Grace M. Choong

PURPOSE: Low-grade serous carcinoma (LGSOC) of the ovary, fallopian tube, or peritoneum is a hormonally driven, relatively chemoresistant malignancy with limited treatment options in the recurrent setting. Given frequent estrogen receptor (ER) expression and dysregulation of the cyclin-dependent kinases 4 and 6 (CDK4/6)–p16–Rb pathway, features shared with hormone receptor–positive breast cancer, dual endocrine, and CDK4/6 inhibition is a biologically rational strategy. This phase II trial evaluated ribociclib plus letrozole in recurrent LGSOC. METHODS: This open-label, single-arm, multicenter phase II study enrolled women with measurable, recurrent LGSOC. Patients received ribociclib (600 mg orally, once daily, days 1-21 of a 28-day cycle) and letrozole (2.5 mg orally, once daily). The primary end point was investigator-assessed objective response rate (ORR) per RECIST 1.1. Secondary end points included clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Of 74 patients screened, 51 were enrolled and 49 treated. The confirmed ORR was 30.6% (90% CI, 19.9 to 43.2), including one complete and 14 partial responses. Among responders, the median duration of response was 21.2 months. The CBR was 84% (90% CI, 72.5 to 91.6). The median PFS was 14.5 months (90% CI, 10.1 to 28.8), and the median OS was 44.5 months (90% CI, 31.8 to not reached). The most common grade ≥3 adverse event (AE) was neutropenia (47%), managed with dose modifications. Three grade 5 events (6%) occurred but were unrelated to treatment. Treatment discontinuation because of AEs occurred in 4%. No dose-limiting toxicities were observed. CONCLUSION: Ribociclib plus letrozole met the primary end point, achieving meaningful response rates and durable disease control in recurrent LGSOC. The safety profile was consistent with prior CDK4/6 inhibitor studies. This combination represents a therapeutic option in this rare and genomically distinct subtype.

PURPOSE: The difference in time to serum calcium normalization and rates of subsequent refractory hypocalcemia between bisphosphonates requires further investigation. Our primary objective was to assess the difference in normalization of serum calcium between pamidronate and zoledronic acid during treatment of hypercalcemia of malignancy (HCM) and rates of subsequent, refractory hypocalcemia following therapy. METHODS: A retrospective review of patients with cancer who received pamidronate or zoledronic acid inpatient at Mayo Clinic for treatment of HCM between January 2018 and January 2024 was conducted. Logistic regression evaluated the association between treatment groups and outcomes. Multivariable modeling was adjusted for baseline differences, including severity of hypercalcemia. RESULTS: We evaluated 856 patients. The median age was 68 (IQR, 59-75) years, and 476 (55.6%) were male. The most common cancer diagnoses were lymphoma (n = 158, 18.5%), followed by multiple myeloma (n = 145, 16.9%) and lung cancer (n = 111, 13%). Overall, 292 (46.8%) patients and 154 (32.8%) patients achieved serum calcium normalization by hospital day 4 and day 7, respectively. The rate of normalization was similar between all bisphosphonates, regardless of pamidronate dose. Significantly higher rates of hypocalcemia were observed on day 4 for patients who received zoledronic acid 4 mg once compared with either dose (60 mg once and 90 mg once) of pamidronate (40.7% v 27.6% v 26.8%, P = .049, respectively). No significant difference in rates of hypocalcemia were observed on day 7 (56.8% v 50% v 42.9%, P = .26, respectively) and day 30 (39.1% v 39.0% v 37.5%, P = .50, respectively). CONCLUSION: Bisphosphonates were equally efficacious in normalizing serum calcium in patients with HCM. Pamidronate 90 mg was not more efficacious than 60 mg. Rates of refractory hypocalcemia were similar.

PURPOSE: Adjuvant endocrine therapy (ET) improves overall survival (OS) in estrogen receptor (ER)–positive early-stage breast cancer (BC). However, the benefit of ET for those with ER-low BC (ER 1%-10%) is unclear. METHODS: Using the National Cancer Database, we studied patients with high-risk stage I to III, ER-low BC (defined as immunohistochemistry 1%-10%) who received (neo)adjuvant chemotherapy and did or did not initiate ET. OS was analyzed with ET initiation as a time-dependent covariate using Cox proportional hazards regression. RESULTS: Of 10,362 patients with stage I to III ER-low BC, 7,018 received chemotherapy and met inclusion criteria. ET omission was 42% at 12 months and more common in patients with tumors that were progesterone receptor–negative, human epidermal growth factor receptor 2–negative, higher-grade (grade 2/3) and higher Ki-67 (≥20%; all P < .001) and those who received neoadjuvant chemotherapy (NAC; P < .001). With a median follow-up of 3 years, 586 deaths were observed. In a multivariable analysis, ET omission was associated with a higher risk of death (hazard ratio [HR], 1.23 [95% CI, 1.04 to 1.46]; P = .02), with a greater impact in those with higher ER levels: ER 1%-5% (HR, 1.15 [95% CI, 0.91 to 1.45]; P = .24) versus ER 6%-10% (HR, 1.42 [95% CI, 1.00 to 2.02]; P = .048). Among patients treated with NAC (n = 4,377, 62%), ET omission was associated with worse OS in those with residual disease (RD; HR, 1.26 [95% CI, 1.00 to 1.57]; P = .046) but not in those who achieved a pathologic complete response (HR, 1.06 [95% CI, 0.62 to 1.80]; P = .84). CONCLUSION: In ER-low, early-stage BC, ET omission is associated with significantly worse OS, especially in patients with RD after NAC and those with higher (6%-10%) ER levels. Until prospective data are available, patients with ER-low BC should be counseled regarding the potential benefit of ET.

Background: Bimiralisib is a pan-PI3K/mTOR inhibitor demonstrating antitumor efficacy in preclinical models. The objectives of this study were to identify a maximum tolerated dose (MTD), pharmacokinetics (PK), a dosing schedule, and adverse events (AEs) in patients with advanced solid tumors. Patients and Methods: Patients received oral bimiralisib to determine the MTD of one continuous (once daily) and two intermittent schedules (A: Days 1, 2 weekly; B: Days 1, 4 weekly) until progression or unacceptable AEs occurred. Results: The MTD for the continuous schedule was 80 mg, with grade three fatigue as the dose-limiting toxicity (DLT). No MTD was reached with intermittent schedules, with only one DLT in schedule B. PK analysis suggested that 140 mg (schedule A) was within the biologically active dose range and was selected for further exploration. The most frequent treatment-emergent AEs were hyperglycemia (76.2%) in the continuous schedule, and nausea (56–62.5%) in schedules A and B. The most frequent treatment-emergent > grade three AE for all schedules combined was hyperglycemia (28.6%, continuous schedule; 12.0%, schedule A; 12.5%, schedule B). There was one partial response in a head and neck squamous cancer patient with a NOTCH1^T1997M mutation. Conclusions: Bimiralisib demonstrated a manageable AE profile consistent with this compound class. Intermittent schedules had fewer > grade three AEs, while also maintaining favorable PK profiles. Intermittent schedule A is proposed for further development in biomarker-selected patient populations.

Purpose Cyclin dependent kinase 4/6 inhibitors (CDK4/6is), in combination with endocrine therapy (ET), are standard either in the first (1L) or second line (2L) setting for the treatment of hormone receptor (HR) positive, HER2-negative metastatic breast cancer (MBC). However, the optimal sequencing of treatments after progression on CDK4/6i remains unknown. We performed a single institution analysis to identify treatments and outcomes after progression on a CDK4/6i. Methods We identified patients with HR-positive, HER2-negative MBC prescribed a CDK4/6i in the 1L or 2L settings from December 2014-February 2018 at Mayo Clinic in Rochester, Minnesota. Outcomes were collected through September 30, 2020. Results Palbociclib, in combination with letrozole or fulvestrant, was the most prescribed CDK4/6i. The 1L and 2L CDK4/6i cohorts exhibited comparable overall survival (OS), but progression free survival (PFS) was longer in the 1L than the 2L cohort [28.2 months (95% CI 19.6–34.9) vs 19.8 months (95% CI 15.7–29.6)]. The most common post-CDK4/6i treatments were PI3K/mTOR inhibitors (PI3K/mTORi), single agent ET, or chemotherapy. PFS in the 1L CDK4/6i cohort following PI3K/mTORi was 8.5 months (95% CI 5.5 months – NE), single-agent ET was 6.0 months (95% CI 3.3–14.0 months), and chemotherapy PFS was 5.4 months (95% CI 3.3 months- NE). Conclusions Following progression on a CDK 4/6i, mPFS was short, with similar PFS times comparing chemotherapy and ET, with slightly longer PFS for targeted strategies (PI3K/mTOR). These results highlight a major need to better understand the mechanisms of CDK4/6i resistance and identify new therapeutic strategies for these patients.

The management of human epidermal growth factor receptor (HER2)–positive breast cancer (BC) has rapidly evolved over the last 20 years. Major advances have led to US Food and Drug Administration approval of 7 HER2‐targeted therapies for the treatment of early‐stage and/or advanced‐stage disease. Although oncologic outcomes continue to improve, most patients with advanced HER2‐positive BC ultimately die of their disease because of primary or acquired resistance to therapy, and patients with HER2‐positive early BC who have residual invasive disease after preoperative systemic therapy are at a higher risk of distant recurrence and death. The concept of treatment de‐escalation and escalation is increasingly important to optimally tailor therapy for patients with HER2‐positive BC and is a major focus of the current review. Research efforts in this regard are discussed as well as updates regarding the evolving standard of care in the (neo)adjuvant and metastatic settings, including the use of novel combination therapies. The authors also briefly discuss ongoing challenges in the management of HER2‐positive BC (eg, intrinsic vs acquired drug resistance, the identification of predictive biomarkers, the integration of imaging techniques to guide clinical practice), and the treatment of HER2‐positive brain metastases. Research aimed at superseding these challenges will be imperative to ensure continued progress in the management of HER2‐positive BC going forward.

Objective Metaplastic breast cancer (MetaBC) is a rare breast cancer subtype poorly responsive to systemic therapy in the metastatic setting with high recurrence rates in the adjuvant setting. However, limited data exist regarding response to neoadjuvant chemotherapy (NAC). We performed a single institutional study to assess the clinical and pathological complete response rates (pCR) of MetaBC to NAC. Methods Mayo Clinic Rochester patients with MetaBC treated with NAC were identified using the institutional medical index. Patient demographics, tumor characteristics, chemotherapy treatment, clinical and pathological response, and long-term outcomes were reviewed. Pathologic response was assessed by direct pathology review (n = 14) or review of outside surgical and pathology reports (n = 4). Results Women with MetaBC (n = 18) received NAC from January 1991 to June 2014. The mean age was 50 years (range 33–79) with a mean tumor size of 5.1 cm (range 2.3–11 cm) and 6/18 had pathologically confirmed lymph nodes prior to surgery. The majority (13/18; 72%) were estrogen receptor (ER), progesterone receptor (PR) and HER-2 negative (TNBC), and 1/18 (5.5%) was HER-2 positive. Five had BRCA testing and 2/5 were BRCA-2 positive. The chemotherapy regimens included anthracycline/cyclophosphamide (AC) (n = 1), AC/taxane (n = 3), AC/taxane/platinum (n = 8), taxane/platinum-based regimens (n = 4), taxane/cyclophosphamide (n = 1) and taxane/trastuzumab (n = 1). Five of 18 (28%) progressed on initial treatment including two who developed metastatic disease during NAC. The overall pCR rate was 2/18 (11%). Conclusion MetaBC is poorly responsive to NAC, with a pCR rate (11%), that is lower than expected in a predominantly TNBC cohort. MetaBC patients should be considered for clinical trials testing new NAC regimens and in the absence of clinical trial enrollment, MetaBC patients with resectable disease should proceed directly to definitive operative management.

To provide an overview of the clinical development of poly(ADP-ribose) polymerase inhibitors (PARPi) in breast cancer to date and to review existing challenges and future research directions.