Annals of Oncology最新文献

Background: The use of first-line poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is increasing in advanced ovarian cancer. Understanding the efficacy of first subsequent therapy (FST) in patients experiencing disease progression in the first-line setting is important to optimize postprogression treatments. We evaluated the efficacy of FST in patients from PAOLA-1/ENGOT-ov25 (NCT02477644) who received first-line olaparib maintenance.

Patients and methods: This post hoc analysis evaluated the efficacy of subsequent chemotherapy following disease progression by assessing time from FST to second subsequent therapy (SST) according to whether progression occurred during versus after first-line olaparib maintenance and FST type. A multivariate Cox model was used in the olaparib plus bevacizumab arm to identify prognostic factors influencing the efficacy of subsequent chemotherapy.

Results: Of 806 randomized patients, 544 (67.5%) progressed and received subsequent chemotherapy. The median time from FST to SST was shorter in patients in the olaparib plus bevacizumab arm who progressed during first-line olaparib maintenance (6.1 months) than in those who progressed after first-line olaparib maintenance (11.4 months). Multivariate analysis indicated that progression after (versus during) first-line olaparib maintenance influenced time from FST to SST (hazard ratio 0.65, 95% confidence interval 0.50-0.84; P = 0.0011) independently of platinum-free interval or clinical risk. Among patients who progressed and received platinum-based chemotherapy with a PARP inhibitor as FST, the efficacy of subsequent therapies was also dependent on whether progression occurred during versus after first-line olaparib maintenance.

Conclusions: These results suggest that the timing of disease progression relative to first-line olaparib maintenance may impact the efficacy of subsequent platinum-based chemotherapy. Although results should be interpreted with caution, across all subgroups, including patients who received platinum-based chemotherapy with PARP inhibitor rechallenge as FST, the median time from FST to SST was longer if progression occurred after versus during first-line olaparib maintenance.

Estrogens have been associated with an increase in breast cancer risk. Yet emerging clinical and experimental evidence points to progestogens [endogenous progesterone or synthetic progesterone (progestin)] as the primary hormonal driver underlying seemingly estrogen-associated breast cancer risk. Estrogens may contribute to breast cancer risk indirectly by induction of the progesterone receptor and thus amplifying progesterone signaling. Large studies of hormonal contraceptives suggest that the small increase in breast cancer risk from hormonal contraceptives is mainly attributable to progestins, not estrogens. Estrogen-plus-progestin hormone replacement therapy (HRT) has consistently shown an increase in breast cancer risk among postmenopausal women, whereas estrogen-alone HRT has little impact on breast cancer risk in naturally or surgically menopausal women. In particular, the long-term follow-up of the Women's Health Initiative (WHI) randomized trials suggests a benefit of estrogen alone. Recent data further indicate that endogenously elevated estrogen during assisted reproductive technology (ART) exhibits little adverse effect on or potentially a reduction in breast cancer risk and recurrence. Also, accumulating evidence suggests that inhibition of progesterone signaling is a critical mechanism underlying the risk-reducing and therapeutic effects of antiestrogens. Estrogen HRT has shown an array of proven benefits, including ameliorating menopausal symptoms and improving bone health. Collective evidence thus suggests that estrogen HRT is likely to offer health benefits to perimenopausal or postmenopausal women, including breast cancer survivors, as well as young BRCA1/2 carriers with prophylactic oophorectomy for ovarian cancer prevention.

Background: Hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative 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-negative EBC in eight neoadjuvant arms in the I-SPY2 trial by clinical/molecular features: age, stage, histology, percentage estrogen receptor (ER) positivity, ER/progesterone receptor 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: Three hundred and seventy-nine patients with HR+/HER2-negative 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.

Conclusions: Among patients with high molecular-risk HR+/HER2-negative 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.