS events. Results: Of 130 patients treated (64 everolimus, 66 placebo), median age was 61 years (range 35-92), and treatment arms were balanced for stratification factors used in randomization, including ECOG PS 0 vs. 1 (59%/41%), measurable disease (66%), and prior chemotherapy for metastasis (17%). Grade 3/4 AEs were more common in the everolimus arm (53%/3% vs. 23%3%), including hyperglycemia (16%/0% vs. 0%), stomatitis (11%/0% vs. 0%), hypertriglyceridemia (9%/2% vs. 0%), lymphopenia (9%/0% vs. 0%), and pneumonitis (6%/2% vs. 0%). There were 3 grade 5 events (2 everolimus, 1 placebo arm), none of which were attributed to therapy. Selected grade 2 events of interest included fatigue (17% vs. 6%), hyperglycemia (6% vs. 0%), and stomatitis (6% vs. 0%). Everolimus/placebo was discontinued for adverse events, patient withdrawal, or physician discretion in 39% in the everolimus arm and 21% in the placebo arm. After 98 PFS events, median PFS was 10.4 months in the everolimus arm versus 5.1 months in the placebo arm (hazard ratio: 0.61, 95% C.I. 0.40 – 0.92; stratified logrank p= 0.02). Conclusions: The addition of everolimus to fulvestrant significantly improved PFS in post-menopausal women with AI-resistant MBC. Everolimus used without prophylactic corticosteroid mouthwash exhibited a similar rate of oral mucositis and overall AE profile when combined with fulvestrant as when combined with exemestane. Keywords: advanced breast cancer, PrECOG 0102, endocrine resistance, everolimus, exemestane, hormone receptor-positive, mTOR inhibitor, postmenopausal. Citation Format: Kornblum NS, Manola J, Klein P, Ramaswamy B, Brufsky A, Stella PJ, Burnette B, Telli M, Makower DF, Leach J, Truica CI, Wolff AC, Soori GS, Haley B, Nagarajan A, Wassenaar TR, Goldstein L, Miller KD, Sparano JA. PrECOG 0102: A randomized, double-blind, phase II trial of fulvestrant plus everolimus or placebo in post-menopausal women with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC) resistant to aromatase inhibitor (AI) therapy [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 S1-02.

Cediranib in Combination with Fulvestrant in Hormone-Sensitive Metastatic Breast Cancer: A Phase II Randomized Study.

Background: Cediranib (RECENTIN™) is a highly potent VEGF signaling inhibitor that has shown clinical activity across a range of tumors at doses of 20, 30 and 45 mg, both as monotherapy and in combination with other agents. Fulvestrant (FASLODEX™) is a selective estrogen-receptor antagonist with no agonist effects that is effective in patients (pts) with hormone-sensitive, postmenopausal metastatic breast cancer (MBC) who have progressed or recurred on prior hormonal therapy. This randomized screening study evaluated cediranib in combination with fulvestrant.Methods: Eligible pts were postmenopausal women with histologically/cytologically confirmed hormone-sensitive MBC with measurable or non-measurable disease, no prior anti-VEGF or fulvestrant treatment and ≤1 prior cytotoxic chemotherapy. Pts received once-daily oral cediranib 45 mg or placebo, both in combination with fulvestrant (loading dose schedule: 500 mg im [2 x 250 mg] on day 1, 250 mg im on day 14, then 250 mg im every month). The primary objective was to determine whether cediranib + fulvestrant prolonged progression-free survival (PFS) vs placebo + fulvestrant (≥80% power to detect a hazard ratio [HR] of 0.50; P Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 204.

Clinical Significance of HER2-Positive and Triple-Negative Status in Small (≤ 1 cm) Node-Negative Breast Cancer

BACKGROUND Data regarding the clinical significance of HER2(+) and TN status in patients with small node-negative tumors are limited and conflicting. It remains unclear who, among those with small lesions, might benefit from more aggressive adjuvant therapy. PATIENTS AND METHODS We identified all node-negative breast cancer patients with tumor size ≤ 1 cm diagnosed between January 1, 1995 and December 31, 2008 using our institutional breast service database. Patients were classified according to their receptor status into 3 groups: (1) hormone receptor (HR)-positive (estrogen receptor [ER]- or progesterone receptor [PR]-positive, HER2(-)); (2) HER2(+) (immunohistochemistry 3(+) or fluorescence in situ hybridization amplification ≥ 2); and (3) TN (ER(-), PR(-), and HER2(-)). RFS was calculated using Kaplan-Meier methods. RESULTS Among 656 patients with tumors ≤ 1 cm, 494 (75%) of the patients were HR(+), 107 (16%) were HER2(+), and 55 (9%) were TN. Median age was 59 years (range, 27-92 years). Median follow-up was 3.5 years. The 5-year RFS rates were 98.2%, 97.1%, and 83.5% in patients with HR(+), HER2(+), and TN tumors, respectively (P < .001). In multivariate analysis, TN status was associated with worse RFS (hazard ratio, 6.70; 95% confidence interval [CI], 3.02-14.86), and HER2(+) was not (hazard ratio, 1.64; 95% CI, 0.73-3.69). CONCLUSION TN, but not HER2(+) status, was associated with worse RFS in patients with T1abN0 tumors, and adjuvant chemotherapy might be considered in patients with TN breast cancer.

Randomized phase II trial of fulvestrant alone or in combination with bortezomib in hormone receptor-positive metastatic breast cancer resistant to aromatase inhibitors: a New York Cancer Consortium trial

The proteasome inhibitor bortezomib enhances the effect of the selective estrogen receptor (ER) downregulator (SERD) fulvestrant by causing accumulation of cytoplasmic ER aggregates in preclinical models. The purpose of this trial was to determine whether bortezomib enhanced the effectiveness of fulvestrant. One hundred eighteen postmenopausal women with ER-positive metastatic breast cancer resistant to aromatase inhibitors (AIs) were randomized to fulvestrant alone (Arm A—500 mg intramuscular (i.m.) day −14, 1, 15 in cycle 1, and day 1 of additional cycles) or in combination with bortezomib (Arm B—1.6 mg/m2 intravenous (i.v.) on days 1, 8, 15 of each cycle). The study was powered to show an improvement in median progression-free survival (PFS) from 5.4 to 9.0 months and compare PFS rates at 6 and 12 months (α=0.10, β=0.10). Patients with progression on fulvestrant could cross over to the combination (arm C). Although there was no difference in median PFS (2.7 months in both arms), the hazard ratio for PFS in Arm B versus Arm A (referent) was 0.73 (95% confidence interval (CI)=0.49, 1.09, P=0.06, 1-sided log-rank test, significant at the prespecified 1-sided 0.10 α level). At 12 months, the PFS proportion in Arm A and Arm B was 13.6% and 28.1% (P=0.03, 1-sided χ2-test; 95% CI for difference (14.5%)=−0.06, 29.1%). Of 27 patients on arm A who crossed over to the combination (arm C), 5 (18%) were progression-free for at least 24 weeks. Bortezomib likely enhances the effectiveness of fulvestrant in AI-resistant, ER-positive metastatic breast cancer by reducing acquired resistance, supporting additional evaluation of proteasome inhibitors in combination with SERDs.

Randomized Phase II Trial of Fulvestrant Plus Everolimus or Placebo in Postmenopausal Women With Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer Resistant to Aromatase Inhibitor Therapy: Results of PrE0102

Purpose The mammalian target of rapamycin inhibitor everolimus targets aberrant signaling through the PI3K/AKT/mammalian target of rapamycin pathway, a mechanism of resistance to anti-estrogen therapy in estrogen receptor (ER)-positive breast cancer. We hypothesized that everolimus plus the selective ER downregulator fulvestrant would be more efficacious than fulvestrant alone in ER-positive metastatic breast cancer resistant to aromatase inhibitor (AI) therapy. Patients and Methods This randomized, double-blind, placebo-controlled, phase II study included 131 postmenopausal women with ER-positive, human epidermal growth factor receptor 2-negative, AI-resistant metastatic breast cancer randomly assigned to fulvestrant (500 mg days 1 and 15 of cycle 1, then day 1 of cycles 2 and beyond) plus everolimus or placebo. The study was designed to have 90% power to detect a 70% improvement in median progression-free survival from 5.4 months to 9.2 months. Secondary end points included objective response and clinical benefit rate (response or stable disease for at least 24 weeks). Prophylactic corticosteroid mouth rinses were not used. Results The addition of everolimus to fulvestrant improved the median progression-free survival from 5.1 to 10.3 months (hazard ratio, 0.61 [95% CI, 0.40 to 0.92]; stratified log-rank P = .02), indicating that the primary trial end point was met. Objective response rates were similar (18.2% v 12.3%; P = .47), but the clinical benefit rate was significantly higher in the everolimus arm (63.6% v 41.5%; P = .01). Adverse events of all grades occurred more often in the everolimus arm, including oral mucositis (53% v 12%), fatigue (42% v 22%), rash (38% v 5%), anemia (31% v. 6%), diarrhea (23% v 8%), hyperglycemia (19% v 5%), hypertriglyceridemia (17% v 3%), and pneumonitis (17% v 0%), although grade 3 to 4 events were uncommon. Conclusion Everolimus enhances the efficacy of fulvestrant in AI-resistant, ER-positive metastatic breast cancer.

Prevalence of self-reported cognitive dysfunction in breast cancer patients.

131 Background: In 2011 a series of four time-limited, psycho-educational workshops was conducted by a neuropsychologist at a major urban academic medical center, providing information, coping strategies, and resources to women who had been treated for breast cancer (BrCa) and who then sought cognitive treatment. Based on positive evaluations of these workshops, we assessed the prevalence of self-reported cognitive dysfunction in BrCa patients with the goal of expanding cognitive services to all affected cancer patients. METHODS The study was IRB approved. We surveyed a convenience sample of 50 BrCa patients in a single medical oncology waiting room over several weeks. Subjects completed a 16 item questionnaire assessing potential cognitive problems on a 4 point-scale. RESULTS Fifty patients completed the survey, of whom 46% were currently employed. Sixty-eight percent of respondents were currently receiving cancer treatment and of those, 61.8% had also received prior treatment. CONCLUSIONS An unexpectedly large proportion of BrCa patients perceived cognitive difficulties that may have been compounded by fatigue and emotional dysfunction. Others may have failed to report cognitive difficulties, unaware of their onset. Quality of life of cancer patients is diminished by cognitive decline. The current data indicate a need for formal assessment and intervention programs that will identify patients with cognitive and emotional dysfunction and remediate the difficulties via workshops and therapy. Formal neuropsychological assessment and treatment resourcestargeting cognitive changes associated with cancer should be expanded to meet documented need. Further research will optimize the scheduling and structure of therapeutic interventions. [Table: see text].

Isolated Sternal Involvement in Breast Cancer: Is it Truly Stage IV Disease?

PURPOSE There is no consensus regarding treatment for patients with breast cancer and isolated sternal involvement. Though classified as AJCC stage IV, this group of patients may have prolonged distant disease free survival. PATIENTS AND METHODS Retrospective case series of 8 patients with isolated sternal recurrence. Information regarding age, menopausal status, hormonal receptor status, HER2 status, initial treatment, time to sternal recurrence, treatment of sternal involvement, and outcome was obtained. RESULTS Median follow-up, 6 years. Seven of 8 diagnosed with metachronous sternal recurrence at a median of 3 years from initial breast cancer diagnosis, 1 with sternal involvement at initial diagnosis. Seven of 8 are alive, with one death from metastatic breast cancer 10 years after sternal recurrence. Six of 8 are without evidence of distant spread, 2 in continuous complete remission (CR) at 7 and 14 years from sternal recurrence. CONCLUSION While a small cohort, the excellent survival of the group identifies this as a distinct subset of metastatic disease, requiring special treatment considerations. Isolated sternal involvement could represent direct local-regional extension rather than systemic spread.

Abstract P3-07-07: The updated ASCO/CAP guidelines for HER2 testing create more uncertainty for clinicians

Background: Accurate assessment of the Human Epidermal Growth Factor Receptor 2 (HER2) status has been an integral part of clinical decision making in treatments of breast cancer. In 2007, American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) published a series of guidelines on how to determine the status of HER2. The guidelines were updated in 2013 with the goal of reducing the numbers of false negative cases. The new guidelines are based on a combination of HER2:CEP17 ratio and average HER2 copy number. We sought to assess the overall effect of the new guidelines. Methods: We retrospectively identified all cases of invasive breast cancer with HER2 testing done in 2014 from the pathology database of Mount Sinai Beth Israel, Mount Sinai St. Luke9s and Roosevelt Hospitals. Our pathology department guideline is to perform initial testing for HER2 with immunohistochemistry (IHC) by the HercepTest (Dako) method. Those with IHC of 2+ would be followed by reflex HER2 dual probe FISH. The HER2:CEP 17 ratio and average HER2 copy number were then reviewed for each IHC 2+ case using the 2013 guidelines. These cases were then rescored using the 2007 guidelines. All equivocal cases as determined by the new 2013 guidelines (HER2:CEP17 ratio Results: Among 853 cases identified in the database, 337 were IHC 2+. Using 2007 guidelines, 27/337 cases (8.0%) were amplified (HER2:CEP 17 ratio >2.2), 6 (1.8%) were equivocal (HER2:CEP 17 ratio 1.8-2.2), and 305 cases (90.2%) were non-amplified (HER2:CEP 17 ratio Conclusion: The 2013 ASCO/CAP guidelines for HER2 assessment identified a slightly increased number of patients eligible for HER2 directed therapy, but also resulted in a significant increase in the number of equivocal cases. The new guidelines appear to have generated more uncertainty for the clinician due to the rise in equivocal cases. Further studies are needed to determine whether patients with equivocal HER2 status would benefit from HER2 directed therapy. Citation Format: Chen J, Klein P, Shao T. The updated ASCO/CAP guidelines for HER2 testing create more uncertainty for clinicians. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-07.