Background The post-treatment quality of life (QOL) impacts of receiving pre-cancer-treatment infertility counseling and of pursuing fertility preservation have not been described in large-scale studies of reproductive age women with cancer. Methods 1041 women diagnosed between the ages of 18 and 40 responded to a retrospective survey and reported whether they received infertility counseling before cancer treatment and whether they took action to preserve fertility. Five cancer types were included: leukemia, Hodgkin’s disease, non-Hodgkin lymphoma, breast cancer, and gastrointestinal cancer. Validated QOL scales were used: Decision Regret Score (DRS), Satisfaction with Life Scale (SWLS), and World Health Organization QOL BREF (WHOQOL-BREF). Results 560 women (61%) whose treatment could affect fertility were counseled by the oncology team, 45 (5%) were counseled by fertility specialists, 36 (4%) took action to preserve fertility. Pre-treatment infertility counseling by a fertility specialist and an oncologist resulted in lower regret than counseling by an oncologist alone (8.4 vs. 11.0, P<0.0001). The addition of fertility preservation (6.6 vs. 11.0, P<0.0001) was also associated with even lower regret scores than counseling by an oncologist alone.. Further improvements were similarly seen in SWLS with the addition of fertility specialist counseling (23.0 vs. 19.8, P=0.09) or preserving fertility (24.0 vs. 19.0, P=0.05). Conclusions Receiving specialized counseling about reproductive loss and pursuing fertility preservation is associated with less regret and greater QOL for survivors, yet few patients are exposed to this potential benefit. Reproductive aged women should have expert counseling and be given the opportunity to make active decisions about preserving fertility.

PURPOSE In the HER2CLIMB study, patients with human epidermal growth factor receptor 2 (HER2)–positive breast cancer with brain metastases (BMs) showed statistically significant improvement in progression-free survival (PFS) with tucatinib. We describe exploratory analyses of intracranial efficacy and survival in participants with BMs. PATIENTS AND METHODS Patients were randomly assigned 2:1 to tucatinib or placebo, in combination with trastuzumab and capecitabine. All patients underwent baseline brain magnetic resonance imaging; those with BMs were classified as active or stable. Efficacy analyses were performed by applying RECIST 1.1 criteria to CNS target lesions by investigator assessment. CNS-PFS (intracranial progression or death) and overall survival (OS) were evaluated in all patients with BMs. Confirmed intracranial objective response rate (ORR-IC) was evaluated in patients with measurable intracranial disease. RESULTS There were 291 patients with BMs: 198 (48%) in the tucatinib arm and 93 (46%) in the control arm. The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (hazard ratio [HR], 0.32; 95% CI, 0.22 to 0.48; P < .0001). Median CNS-PFS was 9.9 months in the tucatinib arm versus 4.2 months in the control arm. Risk of death was reduced by 42% in the tucatinib arm (OS HR, 0.58; 95% CI, 0.40 to 0.85; P = .005). Median OS was 18.1 versus 12.0 months. ORR-IC was higher in the tucatinib arm (47.3%; 95% CI, 33.7% to 61.2%) versus the control arm (20.0%; 95% CI, 5.7% to 43.7%; P = .03). CONCLUSION In patients with HER2-positive breast cancer with BMs, the addition of tucatinib to trastuzumab and capecitabine doubled ORR-IC, reduced risk of intracranial progression or death by two thirds, and reduced risk of death by nearly half. To our knowledge, this is the first regimen to demonstrate improved antitumor activity against BMs in patients with HER2-positive breast cancer in a randomized, controlled trial.

Background Previous studies have independently validated the prognostic relevance of residual cancer burden (RCB) after neoadjuvant chemotherapy. We used results from several independent cohorts in a pooled patient-level analysis to evaluate the relationship of RCB with long-term prognosis across different phenotypic subtypes of breast cancer, to assess generalisability in a broad range of practice settings. MethodsIn this pooled analysis, 12 institutes and trials in Europe and the USA were identified by personal communications with site investigators. We obtained participant-level RCB results, and data on clinical and pathological stage, tumour subtype and grade, and treatment and follow-up in November, 2019, from patients (aged ≥18 years) with primary stage I-III breast cancer treated with neoadjuvant chemotherapy followed by surgery. We assessed the association between the continuous RCB score and the primary study outcome, event-free survival, using mixed-effects Cox models with the incorporation of random RCB and cohort effects to account for betweenstudy heterogeneity, and stratification to account for differences in baseline hazard across cancer subtypes defined by hormone receptor status and HER2 status. The association was further evaluated within each breast cancer subtype in multivariable analyses incorporating random RCB and cohort effects and adjustments for age and pretreatment clinical T category, nodal status, and tumour grade. Kaplan-Meier estimates of event-free survival at 3, 5, and 10 years were computed for each RCB class within each subtype. FindingsWe analysed participant-level data from 5161 patients treated with neoadjuvant chemotherapy between Sept 12, 1994, and Feb 11, 2019. Median age was 49 years (IQR 20-80). 1164 event-free survival events occurred during follow-up (median follow-up 56 months [IQR 0-186]). RCB score was prognostic within each breast cancer subtype, with higher RCB score significantly associated with worse event-free survival. The univariable hazard ratio (HR) associated with one unit increase in RCB ranged from 1•55 (95% CI 1•41-1•71) for hormone receptor-positive, HER2-negative patients to 2•16 (1•79-2•61) for the hormone receptor-negative, HER2-positive group (with or without HER2-targeted therapy; p<0•0001 for all subtypes). RCB score remained prognostic for eventfree survival in multivariable models adjusted for age, grade, T category, and nodal status at baseline: the adjusted HR ranged from 1•52 (1•36-1•69) in the hormone receptor-positive, HER2-negative group to 2•09 (1•73-2•53) in the hormone receptor-negative, HER2-positive group (p<0•0001 for all subtypes).Interpretation RCB score and class were independently prognostic in all subtypes of breast cancer, and generalisable to multiple practice settings. Although variability in hormone receptor subtype definitions and treatment across patients are likely to affect prognostic performance, the association we observed between RCB and a patient's residual risk suggests that prospective evaluation of RCB could be c...

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Background: I-SPY 2 is a multicenter, phase 2 screening trial using adaptive randomization within biomarker subtypes to evaluate a series of novel agents/combinations when added to standard neoadjuvant therapy (paclitaxel q wk x 12, doxorubicin & cyclophosphamide q 2-3 wk x 4, T/AC) vs. T/AC (control arm) for women with high-risk stage II/III breast cancer. The primary endpoint is pathologic complete response (pCR) at surgery. Our goal is to identify/graduate regimens that have ≥85% Bayesian predictive probability of success (statistical significance) in a 300-patient biomarker-linked Phase 3 neoadjuvant trial. Experimental regimens can "graduate" in at least 1 of 10 possible signatures defined by hormone-receptor (HR) & HER2 status & MammaPrint (MP), with a maximum number of 120 total patients enrolled. We report final efficacy results of the oral PARP inhibitor veliparib (V, ABT-888) in combination with carboplatin (carbo), 1 of 7 experimental regimens evaluated in the trial to date. Methods: Women with tumors ≥2.5 cm by clinical exam and ≥2 cm by imaging are eligible for screening. Tumors that are MP low/HR+/HER2-are ineligible for randomization. MRI scans (baseline, 3 weeks after start of therapy, at completion of weekly T, and prior to surgery) were used in a longitudinal statistical model to improve the efficiency of adaptive randomization. V+carbo was assigned to HER2-tumors only, which limits its possible signatures to: all HER2-, HR+/HER2-, HR-/HER2-. For these 3 signatures we provide estimated pCR rates with associated 95% Bayesian probability intervals for V+carbo and concurrently randomized controls. Analysis is intent to treat with patients who switched to non-protocol therapy regarded as non-pCRs. For each signature we provide probabilities of superiority for V+carbo over control and Bayesian predictive probabilities of success in a neoadjuvant Phase 3 trial equally randomized between V+carbo and control. Results: When V+carbo met the 85% predictive probability criterion in HR-/HER2-and all HER2-, this regimen graduated and accrual to V+carbo was stopped. V+carbo was assigned to 72 patients, and there were 62 concurrently randomized controls (44 HER2-controls). The following table shows final results based on available pCR information. Two patients assigned to V+carbo withdrew consent during treatment and are not included in the table.

Fertility preservation with OS can be performed in the neoadjuvant setting without delay in initiation of systemic therapy and should be discussed with all early-stage BC patients of reproductive age.

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Background: Patients achieving a pathologic complete response (pCR) following neoadjuvant therapy have significantly improved event-free survival relative to those who do not; and pCR is an FDA-accepted endpoint to support accelerated approval of novel agents/combinations in the neoadjuvant treatment of high risk early stage breast cancer. Previous studies have shown that recurrence risk increased with increasing burden of residual disease (as assessed by the RCB index). As well, these studies suggest that patients with minimum residual disease (RCB-I class) also have favorable outcomes (comparable to those achieving a pCR) within high risk tumor subtypes. In this study, we assess whether integrating RCB with MRI functional tumor volume (FTV), which in itself is prognostic, can improve prediction of distant recurrence free survival (DRFS); and identify a subset of patients with minimal residual disease with comparable DRFS as those who achieved a pCR. Imaging tools can then be used to identify the subset that will do well early and guide the timing of surgical therapy. Method: We performed a pooled analysis of 596 patients from the I-SPY2 TRIAL with RCB, pre-surgical MRI FTV data and known follow-up (median 2.5 years). We first assessed whether FTV predicts residual disease (pCR or pCR/RCB-I) using ROC analysis. We applied a power transformation to normalize the pre-surgical FTV distribution; and assessed its association with DRFS using a bi-variate Cox proportional hazard model adjusting for HR/HER2 subtype. We also fitted a bivariate Cox model of RCB index adjusting for subtype; and assessed whether adding pre-surgical FTV to this model further improves association with DRFS using a likelihood ratio (LR) test. For the Cox modeling, penalized splines approximation of the transformed FTV and RCB index with 2 degrees of freedom was used to allow for non-linear effects of FTV and RCB on DRFS. Result: Pre-surgical MRI FTV is significantly associated with DRFS (Wald p&lt;0.00001), and more effective at predicting pCR/RCB-I than predicting pCR alone (AUC: 0.72 vs. 0.65). Larger pre-surgical FTV remains associated with worse DRFS adjusting for subtype (Wald p &lt;0.00001). The RCB index is also significantly associated with DRFS adjusting for subtype (Wald p&lt;0.00001). Adding FTV to a model containing RCB and subtype further improves association with DRFS (LR p=0.0007). RCB-I patients have excellent DRFS (94% at 3 years compared to 95% in the pCR group). Efforts are underway to identify an optimal threshold for dichotomizing pre-surgical FTV and FTV change measures for use in combination with pCR/RCB-I class to generate integrated RCB (iRCB) groups as a composite predictor of DRFS. Conclusion: Pre-surgical MRI FTV is effective at predicting minimal residual disease (RCB0/I) in the I-SPY 2 TRIAL. Despite the association between FTV and RCB, FTV appears to provide independent added prognostic value (to RCB and subtype), suggesting that integrating MRI volume measures and RCB into a composite predictor may improve DRFS prediction. Citation Format: Hylton NM, Symmans WF, Yau C, Li W, Hatzis C, Isaacs C, Albain KS, Chen Y-Y, Krings G, Wei S, Harada S, Datnow B, Fadare O, Klein M, Pambuccian S, Chen B, Adamson K, Sams S, Mhawech-Fauceglia P, Magliocco A, Feldman M, Rendi M, Sattar H, Zeck J, Ocal I, Tawfik O, Grasso LeBeau L, Sahoo S, Vinh T, Yang S, Adams A, Chien AJ, Ferero-Torres A, Stringer-Reasor E, Wallace A, Boughey JC, Ellis ED, Elias AD, Lang JE, Lu J, Han HS, Clark AS, Korde L, Nanda R, Northfelt DW, Khan QJ, Viscusi RK, Euhus DM, Edmiston KK, Chui SY, Kemmer K, Wood WC, Park JW, Liu MC, Olopade O, Tripathy D, Moulder SL, Rugo HS, Schwab R, Lo S, Helsten T, Beckwith H, Haugen PK, van't Veer LJ, Perlmutter J, Melisko ME, Wilson A, Peterson G, Asare AL, Buxton MB, Paoloni M, Clennell JL, Hirst GL, Singhrao R, Steeg K, Matthews JB, Sanil A, Berry SM, Abe H, Wolverton D, Crane EP, Ward KA, Nelson M, Niell BL, Oh K, Brandt KR, Bang DH, Ojeda-Fournier H, Eghtedari M, Sheth PA, Bernreuter WK, Umphrey H, Rosen MA, Dogan B, Yang W, Joe B, I-SPY 2 TRIAL Consortium, Yee D, Pusztai L, DeMichele A, Asare SM, Berry DA, Esserman LJ. Refining neoadjuvant predictors of three year distant metastasis free survival: Integrating volume change as measured by MRI with residual cancer burden [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-07-03.