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Background: Hormone receptor positive (HR+), HER2- early-stage breast cancer (EBC) is a heterogenous disease. Identification of better clinical and molecular biomarkers is essential to guide optimal therapy for each patient., Patients and Methods: We analyzed rates of pathologic complete response (pCR) and distant recurrence-free survival (DRFS) for patients with HR+/HER2- EBC in 8 neoadjuvant arms in the I-SPY2 trial by clinical/molecular features: age, stage, histology, percentage ER positivity, ER/PR status, MammaPrint (MP)-High1 (0 to -0.57) versus MP-High2 (<-0.57), BluePrint (BP)-Luminal-type versus BP-Basal-type, and ImPrint immune signature. We quantified the clinical/molecular heterogeneity, assessed overlap among these biomarkers, and evaluated associations with pCR and DRFS., Results: 379 patients with HR+/HER2- EBC were included in this analysis, with an observed pCR rate of 17% across treatment arms. pCR rates were higher in patients with stage II versus III disease (21% versus 9%, p=0.0013), ductal versus lobular histology (19% versus 11%, p=0.049), lower %ER positivity (≤66% versus >66%) (35% versus 9%, p=3.4E-09), MP-High2 versus MP-High1 disease (31% versus 11%, p=1.1E-05), BP-Basal-type versus BP-Luminal-type disease (34% versus 10%, p=1.62E-07), and ImPrint positive versus negative disease (38% versus 10%, p=1.64E-09). Patients with lower %ER were more likely to have MP-High2 and BP-Basal-type disease. At a median follow-up of 4.8 years, patients who achieved pCR had excellent outcomes irrespective of clinical/molecular features. Among patients who did not achieve pCR, DRFS events were more frequent in patients with MP-High2 and BP-Basal-type disease than those with MP-High1 and BP-Luminal-type disease., Conclusion: Among patients with high molecular-risk HR+/HER2- EBC, the MP-High2, BP-Basal-type, and ImPrint positive signatures identified a partially overlapping subset of patients who were more likely to achieve pCR in response to neoadjuvant chemotherapy +/- targeted agents or immunotherapy compared to patients with MP-High1, BP-Luminal-type, and ImPrint negative disease. I-SPY2.2 is incorporating the use of these biomarkers to molecularly define specific patient populations and optimize treatment selection., (Copyright © 2024. Published by Elsevier Ltd.)

Sequential adaptive trial designs can help accomplish the goals of personalized medicine, optimizing outcomes and avoiding unnecessary toxicity. Here we describe the results of incorporating a promising antibody-drug conjugate, datopotamab-deruxtecan (Dato-DXd) in combination with programmed cell death-ligand 1 inhibitor, durvalumab, as the first sequence of therapy in the I-SPY2.2 phase 2 neoadjuvant sequential multiple assignment randomization trial for high-risk stage 2/3 breast cancer. The trial includes three blocks of treatment, with initial randomization to different experimental agent(s) (block A), followed by a taxane-based regimen tailored to tumor subtype (block B), followed by doxorubicin-cyclophosphamide (block C). Subtype-specific algorithms based on magnetic resonance imaging volume change and core biopsy guide treatment redirection after each block, including the option of early surgical resection in patients predicted to have a high likelihood of pathologic complete response, which is the primary endpoint assessed when resection occurs. There are two primary efficacy analyses: after block A and across all blocks for six prespecified HER2-negative subtypes (defined by hormone receptor status and/or response-predictive subtypes). In total, 106 patients were treated with Dato-DXd/durvalumab in block A. In the immune-positive subtype, Dato-DXd/durvalumab exceeded the prespecified threshold for success (graduated) after block A; and across all blocks, pathologic complete response rates were equivalent to the rate expected for the standard of care (79%), but 54% achieved that result after Dato-DXd/durvalumab alone (block A) and 92% without doxorubicin-cyclophosphamide (after blocks A + B). The treatment strategy across all blocks graduated in the hormone-negative/immune-negative subtype. No new toxicities were observed. Stomatitis was the most common side effect in block A. No patients receiving block A treatment alone had adrenal insufficiency. Dato-DXd/durvalumab is a promising therapy combination that can eliminate standard chemotherapy in many patients, particularly the immune-positive subtype.ClinicalTrials.gov registration: NCT01042379 ., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

While adjuvant treatment with the selective-estrogen receptor modulator (SERM) tamoxifen has been the standard of care for pre-menopausal patients with hormone receptor (HR) positive breast cancer, recent trials showed a benefit of aromatase inhibitors (AI) and ovarian function suppression (OFS) for some patients. The approach to endocrine therapy has not been well studied in pre-menopausal patients with invasive lobular carcinoma (ILC). We identified 202 pre-menopausal patients with HR positive stage I-III ILC in an institutional database. We investigated factors associated with endocrine therapy type and determined changes in systemic therapy from 1990-2021. We evaluated associations between endocrine therapy type and disease-free survival (DFS) with a multivariate Cox proportional hazards model. Of 202 patients, most (69.3%) were prescribed a SERM (99.3% tamoxifen). Those who received an AI had significantly higher stage disease. Over time, use of OFS and AI increased significantly in stage II or III cases (from 0% in 1990 to 56% after 2015 for stage II; from 0% to 80% after 2015 for stage III). Concurrently, adjuvant chemotherapy use significantly decreased in stage II cases (from 67% to 19%). In an exploratory multivariable model, longer duration of AI compared to tamoxifen was associated with significantly improved DFS (HR 0.31; 95% CI 0.11-0.86; p = 0.025). While most pre-menopausal patients received adjuvant tamoxifen, the use of OFS and AIs increased significantly over time. The association between AI use and improved DFS may be consistent with prior randomized trials and warrants further investigation into predictive factors to guide treatment selection., (© 2023. The Author(s).)

Metabolic PET, most commonly 18F-fluorodeoxyglucose (FDG) PET/computed tomography (CT), has had a major impact on the imaging of breast cancer and can have important clinical applications in appropriate patients. While limited for screening, FDG PET/CT outperforms conventional imaging in locally advanced breast cancer. FDG PET/CT is more sensitive than conventional imaging in assessing treatment response, accurately predicting complete response or nonresponse in early-stage cases. It also aids in determining disease extent and treatment response in the metastatic setting. Further research, including randomized controlled trials with FDG and other metabolic agents such as fluciclovine, is needed for optimal breast cancer imaging., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: EGFR mutations drive a subset of NSCLC. Patients harboring the common EGFR mutations, deletion of exon 19 and L858R, respond well to osimertinib, a third-generation tyrosine kinase inhibitor. Nevertheless, the effect of osimertinib on NSCLC with atypical EGFR mutations is not well described. This multicenter retrospective study evaluates the efficacy of osimertinib among patients with NSCLC harboring atypical EGFR mutations., Methods: Patients with metastatic NSCLC treated with osimertinib, harboring at least one atypical EGFR mutation, excluding concurrent deletion of exon 19, L858R, or T790M mutations, from six U.S. academic cancer centers were included. Baseline clinical characteristics were collected. The primary end point was the time to treatment discontinuation (TTD) of osimertinib. Objective response rate by the Response Evaluation Criteria in Solid Tumors version 1.1 was also assessed., Results: A total of 50 patients with NSCLC with uncommon EGFR mutations were identified. The most frequent EGFR mutations were L861Q (40%, n = 18), G719X (28%, n = 14), and exon 20 insertion (14%, n = 7). The median TTD of osimertinib was 9.7 months (95% confidence interval [CI]: 6.5-12.9 mo) overall and 10.7 months (95% CI: 3.2-18.1 mo) in the first-line setting (n = 20). The objective response rate was 31.7% (95% CI: 18.1%-48.1%) overall and 41.2% (95% CI: 18.4%-67.1%) in the first-line setting. The median TTD varied among patients with L861Q (17.2 mo), G719X (7.8 mo), and exon 20 insertion (1.5 mo) mutations., Conclusions: Osimertinib has activity in patients with NSCLC harboring atypical EGFR mutations. Osimertinib activity differs by the type of atypical EGFR -activating mutation., (© 2023 The Authors.)

Identification of biomarkers to drive treatment using cell-free DNA allows dynamic and safe assessment of tumor biology representing an important advance adding to tissue-based genotyping. Caution must be exercised interpreting commercial matching information as validation is often lacking, and true matching is feasible in a minority of patients. See related article by Vidula et al., p. 3404 ., (©2021 American Association for Cancer Research.)

Objectives: To examine seminal parameters predictive for success in a cycle of GIFT and to construct an algorithm using pertinent seminal data as well as easily obtained historical data to predict pregnancy and viable pregnancy rates., Design: A retrospective study of 544 cycles in 376 couples., Setting: A private IVF-ET and GIFT center., Patients: Couples in a GIFT program with a mean of 53.6 months of infertility who had failed to conceive with other therapies., Interventions: Gamete intrafallopian transfer., Main Outcome Measures: Pregnancy as a function of laboratory historical data with emphasis on seminal parameters., Results: Motility was the only seminal parameter that was predictive. Success was correlated with the number of oocytes returned and inversely related to female age. An algorithm to predict pregnancy in a GIFT cycle as well as viable pregnancy was constructed., Conclusions: Motility is the only seminal parameter predictive for success in a GIFT cycle. An easily programmable algorithm can be constructed to help patient and physician decide on the appropriateness of GIFT for each couple.

Objective: To evaluate the effect of gonadotropin-releasing hormone agonist (GnRH-a) when given through stimulation with gonadotropins versus stopping it as stimulation was initiated versus a control group unprepared in this manner. Also, to construct a cost analysis for this type of therapy in an in vitro fertilization-gamete intrafallopian transfer program (IVF-GIFT)., Design: Prospective, consecutive, randomized, with a control group., Setting: An out-patient IVF-GIFT program., Patients: One hundred new patients entering an IVF-GIFT program., Interventions: In vitro fertilization or GIFT cycles with or without preparation (pituitary suppression) by GnRH-a administration in which suppression was continued or halted as gonadotropins were begun., Main Outcome Measures: Cancellation rates, ampules, and days of gonadotropin use, costs, estradiol (E2) level, egg numbers and quality, and pregnancy rates., Results: Stopping GnRH-a (leuprolide acetate) therapy as stimulation was begun did not lessen the suppressive effect in reduction of spontaneous luteinizing hormone surge as seen with continued use of agonist. In contrast, the control group had a 30.3% cancellation rate before ovum retrieval. The E2 and egg data among the groups were similar, but as expected, agonist use led to the need for more and longer duration of gonadotropin stimulation. Pregnancy rates were not different by group. Costs were approximately even by the third initiated cycle.

Gamete intrafallopian transfer (GIFT) was performed on 77 women with endometriosis in 92 cycles with or without concomitant laser therapy or electrofulguration of endometriosis. The pregnancy rates were 45% for laser cases, 25% for electrofulguration cases and 36.4% for GIFT only. The pregnancy rate for stage III endometriosis was 53% versus 14% and 47% for stages II and I, respectively. Although there was a trend toward an increased pregnancy yield with active therapy, no statistically significant difference was achieved. The postoperative fecundity in patients not conceiving with GIFT was poor for all the groups.

Two centers combined data on 152 in vitro fertilization embryo replacement and 90 gamete intrafallopian transfer generated pregnancies. The outcomes of the pregnancies with respect to abortion, ectopic gestation, and multiple gestation were evaluated independently by method and by center. Only with multiple gestation by center was a difference seen. Variables examined included estradiol levels, luteal phase support, maternal age, and prior reproductive history, and the number of eggs or embryos replaced.

There are specific indications for the use of clomiphene. When used with the simple precautions that have been outlined, it is a safe, relatively inexpensive and convenient method of ovulation induction. Clomiphene certainly deserves its prominent place in the treatment of the infertile woman.

This chapter presents information on the indications for the use of post menopausal hormone therapy. Side effects and risks of this form of therapy are also summarized. Recommendations are made concerning the clinical management of patients receiving hormone treatment.