Impact of Hormone Receptor Status and Tumor Subtypes of Breast Cancer in Young BRCA Carriers.

BACKGROUND: Hormone receptor expression is a known positive prognostic and predictive factor in breast cancer; however, limited evidence exists on its impact on prognosis of young patients harboring BRCA pathogenic variant (PV). PATIENTS AND METHODS: This international, multicenter, retrospective cohort study included young patients (≤40 years) diagnosed with invasive breast cancer and harboring germline PV in BRCA genes. We investigated the impact of hormone receptor status on clinical behavior and outcomes of breast cancer. Outcomes of interest (disease-free survival [DFS], breast cancer specific survival [BCSS] and overall survival [OS]) were first investigated according to hormone receptors expression (positive vs. negative), and then according to breast cancer subtype (luminal A-like vs. luminal B-like vs. triple-negative vs. HER2-positive breast cancer). RESULTS: From 78 centers worldwide, 4,709 BRCA carriers were included, of whom 2,143 (45.5%) had hormone receptor-positive and 2,566 (54.5%) hormone receptor-negative breast cancer. Median follow-up was 7.9 years. The rate of distant recurrences was higher in patients with hormone receptor-positive disease (13.1% vs. 9.6%, p<0.001), while the rate of second primary breast cancer was lower (9.1% vs. 14.7%, p<0.001) compared to patients with hormone receptor-negative disease. The 8-years DFS was 65.8% and 63.4% in patients with hormone receptor-positive and negative disease, respectively. The hazard ratio of hormone receptor-positive vs. negative disease changed over time for DFS, BCSS, and OS (p<0.05 for interactions of hormone receptor status and survival time). Patients with luminal A-like breast cancer had the worst long-term prognosis in terms of DFS compared to all the other subgroups (8-years DFS: 60.8% in luminal A-like vs. 63.5% in triple-negative vs. 65.5% in HER2-positive and 69.7% in luminal B-like subtype). CONCLUSIONS: In young BRCA carriers, differences in recurrence pattern and second primary breast cancer among hormone receptor-positive vs. negative disease warrants consideration in counseling patients on treatment, follow-up, and risk-reducing surgery.

Prognostic value of tumor-infiltrating lymphocytes in patients with early-stage triple-negative breast cancers (TNBC) who did not receive adjuvant chemotherapy.

BACKGROUND: Although stromal tumor-infiltrating lymphocytes (sTILs) have been considered an important prognostic factor in early-stage triple-negative breast cancer (TNBC), there have been limited data on their prognostic value in the absence of adjuvant chemotherapy. PATIENTS AND METHODS: A pooled analysis was carried out using four cohorts of TNBC patients not treated with chemotherapy. sTILs were evaluated in the most representative tumoral block of surgical specimens. Cox proportional hazards regression models were used for invasive disease-free survival (iDFS), distant disease-free survival (D-DFS), and overall survival (OS), fitting sTILs as a continuous variable adjusted for clinicopathologic factors. RESULTS: We analyzed individual data of 476 patients from 4 centers diagnosed between 1989 and 2015. Their median age was 64 years. The median tumor size was 1.6 cm and 83% were node-negative. The median level of sTILs was 10% (Q1-Q3, 4%-30%). Higher grade was associated with higher sTILs (P < 10-3). During follow-up, 107 deaths, and 173 and 118 events for iDFS and D-DFS were observed, respectively. In the multivariable analysis, sTILs obtained an independent prognostic value for all end points (likelihood ratio χ2 = 7.14 for iDFS; P < 10-2; χ2 = 9.63 for D-DFS, P < 10-2; χ2 = 5.96 for OS, P = 0.015). Each 10% increment in sTILs corresponded to a hazard ratio of 0.90 [95% confidence interval (CI) 0.82 - 0.97] for iDFS, 0.86 (95% CI 0.77 - 0.95) for D-DFS, and 0.88 (95% CI 0.79 - 0.98) for OS, respectively. In patients with pathological stage I tumors with sTILs ≥30% (n = 74), 5-year iDFS was 91% (95% CI 84% to 96%), D-DFS was 97% (95% CI 93% to 100%), and OS was 98% (95% CI 95% to 100%). CONCLUSION: sTILs add important prognostic information in systemically untreated early-stage TNBC patients. Notably, sTILs can identify a subset of stage I TNBC patients with an excellent prognosis without adjuvant chemotherapy.

De-escalated therapy for HR+/HER2+ breast cancer patients with Ki67 response after 2-week letrozole: results of the PerELISA neoadjuvant study.

BACKGROUND: In human epidermal growth factor receptor 2 (HER2+) breast cancers, neoadjuvant trials of chemotherapy plus anti-HER2 treatment consistently showed lower pathologic complete response (pCR) rates in hormone receptor (HR) positive versus negative tumors. The PerELISA study was aimed to evaluate the efficacy of a de-escalated, chemotherapy-free neoadjuvant regimen in HR+/HER2+ breast cancer patients selected on the basis of Ki67 inhibition after 2-week letrozole. PATIENTS AND METHODS: PerELISA is a phase II, multicentric study for postmenopausal patients with HR+/HER2+ operable breast cancer. Patients received 2-week letrozole, and then underwent re-biopsy for Ki67 evaluation. Patients classified as molecular responders (Ki67 relative reduction >20% from baseline) continued letrozole and started trastuzumab-pertuzumab for five cycles. Patients classified as molecular non-responders started weekly paclitaxel for 13 weeks combined with trastuzumab-pertuzumab. Primary aim was breast and axillary pCR. According to a two-stage Simon's design, to reject the null hypothesis, at least 8/43 pCR had to be documented. RESULTS: Sixty-four patients were enrolled, 44 were classified as molecular responders. All these patients completed the assigned treatment with letrozole-trastuzumab-pertuzumab and underwent surgery. A pCR was observed in 9/44 cases (20.5%, 95% confidence interval 11.1% to 34.5%). Among molecular non-responders, 16/17 completed treatment and underwent surgery, with pCR observed in 81.3% of the cases. PAM50 intrinsic subtype was significantly associated with Ki67 response and pCR. Among molecular responders, the pCR rate was significantly higher in HER2-enriched than in other subtypes (45.5% versus 13.8%, P = 0.042). CONCLUSIONS: The primary end point of the study was met, by reaching the pre-specified pCRs. In patients selected using Ki67 reduction after short-term letrozole exposure, a meaningful pCR rate can be achieved without chemotherapy. PAM50 intrinsic subtyping further refines our ability to identify a subset of patients for whom chemotherapy might be spared. EUDRACT NUMBER: 2013-002662-40. CLINICALTRIALS.GOV IDENTIFIER: NCT02411344.

Association of tumor-infiltrating lymphocytes with distant disease-free survival in the ShortHER randomized adjuvant trial for patients with early HER2+ breast cancer.

BACKGROUND: There is the need to identify new prognostic markers to refine risk stratification for HER2-positive early breast cancer patients. The aim of this study was to evaluate the association of tumor-infiltrating lymphocytes (TILs) with distant disease-free survival (DDFS) in patients with HER2-positive early breast cancer enrolled in the ShortHER adjuvant trial which compared 9 weeks versus 1-year trastuzumab in addition to chemotherapy, and to test the interaction between TILs and treatment arm. PATIENTS AND METHODS: Stromal TILs were assessed for 866 cases on centralized hematoxylin and eosin-stained tumor slides. The association of TILs as 10% increments with DDFS was assessed with Cox models. Kaplan-Meier curves were estimated for patients with TILs ≥20% and TILs <20%. Median follow-up was 6.1 years. RESULTS: Median TILs was 5% (Q1-Q3 1%-15%). Increased TILs were independently associated with better DDFS in multivariable model [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.59-0.89, P = 0.006, for each 10% TILs increment]. Five years DDFS rates were 91.1% for patients with TILs <20% and 95.7% for patients with TILs ≥20% (P = 0.025). The association between 10% TILs increments and DDFS was significant for patients randomized to 9 weeks of trastuzumab (HR 0.60, 95% CI 0.41-0.88) but not for patients treated with 1 year of trastuzumab (HR 0.89, 95% CI 0.71-1.12; test for interaction P = 0.088). For patients with TILs <20%, the HR for the comparison between the short versus the long arm was 1.75 (95% CI 1.09-2.80, P=0.021); whereas, for patients with TILs ≥20% the HR for the comparison of short versus long arm was 0.23 (95% CI 0.05-1.09, P = 0.064), resulting in a significant interaction (P = 0.015). CONCLUSIONS: TILs are an independent prognostic factor for HER2-positive early breast cancer patients treated with adjuvant chemotherapy and trastuzumab and may refine the ability to identify patients at low risk of relapse eligible for de-escalated adjuvant therapy.

Prognostic implications of residual disease tumor-infiltrating lymphocytes and residual cancer burden in triple-negative breast cancer patients after neoadjuvant chemotherapy.

BACKGROUND: For primary triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NAC), higher pretreatment tumor-infiltrating lymphocytes (TILs) correlates with increased pathologic complete response (pCR) rates, and improved survival. We evaluated the added prognostic value of residual disease (RD) TILs to residual cancer burden (RCB) in predicting survival post-NAC. PATIENTS AND METHODS: We combined four TNBC NAC patient cohorts who did not achieve pCR. RD TILs were investigated for associations with recurrence-free survival (RFS), and overall survival (OS) using Cox models with stromal TILs as a continuous variable (per 10% increment). The likelihood ratio test was used to evaluate added prognostic value of RD TILs. RESULTS: A total of 375 RD TNBC samples were evaluable for TILs and RCB. The median age was 50 years, with 62% receiving anthracycline/taxane chemotherapy. The RCB class after NAC was 11%, 50%, and 39% for I, II, and III, respectively. The median RD TIL level was 20% (IQR 10-40). There was a positive correlation between RD TIL levels and CD8+ T-cell density (ρ = 0.41). TIL levels were significantly lower with increasing post-NAC tumor (P = 0.005), nodal stage (P = 0.032), but did not differ by RCB class (P = 0.84). Higher RD TILs were significantly associated with improved RFS (HR: 0.86; 95% CI 0.79-0.92; P < 0.001), and improved OS (HR: 0.87; 95% CI 0.80-0.94; P < 0.001), and remained significant predictors in multivariate analysis (RFS P = 0.032; OS P = 0.038 for OS). RD TILs added significant prognostic value to multivariate models including RCB class (P < 0.001 for RFS; P = 0.021 for OS). The positive prognostic effect of RD TILs significantly differed by RCB class for RFS (PInt=0.003) and OS (PInt=0.008) with a greater magnitude of positive effect observed for RCB class II than class III. CONCLUSIONS: TIL levels in TNBC RD are significantly associated with improved RFS and OS and add further prognostic information to RCB class, particularly in RCB class II.

Tumor-infiltrating lymphocytes and molecular response after neoadjuvant therapy for HR+/HER2- breast cancer: results from two prospective trials.

PURPOSE: The aim was to evaluate the role of tumor-infiltrating lymphocytes (TIL) in predicting molecular response after preoperative endocrine or cytotoxic treatment for HR+/HER2- patients who do not achieve a pathological complete response. METHODS: Stromal (Str) TIL were centrally evaluated on samples from diagnostic core-biopsies of HR+/HER2- patients included in two prospective randomized trials: the LETLOB trial (neoadjuvant endocrine-based treatment) and the GIOB trial (neoadjuvant chemotherapy-based treatment). Pre- and post-treatment Ki67 was centrally assessed. RESULTS: StrTIL were evaluable in 111 cases (n = 73 from the LETLOB trial and n = 38 from the GIOB trial). Median StrTIL was 2%. Patients with high StrTIL (StrTIL ≥10%, n = 28) had more frequently breast cancer of ductal histology (p = 0.02), high grade (p = 0.049), and high Ki67 (p = 0.02). After neoadjuvant endocrine treatment (LETLOB cohort), a significant Ki67 suppression (p < 0.01) from pre- to post-treatment was observed in both the low and high StrTIL groups. High StrTIL patients achieve more frequently a relative Ki67 suppression ≥50% from baseline as compared to low StrTIL patients (55 vs. 35%, p non significant). After neoadjuvant chemotherapy (GIOB cohort), a significant Ki67 suppression was observed only for low StrTIL patients (Wilcoxon p = 0.001) and not in the high StrTIL group (p = 0.612). In this cohort, the rate of patients achieving a relative Ki67 suppression ≥50% from baseline was significantly higher in the low vs high StrTIL group (64% vs 10%, p = 0.003). Geometric mean Ki67 suppression was evaluated in each cohort according to StrTIL: the lowest value (-41%) was observed for high StrTIL cases treated with chemotherapy. CONCLUSIONS: This hypothesis-generating study suggests that in HR+/HER2- breast cancer StrTIL at baseline may influence the achievement of a molecular response after neoadjuvant treatment. Further evaluation in large studies is needed, and interaction with the type of treatment warrants to be explored.

Integrated evaluation of PAM50 subtypes and immune modulation of pCR in HER2-positive breast cancer patients treated with chemotherapy and HER2-targeted agents in the CherLOB trial.

BACKGROUND: The aim of this work was to evaluate the impact of (and relative contribution of) tumor-related and immune-related diversity of HER2-positive disease on the response to neoadjuvant chemotherapy plus anti-HER2 agents. PATIENTS AND METHODS: The CherLOB phase II study randomized 121 HER2-positive breast cancer patients to neoadjuvant chemotherapy plus trastuzumab, lapatinib or both. Tumor samples from diagnostic core biopsy were centralized. Tumor-infiltrating lymphocytes (TILs) were evaluated on H&E slides. Intrinsic subtyping was carried out using the research-based 50-gene prediction analysis of a microarray (PAM50) subtype predictor. Immune-related gene signatures were also evaluated. RESULTS: Continuous Str-TILs and It-TILs were significantly associated with pCR [OR 1.03, 95% CI 1.02-1.05 (P < 0.001) and OR 1.09, 95% CI 1.04-1.15 (P < 0.001) for Str-TILs and It-TILs, respectively]. According to PAM50, the subtype distribution was as follows: HER2-enriched 26.7%, Luminal A 25.6%, Luminal B 16.3%, Basal-like 14% and Normal-like 17.4%. The highest rate of pCR was observed for the HER2-enriched subtype (50%), followed by Basal-like, Luminal B and Luminal A (χ(2) test, P = 0.026). Immune gene signatures significantly associated with pCR in univariate analyses were identified: most of them maintained a significant association with pCR in multivariate analyses corrected for PAM50 subtypes, whereas TILs did not. CONCLUSIONS: In this study, both tumor-related and immune-related features contribute to the modulation of pCR after neoadjuvant chemotherapy plus anti-HER2 agents. Immune signatures rather than TILs added significant prediction of pCR beyond PAM50 intrinsic subtypes.

Immunoglobulin G fragment C receptor polymorphisms and efficacy of preoperative chemotherapy plus trastuzumab and lapatinib in HER2-positive breast cancer.

Lapatinib enhances antibody-dependent cell-mediated cytotoxicity (ADCC) activity of trastuzumab. FcγR polymorphisms have been associated with both ADCC and clinical activity of trastuzumab in HER2+ breast cancer (BC) patients (pts). We analyzed FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms in the CHER-LOB trial population of HER2+ BCs treated with preoperative chemotherapy plus trastuzumab (arm A), lapatinib (arm B) or both (arm C). Genotyping was successfully performed in 73/121 (60%) pts. A significant improvement in pathological complete response (pCR) rate was observed for the combination arm C, but only in FcγRIIIa V allele carriers (C vs A, 67 vs 27%, P=0.043; C vs B, 67 vs 22%, P=0.012). An independent interaction between arm C and FcγRIIIa V allele was found for pCR (odds ratio=9.4; 95% confidence interval, 2.3-39.6; P=0.003). No significant associations were observed between pCR and FcγRIIa polymorphism, and between pre-treatment tumor-infiltrating lymphocytes and FcγR polymorphisms. Our study provides evidence for a FcγRIIIa V allele-restricted pCR benefit from neoadjuvant trastuzumab plus lapatinib in HER2+ BC.

Prognostic and predictive value of tumor-infiltrating lymphocytes in two phase III randomized adjuvant breast cancer trials.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) are emerging as strong prognostic factor for early breast cancer patients, especially in the triple-negative subtype. Here, we aim to validate previous findings on the prognostic role of TIL in the context of two randomized adjuvant trials and to investigate whether lymphocyte infiltrates can predict benefit from adjuvant anthracyclines. PATIENTS AND METHODS: A total of 816 patients enrolled and treated at the Gustave Roussy in the context of two multicentric randomized trials comparing adjuvant anthracyclines versus no chemotherapy were included in the present analysis. Primary end point was overall survival (OS). Hematoxilin and eosin slides of primary tumors were retrieved and evaluated for the percentage of intratumoral (It) and stromal (Str) TIL. Each case was also defined as high-TIL or low-TIL breast cancer adopting previously validated cutoffs. RESULTS: TIL were assessable for 781 of 816 cases. High-TIL cases were more likely grade 3 and estrogen receptor (ER)-negative (P < 0.001). In multivariate analysis, both continuous It-TIL and Str-TIL were strong prognostic factors for OS [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77-0.95 P = 0.003; HR 0.89, 95% CI 0.81-0.96, P = 0.005 for It-TIL and Str-TIL, respectively]. The prognostic effect of continuous TIL was limited to triple-negative and HER2-positive patients. Ten-year OS rates were: 89% and 68% for triple-negative high-TIL and low-TIL, respectively (HR 0.44, 95% CI 0.18-1.10, P = 0.07) and 78% and 57% for HER2-positive high-TIL versus low-TIL, respectively (HR 0.46, 95% CI 0.20-1.11, P = 0.08). Either continuous or binary TIL variables did not predict for the efficacy of anthracyclines. Test for interaction P value was not significant in the whole study population and in subgroups (ER+/HER2-, HER2+, ER-/HER2-). CONCLUSIONS: We confirmed the prognostic role of TIL in triple-negative early breast cancer and suggested a prognostic impact in HER2+ patients as well. Basing on our data, TIL should not be used as a parameter to select patients for anthracyclines chemotherapy.

Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study.

BACKGROUND: There is a need to develop surrogates for treatment efficacy in the neoadjuvant setting to speed-up drug development and stratify patients according to outcome. Preclinical studies showed that chemotherapy induces an antitumor immune response. In order to develop new surrogates for drug efficacy, we assessed the prognostic value of tumor-infiltrating lymphocytes (TIL) on residual disease after neoadjuvant chemotherapy (NACT) in patients with triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Three hundred four TNBC patients with residual disease after NACT were retrospectively identified in three different hospitals. Hematoxylin and eosin-stained slides from surgical postchemotherapy specimens were evaluated for intratumoral (It-TIL) and stromal (Str-TIL) TIL. Cases were classified as High-TIL if It-TIL and/or Str-TIL >60%. RESULTS: TIL were assessable for 278 cases. Continuous It-TIL and Str-TIL variables were strong prognostic factors in the multivariate model, both for metastasis-free [hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.77-0.96, P = 0.01 and HR 0.85, 95% CI 0.75-0.98, P = 0.02 for Str-TIL and It-TIL, respectively] and overall survival (HR 0.86, 95% CI 0.77-0.97, P = 0.01 and HR 0.86, 95% CI 0.75-0.99, P = 0.03 for Str-TIL and It-TIL, respectively). The 5-year overall survival rate was 91% (95% CI 68% to 97%) for High-TIL patients (n = 27) and 55% (95% CI 48% to 61%) for Low-TIL patients (HR 0.19, 95% CI 0.06-0.61, log-rank P = 0.0017). The major prognostic impact of TIL was seen for patients with large tumor burden following NACT (residual tumor >2 cm and/or node metastasis). In all but one High-TIL case, It-TIL and Str-TIL values were lower on the prechemotherapy sample. CONCLUSIONS: The presence of TIL in residual disease after NACT is associated with better prognosis in TNBC patients. This parameter may represent a new surrogate of drug efficacy to test investigational agents in the neoadjuvant setting and a new prognostic marker to select patients at high risk of relapse.

Discordance in receptor status between primary and recurrent breast cancer has a prognostic impact: a single-institution analysis.

BACKGROUND: Tumor phenotype may change during breast cancer progression. This study evaluates the prognostic impact of receptor discordance between paired primaries and recurrences. PATIENTS AND METHODS: One hundred and thirty-nine patients underwent histological sampling of suspected breast cancer recurrence. All the pathology assessments [ER, PgR and human epidermal growth factor receptor 2 (HER2)] on both primaries and confirmed recurrences were performed at the same laboratory. RESULTS: A breast cancer recurrence was confirmed in 119 cases. Rates of discordance were 13.4%, 39% and 11.8% for ER, PgR and HER2, respectively. Ninety-two patients maintained the same tumor phenotype [i.e. the same hormone receptors (HR) and HER2 status], whereas 27 (22.7%) changed during progression. The loss of HR positivity and the loss of HER2 positivity resulted in a worse post-recurrence survival (P=0.01 and P=0.008, respectively) and overall survival (OS; P=0.06 and P=0.0002, respectively), compared with the corresponding concordant-positive cases. Tumor phenotype discordance was associated with worse post-recurrence and OS (P=0.006 and P=0.002, respectively); those cases who turned into triple-negative experienced the poorest outcome, respect to the concordant group (P=0.001, OS). CONCLUSIONS: We demonstrated for the first time an impact on OS of phenotype discordance between primary breast cancer and relapse. Among discordant cases, receptor loss resulted in the main determinant of poorer outcome.

Loss of HER2 positivity and prognosis after neoadjuvant therapy in HER2-positive breast cancer patients.

BACKGROUND: Emerging literature data are showing that a change in human epidermal growth factor receptor (HER2) status adversely affects breast cancer patient's prognosis. The aim of this study was to evaluate the prognostic impact of HER2 loss in patients with HER2-positive disease treated with neoadjuvant therapy with or without anti-HER2 agents. METHODS: One hundred and seven consecutive HER2-positive patients were identified from a prospectively maintained database. The first cohort includes 40 patients treated with chemotherapy (CT) alone. The second cohort includes 67 patients treated with neoadjuvant CT plus anti-HER2 agents (trastuzumab and/or lapatinib). HER2 expression was evaluated by immunihistochemistry or fluorescence in situ hybridization on pretreatment core biopsy and on surgical specimen after therapy. RESULTS: The rates of pathologic complete response (pCR) and breast-conserving surgery were higher in the CT + anti-HER2 cohort. A loss of HER2 expression was observed in 40% of the patients with residual disease after CT alone versus 14.7% of the patients after CT + anti-HER2 agents (P = 0.019). Patients not achieving a pCR have a significant increase in the risk of relapse when compared with those achieving a pCR (hazard ratio [HR] 9.55, P = 0.028). Patients with HER2 loss tended to have a higher risk of relapse as comparing to patients with maintained HER2 positivity (HR 2.41, P = 0.063). CONCLUSION: The pCR is confirmed as a powerful predictor of long-term outcome. The rate of HER2 loss is higher in patients receiving neoadjuvant CT without anti-HER2 agents. HER2 status on residual disease after preoperative therapy can be helpful in selecting patients at different risk of relapse, to be included in prospective trial exploring further adjuvant therapy.

Optimizing choices and sequences in the diagnostic-therapeutic landscape of advanced triple-negative breast cancer: An Italian consensus paper and critical review.

Triple-negative (TN) metastatic breast cancer (mBC) represents the most challenging scenario withing mBC framework, and it has been only slightly affected by the tremendous advancements in terms of drug availability and survival prolongation we have witnessed in the last years for advanced disease. However, although chemotherapy still represents the mainstay of TN mBC management, in the past years, several novel effective agents have been developed and made available in the clinical practice setting. Within this framework, a panel composed of a scientific board of 17 internationally recognized breast oncologists and 42 oncologists working within local spoke centers, addressed 26 high-priority statements, including grey areas, regarding the management of TN mBC. A structured methodology based on a modified Delphi approach to administer the survey and the Nominal Group Technique to capture perceptions and preferences on the management of TN mBC within the Italian Oncology community were adopted. The Panel produced a set of prioritized considerations/consensus statements reflecting the Panel position on diagnostic and staging approach, first-line and second-line treatments of PD-L1-positive/germline BRCA (gBRCA) wild-type, PD-L1-positive/gBRCA mutated, PD-L1-negative/gBRCA wild-type and PD-L1-negative/gBRCA mutated TN mBC. The Panel critically and comprehensively discussed the most relevant and/or unexpected results and put forward possible interpretations for statements not reaching the consensus threshold.

Major advancements in metastatic breast cancer treatment: when expanding options means prolonging survival.

In the last years we have witnessed tremendous advancements in the treatment landscape of metastatic breast cancer (MBC), leading to a progressive prolongation of progression-free survival and, in some cases, also of overall survival. This led to a substantial increase of advanced disease treatability. In the present review we comprehensively and critically describe the most significant progresses in the therapeutic scenario of MBC according to BC subtype. In particular, we reviewed studies reporting practice-changing data in hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative, HER2-positive and triple-negative BC, with also a hint to BRCA-related tumors and the emerging HER2-low-positive category.

Survival after neoadjuvant therapy with trastuzumab-lapatinib and chemotherapy in patients with HER2-positive early breast cancer: a meta-analysis of randomized trials.

BACKGROUND: Studies testing the addition of lapatinib to neoadjuvant trastuzumab + chemotherapy reported an increase in pathologic complete response (pCR), with, nevertheless, discordant results in terms of survival, mainly due to suboptimal power. We here leverage the meta-analytic approach to resolve these inconsistencies. METHODS: We conducted a meta-analysis of randomized phase II/III studies testing lapatinib + trastuzumab in combination with neoadjuvant chemotherapy for human epidermal growth factor receptor (HER2)-positive early breast cancer (BC). Recurrence-free survival (RFS) and overall survival (OS) were adopted as survival endpoints. Pooled hazard ratios (HR) were obtained for the effect of lapatinib + trastuzumab versus trastuzumab, pCR versus no-pCR in the whole study populations and pCR versus no-pCR according to hormone receptor status. RESULTS: Four phase II/III randomized trials were included in the meta-analysis (CALGB 40601, Cher-LOB, NSABP-B41, NeoALTTO) for an overall population of 1410 patients receiving neoadjuvant chemotherapy in association with either trastuzumab, lapatinib or their combination. RFS was significantly improved with dual HER2 blockade as compared to trastuzumab [HR 0.62, 95% confidence interval (CI) 0.46-0.85]. Dual blockade also led to significantly improved OS (HR 0.65, 95% CI 0.43-0.98). For all treatments combined, patients achieving pCR had better RFS and OS than those with residual disease (HR 0.45, 95% CI 0.34-0.60, and HR 0.32, 95% CI 0.22-0.48, for RFS and OS, respectively). In patients with hormone receptor-negative tumors, pCR was associated with 65% and 73% relative reduction of risk of relapse and death, respectively. Patients with hormone receptor-positive tumors also experienced improved RFS if they achieved pCR; however, the benefit was smaller than that in hormone receptor-negative disease. CONCLUSION: Findings from this meta-analysis further validate the role of pCR as a strong predictor of outcome in patients with HER2-positive BC, especially in hormone receptor-negative disease. Moreover, we provide robust evidence that dual blockade with lapatinib + trastuzumab in combination with neoadjuvant chemotherapy prolongs OS, suggesting that the role of lapatinib could be reconsidered in the early setting.

Safety of assisted reproductive techniques in young women harboring germline pathogenic variants in BRCA1/2 with a pregnancy after prior history of breast cancer.

BACKGROUND: Knowledge is growing on the safety of assisted reproductive techniques (ART) in cancer survivors. No data exist, however, for the specific population of breast cancer patients harboring germline BRCA1/2 pathogenic variants. PATIENTS AND METHODS: This is a multicenter retrospective cohort study across 30 centers worldwide including women diagnosed at ≤40 years with stage I-III breast cancer, between January 2000 and December 2012, harboring known germline BRCA1/2 pathogenic variants. Patients included in this analysis had a post-treatment pregnancy either achieved through use of ART (ART group) or naturally (non-ART group). ART procedures included ovulation induction, ovarian stimulation for in vitro fertilization or intracytoplasmic sperm injection, and embryo transfer under hormonal replacement therapy. RESULTS: Among the 1424 patients registered in the study, 168 were eligible for inclusion in the present analysis, of whom 22 were in the ART group and 146 in the non-ART group. Survivors in the ART group conceived at an older age compared with those in the non-ART group (median age: 39.7 versus 35.4 years, respectively). Women in the ART group experienced more delivery complications compared with those in the non-ART group (22.1% versus 4.1%, respectively). No other apparent differences in obstetrical outcomes were observed between cohorts. The median follow-up from pregnancy was 3.4 years (range: 0.8-8.6 years) in the ART group and 5.0 years (range: 0.8-17.6 years) in the non-ART group. Two patients (9.1%) in the ART group experienced a disease-free survival event (specifically, a locoregional recurrence) compared with 40 patients (27.4%) in the non-ART group. In the ART group, no patients deceased compared with 10 patients (6.9%) in the non-ART group. CONCLUSION: This study provides encouraging safety data on the use of ART in breast cancer survivors harboring germline pathogenic variants in BRCA1/2, when natural conception fails or when they opt for ART in order to carry out preimplantation genetic testing.