Distant Disease-free Interval Research Articles

Abstract P4-07-25: Distant metastasis of breast cancer is triggered by changes in the dynamics of metastatic cells after removal of the primary lesion

Abstract PURPOSE Breast cancer subtype influences the dynamics of distant recurrence. We investigated the timing of distant recurrence (distant disease-free interval DDFI) for each subtype and its relationship to stage, and perioperative treatment. PATIENTS AND METHODS We retrospectively analyzed data from 4,658 patients with stage I-III invasive breast cancer operated at Tokyo Metropolitan Komagome Hospital from 1998 to 2018. Patients were classified into five biological subtypes according to estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor 2 (HER2), and nuclear grade using immunohistochemistry findings: luminal A, luminal B/HER2-, luminal B/HER2+, HER2-enriched, Triple negative (TN). We investigated distant disease-free interval (DDFI) and analyzed the dynamics of distant metastasis. One-way analysis of variance was used to compare the recurrence patterns. RESULTS The median observation period was 6.3 years. Of the 4,051 patients for whom subtyping was possible, 422 developed distant recurrence. 5-year distant recurrence-free rates were 97.3% for luminal A, 86.8% for luminal B/HER2-, 89.1% for luminal B/HER2+, 84.6% for HER2-enriched, and 81 .7% for TN. In all subtypes, the recurrence rate increased with stage progression. The recurrence dynamics in luminal A showed a gradual peak at 3 years after starting treatment, after 5 years with more recurrences occurring than in other subtypes, especially late recurrences after 10 years. The median DDFI was 5.5 years (IQR 3.2-8.6 years). luminal B/HER2- and luminal B/HER2+ patients had similar recurrence dynamics, with peak recurrences at 2.4 and 2.3 years after starting treatment, respectively, followed by fewer recurrences over time, but recurrences were still observed after 5 years. Median DDFI was 3.1 years (IQR 1.9-5.9) and 2.9 years (IQR 1.9-5.9), respectively. HER2-enriched and TN showed similar recurrence dynamics, with a high peak of recurrence at 1.5 and 1.4 years, respectively, followed by a rapid decrease in recurrence and a rare recurrence after 5 years. The median DDFI was 1.8 years (IQR 1.1-2.5) and 1.6 years (IQR 1.1-2.9), respectively. When these recurrence dynamics were evaluated by stage for each subtype, the peak DDFI values for stage1, stage2, and stage3 were 3.4, 3.4, and 3.3 years for luminal A, 2.8, 2.7, and 2.1 years for luminal B/HER2-, 1.7, 2.2, and 2.6 years for luminal B/HER2+, 1.2,1.8, and 1.4 years for HER2-enriched, and 1.3,1.5, and 1.2 years for TN. There was no difference by stage for all subtypes (p=0.58, 0.25, 0.20, 0.74, and 0.26, respectively). Furthermore, the recurrence dynamics did not differ by the presence or absence of perioperative chemotherapy for each subtype (p=0.48, 0.31, 0.12, 0.34, and 0.09, respectively). Conclusion In all subtypes, distant metastasis incidence peaks between 1.5 and 3 years after surgery and then declines. The post-peak decline pattern showed characteristic dynamics for each subtype, but each peak in same subgroup was not associated with clinical stage or perioperative chemotherapy. Some kinds of the distant metastatic machinery may be caused by changes in the growth dynamics and microenvironment of distant cancer cells associated with primary tumor resection. Citation Format: Hiromi Tokisawa, Tomoyuki Aruga, Yayoi Honda, Toshiyuki Ishiba, Rika Yonekura, Naoko Iwamoto, Yuichi Kumaki. Distant metastasis of breast cancer is triggered by changes in the dynamics of metastatic cells after removal of the primary lesion [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-07-25.

Preliminary Results of Multi-Institutional Phase 1 Dose Escalation Trial Using Single-Fraction Stereotactic Partial Breast Irradiation for Early Stage Breast Cancer

We report on our early experience of our prospective multicenter phase 1 dose- escalation study of single-fraction stereotactic partial breast irradiation (S-PBI) for early stage breast cancer after partial mastectomy using a robotic stereotactic radiation system. Thirty women with in situ or invasive breast cancer stage 0, I, or II with tumor size <3 cm treated with lumpectomy were enrolled in this phase 1 single-fraction S-PBI dose-escalation trial. Women received either 22.5, 26.5, or 30 Gy in a single fraction using a robotic stereotactic radiation system. The primary outcome was to reach tumoricidal dose of 30 Gy in a single fraction to the lumpectomy cavity without exceeding the maximum tolerated dose. Secondary outcomes were to determine dose-limiting toxicity and cosmesis. Tertiary goals were ipsilateral breast recurrence rate, distant disease-free interval, recurrence-free survival, and overall survival. From June 2016 to January 2021, 11, 8, and 10 patients were treated to doses of 22.5, 26.5, or 30 Gy in a single fraction, respectively, with median follow-up being 47.9, 25.1, and 16.2 months. No patients experienced acute (<90 days) grade 3 or higher treatment-related toxicity, and maximum tolerated dose was not reached. There were 2 delayed grade 3 toxicities. Four patients (13.8%) developed fat necrosis across all 3 cohorts, which compares favorably with results from other PBI trials. No dose cohort had a statistically significant cosmetic detriment from baseline to 12 months or 24 months follow-up by patient- or physician-reported global cosmetic scores. There were no reports of disease recurrence. This phase 1 trial demonstrates that S-PBI can be used to safely escalate dose to 30 Gy in a single fraction with low toxicity and without detriment in cosmesis relative to baseline.

Abstract PD3-04: Prognostic role of distant disease-free interval from completion of adjuvant trastuzumab in HER2-positive early breast cancer: Analysis from the ALTTO (BIG 2-06) trial

Abstract Background: In HER2-positive breast cancer patients, timing from the end of (neo)adjuvant trastuzumab (T)-based therapy to diagnosis of metastatic breast cancer is the key factor in determining the optimal first-line treatment. There is currently lack of clear evidence to support the possible prognostic role of this interval and 12 months has been mostly empirically used. The present analysis aimed to investigate patterns of relapse, first-line choice and survival outcomes of patients with HER2-positive early breast cancer who relapsed after adjuvant T-based therapy depending on T-free interval (TFI, i.e. timing from end of adjuvant T to diagnosis of distant metastases). Methods: In ALTTO, HER2-positive early breast cancer patients were randomized to 1 year of either T alone, lapatinib (L) alone, their sequence (T–&amp;gt;L) or their combination (T+L). This exploratory analysis included only pts in the T or T+L arms who experienced a distant disease-free survival (DDFS) event. Two cohorts of patients were defined depending on TFI: group A (TFI of &amp;lt;12 months) and group B (&amp;gt;12 months). Baseline characteristics, patterns of relapse, first-line choice and overall survival (OS) were compared. OS was defined as time between date of DDFS event to death; age at diagnosis, tumor size and hormone receptor status were the variables included in the final multivariate models. Results: Out of 8,381 patients included in ALTTO, 404 patients in the T and T+L arms developed a DDFS event, of whom 201 occurred &amp;lt;12 months (group A) and 203 &amp;gt;12 months (group B) after the end of adjuvant T. Patients in group A were older (p=0.013), had larger tumors (p=0.004) and more frequently hormone receptor-negative disease (p&amp;lt;0.001). No significant difference in patterns of first DDFS event was observed (p=0.073); however, a numerically higher number of patients in group A compared to group B developed brain metastasis (26% vs. 15%). First-line anti-HER2 therapy was received by 57% of the patients. Choice of first-line anti-HER2 therapy was different between the two groups (p=0.022): the majority of patients received T in both groups (61% vs. 65% in groups A and B, respectively), while more patients in group A received L (25% vs. 11%) and less received pertuzumab (8% vs. 17%). OS survival was significantly shorter in group A compared to group B: median OS was 18.4 and 29.3 months in groups A and B, respectively (adjusted HR 0.69; 95% CI 0.54-0.89; p=0.004). Similar results were observed after the exclusion of patients treated with first-line pertuzumab-based therapy (n=29): median OS was 18.2 and 26.8 months in groups A and B, respectively (adjusted HR 0.66; 95% CI 0.51-0.86; p=0.002). Better outcomes in terms of OS for patients in group B was observed across all analyzed subgroups with no interaction according to hormone receptor status (p=0.814) nor type of adjuvant anti-HER2 treatment (p=0.233): hormone receptor-positive (adjusted HR 0.69; 95% CI 0.48-0.99), hormone receptor-negative (adjusted HR 0.68; 95% CI 0.48-0.98), T+L arm (adjusted HR 0.55; 95% CI 0.38-0.80) and T arm (adjusted HR 0.80; 95% CI 0.55-1.17). Conclusions: In the ALTTO trial, HER2-positive early breast cancer patients who experienced shorter TFI (i.e. &amp;lt;12 months vs. &amp;gt;12 months) following adjuvant T-based therapy had inferior OS after the diagnosis of distant recurrence. Given its prognostic value, TFI can help to individualize clinical recommendations and to design future trials in the metastatic setting for patients relapsing after prior exposure to anti-HER2 therapy for early disease. Citation Format: Matteo Lambertini, Dominique Agbor-Tarh, Otto Metzger-Filho, Noam Ponde, Francesca Poggio, Florentine Hilbers, Larissa A Korde, Saranya Chumsri, Olena Werner, Lucia Del Mastro, Rafael Caparica, Volker Moebus, Alvaro Moreno-Aspitia, Martine Piccart, Evandro de Azambuja. Prognostic role of distant disease-free interval from completion of adjuvant trastuzumab in HER2-positive early breast cancer: Analysis from the ALTTO (BIG 2-06) trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-04.

Breast cancer distant recurrence lead time interval by detection method in an institutional cohort

BackgroundLead time, the interval between screen detection and when a disease would have become clinically evident, has been cited to explain longer survival times in mammography detected breast cancer cases (BC).MethodsAn institutional retrospective cohort study of BC outcomes related to detection method (mammography (MamD) vs. patient (PtD)). Cases were first primary invasive stage I-III BC, age 40–74 years (n = 6603), 1999–2016. Survival time was divided into 1) distant disease-free interval (DDFI) and 2) distant disease-specific survival (DDSS) as two separate time interval outcomes. We measured statistical association between detection method and diagnostic, treatment and outcome variables using bivariate comparisons, Cox proportional hazards analyses and mean comparisons. Outcomes were distant recurrence (n = 422), DDFI and DDSS.Results39% of cases were PtD (n = 2566) and 61% were MamD (n = 4037). MamD cases had a higher percentage of Stage I tumors [MamD 69% stage I vs. PtD 31%, p < .001]. Rate of distant recurrence was 11% among PtD BC cases (n = 289) vs. 3% of MamD (n = 133) (p < .001). Order of factor entry into the distant recurrence time interval (DDFI) model was 1) TNM stage (p < .001), 2) HR/HER2 status (p < .001), 3) histologic grade (p = .005) and 4) detection method (p < .001). Unadjusted PtD DDFI mean time was 4.34 years and MamD 5.52 years (p < .001), however when stratified by stage, the most significant factor relative to distant recurrence, there was no significant difference between PtD and MamD BC. Distant disease specific survival time did not differ by detection method.ConclusionWe observed breast cancer distant disease-free interval to be primarily associated with stage at diagnosis and tumor characteristics with less contribution of detection method to the full model. Patient and mammography detected breast cancer mean lead time to distant recurrence differed significantly by detection method for all stages but not significantly within stage with no difference in time from distant recurrence to death. Lead time difference related to detection method appears to be present but may be less influential than other factors in distant disease-free and disease specific survival.

Results of laparoscopic resection in high-risk rectal cancer patients.

Obesity, neoadjuvant-radiotherapy, tumour proximity to the anal verge and previous abdominal surgery are factors that might increase the intra-operative difficulty of laparoscopic rectal cancer surgery. However, whether patients with these 'high-risk' characteristics are subject to worse short- or long-term outcomes is debated. The aim of this study is to examine the short- and long-term clinical and oncological outcomes of patients receiving laparoscopic rectal surgery with any of these high-risk characteristics and compare them with patients that do not possess any of these high-risk features. For the purpose of this study data from consecutive patients receiving laparoscopic rectal cancer resections between 2006 and 2016 from two centres were analysed. High-risk patients were defined as patients with either one of the following characteristics: BMI ≥ 30, neoadjuvant chemoradiotherapy, tumour < 8cm from the anal verge and previous abdominal surgery. A total of 313 patients were identified (227 high risk, 86 low risk). Short-term outcomes were similar between the two groups with the exception of blood loss and length of stay, which were higher in the high-risk group (10 vs 2.5ml, p = 0.045; 7 vs 5days, p = 0.001). There were no statistically significant differences in 5-year overall survival (79.7% vs 79.8%, p = 0.757), disease-free survival (76.8% vs 69.3%, p = 0.175), distant disease-free interval (84.8% vs 79.7%, p = 0.231) and local recurrence-free interval (100%, 97.4%, p = 0.162) between the two groups. Similar short- and long-term outcomes can be achieved in high-risk and low-risk patients receiving laparoscopic rectal surgery. The presented data support the suitability of laparoscopic surgery for this group of patients.

Prognostic role of distant disease-free interval from completion of adjuvant trastuzumab in HER2-positive early breast cancer: analysis from the ALTTO (BIG 2-06) trial

BackgroundIn HER2-positive breast cancer, time elapsed between completion of (neo)adjuvant trastuzumab and diagnosis of metastatic disease (‘trastuzumab-free interval’, TFI) is crucial to choose the optimal first-line treatment. Nevertheless, there is no clear evidence to support its possible prognostic role.MethodsIn the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) trial, patients with HER2-positive early breast cancer were randomised to 1 year of either trastuzumab alone, lapatinib alone, their sequence or their combination. This exploratory analysis included only patients in the trastuzumab alone or trastuzumab plus lapatinib arms who developed a distant disease-free survival (DDFS) event. Overall survival (OS) was defined as time between date of DDFS event and death; age at diagnosis, tumour size and hormone receptor status were the variables included in the multivariate models.ResultsOut of 8381 patients included in ALTTO, 404 patients in the trastuzumab alone and trastuzumab plus lapatinib arms developed a DDFS event, of which 201 occurred <12 months (group A) and 203 >12 months (group B) after completion of adjuvant trastuzumab. No significant difference in location of first DDFS event was observed (p=0.073); a numerically higher number of patients in group A than in group B developed brain metastasis (26% vs 15%). Choice of first-line therapy differed between the two groups (p=0.022): in group A, more patients received lapatinib (25% vs 11%) and less pertuzumab (8% vs 17%). Median OS was 29.3 and 18.4 months in groups B and A, respectively (adjusted HR 0.69; 95% CI 0.54–0.89; p=0.004). The longer OS for patients in group B was observed across the analysed subgroups without interaction according to hormone receptor status (p=0.814) nor type of administered adjuvant anti-HER2 treatment (p=0.233).ConclusionsTFI has prognostic value in patients with HER2-positive early breast cancer treated with adjuvant trastuzumab-based therapy. TFI is a valid tool to better individualise clinical recommendations and to design future first-line treatment trials for metastatic patients.

Hyperprogressive disease in advanced triple-negative breast cancer (aTNBC) treated with immunotherapy (IO).

1086 Background: Hyperprogression of disease (HPD), a rapid acceleration of tumor growth rate (TGR) has been reported with IO in other tumor types. Here, we explore HPD in aTNBC. Methods: A retrospective chart review identified aTNBC patients who consented for IO clinical trials at Princess Margaret Cancer Centre between June 2013 and June 2018. Demographic data, medical history, details of trial enrolment and RECIST 1.1 response to study treatment were recorded. Patients with RECIST 1.1 measurable disease on CT scans or physical examination before trial entry, at trial baseline and at protocol-defined interval following IO start were evaluable for TGR as defined by Champiat et al. Clin Cancer Res 2017. HPD defined as a ≥2-fold increase in TGR between baseline and on-trial restaging assessment. Univariable logistic regression used to identify variables [age, co-morbidity index, prognostic index, performance status, distant disease free interval (dDFI), lactate dehydrogenase, no. of metastatic sites, visceral disease and no. of prior treatment lines] associated with HPD. Overall survival (OS) curves were estimated with the Kaplan-Meier method and compared by the log-rank test. Results: 99 patients with aTNBC consented for 15 IO clinical trials, 60% IO monotherapy, 22% chemotherapy+/-IO and 18% IO combinations. Median age 52 (range 25-78), median no. of lines of prior systemic therapy for advanced disease 1 (range 0-8). 15% had de-novo metastatic disease, 58% recurred after a dDFI of &lt; 3 years and 25% after a dDFI of &gt; 3 years. 61% had &lt; 3 metastatic disease sites, and 71% had metastases involving the viscera. 66 received IO treatment, 40 patients (20 monotherapy, 7 IO combination, 13 chemotherapy+/-IO) were evaluable for TGR. Median TGR pre-IO was 74.3 (range -17 – 1680) and post-IO was 2.5 (-71.4 – 223). 4 patients (10%) met criteria for HPD. All 4 treated with monotherapy PD1 inhibitor and received at least 2 further lines of therapy post-trial; 1 patient treated with IO as first-line therapy, 3 in the second or later lines. There was no significant difference in the overall OS of patients with HPD and patients who did not meet definition for HPD HR 0.89, (95% CI: 0.26-3.01; p = 0.41). Univariable analysis did not identify factors associated with HPD. Conclusions: HPD was observed in 10% of aTNBC treated on IO clinical trials. HPD was not associated with worse survival outcomes or known prognostic factors in our analysis.

Abstract GS4-04: Primary results of NSABP B-39/RTOG 0413 (NRG Oncology): A randomized phase III study of conventional whole breast irradiation (WBI) versus partial breast irradiation (PBI) for women with stage 0, I, or II breast cancer

Abstract Background: Conventional WBI after lumpectomy for early-stage breast cancer decreases ipsilateral breast tumor recurrence (IBTR), yielding comparable results to mastectomy. Accelerated PBI appears effective in reducing IBTR by treating only the tumor bed area. As the majority of IBTR occur at or in the vicinity of the tumor bed, we hypothesized that PBI would be as effective as WBI in controlling IBTR. The primary aim of NSABP B-39/RTOG 0413 was to determine if PBI provides equivalent local tumor control post lumpectomy compared to WBI in pts with early-stage breast cancer. The equivalency test was based on a 50% margin of increase in the hazard ratio (HR=1.5). Secondary endpoints included: overall survival (OS), recurrence-free interval (RFI), distant disease-free interval (DDFI), and toxicity. Methods: Eligible pts had lumpectomy with histologically-free margins and 0-3 positive axillary nodes. Pts were stratified by stage, menopausal status, hormone receptor status, and intent to receive chemotherapy and then randomized to PBI or WBI. PBI was 10 fractions of 3.4-3.85 Gy, given twice daily with either brachytherapy or 3D external beam radiation. WBI was 50 Gy in 2 Gy fractions given daily with a sequential boost to the surgical cavity. Follow-up was every 6 mos for 5 yrs and then annually. All analyses were by intent-to-treat. Results: From 3-21-05 to 4-16-13, 4216 pts were randomized: 2107 PBI; 2109 WBI. 61% were postmenopausal; 81% were hormone receptor-positive; 29% intended to receive chemotherapy. Stage distribution was: DCIS, 24%; invasive pN0, 65%; invasive pN1, 10%. As of 7-31-18, median follow-up was 10.2 yrs. There were 161 IBTRs as first events: 90 PBI v 71 WBI (HR 1.22; 90%CI 0.94-1.58). Per protocol-defined margin, to declare PBI and WBI equivalent regarding IBTR risk, the 90% CI for the observed HR had to lie entirely between 0.667 and 1.5. The percent of pts IBTR-free at 10 yrs was 95.2% PBI v 95.9% WBI. A statistically significant difference in the 10-yr RFI rate favored WBI (91.9% PBI v 93.4% WBI; HR 1.32; 95%CI 1.04-1.68; p=0.02). No statistically significant differences existed between PBI and WBI in DDFI (HR 1.31; 95%CI 0.91-1.91; p=0.15), OS (HR 1.10; 95%CI 0.90-1.35; p=0.35), or DFS (HR 1.12; 95%CI 0.98-1.29; p=0.11). Grade 3 toxicity was 9.6% PBI v 7.1% WBI, and grade 4-5 toxicity was 0.5% v 0.3%, respectively. Discussion: PBI did not meet the criteria for equivalence to WBI in controlling IBTR based on the upper limit of the hazard ratio confidence interval. However, the absolute difference in 10-yr rate of IBTR was &amp;lt;1% (4.8% PBI v 4.1% WBI). The risk of an RFI event was statistically significantly higher for PBI compared to WBI, but the absolute difference in 10-yr RFI rate was also small (8.1% PBI v 6.6% WBI). DDFI, OS, and DFS were not statistically different for PBI v WBI. Grade 3-5 toxicities, although low, were more common for PBI than WBI. The trial population was heterogeneous, ranging from Stage 0-2 breast cancer, and outcome by risk categories are being analyzed. Support: U10CA180868, -180822, UG1CA189867. Citation Format: Vicini FA, Cecchini RS, White JR, Julian TB, Arthur DW, Rabinovitch RA, Kuske RR, Parda DS, Ganz PA, Scheier MF, Winter KA, Paik S, Kuerer HM, Vallow LA, Pierce LJ, Mamounas EP, Costantino JP, Bear HD, Germaine I, Gustafson G, Grossheim L, Petersen IA, Hudes RS, Curran, Jr. WJ, Wolmark N. Primary results of NSABP B-39/RTOG 0413 (NRG Oncology): A randomized phase III study of conventional whole breast irradiation (WBI) versus partial breast irradiation (PBI) for women with stage 0, I, or II breast cancer [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 GS4-04.

Triple-NOTE (Triple Negative Outcome in ESME): Large recent real-world prognostic data on triple negative metastatic breast cancers (mTNBC).

e12592 Background: During last decade, therapeutic arsenal has expanded for metastatic breast cancer (mBC), but few data are available about mTNBC, a poor prognosis subtype. In 2014, UNICANCER (composed of 18 French Comprehensive Cancer Centers) launched the Epidemiological Strategy and Medical Economics (ESME) program to centralize real-world data. This base represents a great opportunity to update the outcomes and the treatment practice patterns of this population. Methods: The ESME-mBC database was built from information systems, treatment databases and patients’ electronic files including quality control processes. All pts who initiated treatment for mBC between 01-Jan-2008 and 31-Dec-2014 were selected. The primary objective of this study was to assess overall survival (OS) of mTNBC pts. TNBC status was defined as ER and PR &lt; 10% in both primary and metastatic disease, as well as the absence of overexpression or amplification of HER2. The secondary objectives were to describe the characteristics of this population, clinical management (duration and sequence of treatments) and to evaluate the prognostic value of several clinical factors (age, distant disease free interval, location and number of metastatic sites) Results: Among 16703 pts in the ESME-mBC database, 2368 (14%) had mTNBC. Median OS over this time period was 14.8 months (95% CI 14-15.6). Median age at diagnosis of mBC was 57 years. For the pts who relapsed, median metastasis free interval was 24 months, while 25.5% of the pts were de novo metastatic. 61% of the pts presented visceral metastasis and 12% had cerebral metastasis as first metastatic site. The pattern of metastatic involvement (visceral and cerebral) and a short metastasis free interval ( &lt; 24 months) were the most important prognostic factors in multivariate analysis. The description of treatment sequences (duration, prognostic value) will be presented. Conclusions: In this real-life setting database, mTNBC remain of poor prognosis despite a trend for a better OS than the historical data available (12-13 ms). This TNBC ESME cohort is one of the largest available and offers an updated assessment of the outcomes of this population.

Abstract PD6-02: Local recurrence in young women with invasive breast cancer; the prospective study of outcomes in sporadic and hereditary breast cancer (POSH)

Abstract Aim To evaluate the surgical and clinical factors affecting local recurrence and other outcomes in young breast cancer patients using the POSH study. Background POSH (MREC:00/06/69) is a prospective cohort study of 3024 women aged 18-40 with breast cancer. Randomized controlled trials suggest equivalent survival between mastectomy and breast conserving surgery (BCS); however, very few young patients were included in these analyses. Emerging data also suggests a possible survival advantage for mastectomy in gene mutation carriers, and young age may be a predictor of higher rates of local recurrence. Methods Summary statistics were used to describe the cohort by surgical type (mastectomy or BCS). Study endpoints were in-breast ipsilateral local-recurrence interval, distant disease-free interval and overall survival. Cumulative hazard and Kaplan-Meier plots were used to describe survival data. Univariable and multivariable analyses were carried out using Cox proportional hazards models and flexible parametric survival (FPS) models (for any models with time-varying covariates). Results Of 2882 patients analysed, 1464 underwent mastectomy, 1395 BCS; and 23 had lymph node surgery only. Patients undergoing mastectomy had significantly larger tumours and higher proportions of positive Family History, positive estrogen receptor (ER+), progesterone receptor (PR+) and/or human epidermal growth factor 2 (HER2+) tumours. Local events only accounted for 15% of recurrences. Local recurrence varied over time by surgical type; local recurrence rate was similar at 18 months but higher for BCS compared to mastectomy at 5- and 10-years (18-months: 1.0% vs 1.0%, FPS-HR[95%CI]=1.43[0.89,2.32], p=0.348; 5-years: 5.3% vs 2.6%, FPS-HR[CI]=3.39[2.03,5.66], p&amp;lt;0.001; and 10-years: 11.7% vs 4.9%, FPS-HR[CI]=5.27[2.43,11.43], p&amp;lt;0.001, respectively). Similar results were found in the adjusted model and when restricting the analyses to patients with smaller tumours. Conversely, distant-metastases and death events were significantly lower for BCS but not after adjusting for prognostic factors. Chest-wall radiotherapy following mastectomy was associated with improved local recurrence interval (HR[CI]=0.46[0.24,0.86],p=0.015). Positive surgical margins, and the development of a local event, predicted for reduced distant disease free interval (HR[CI]=0.50[0.35,0.71],p&amp;lt;0.001; and 10-year FPS-HR[CI]=0.29[0.14,0.62],p=0.001, respectively). Conclusions In the short term, there is no difference in local recurrence between BCS and mastectomy in young women. Longer term, local recurrence is higher in BCS, but there is no difference in survival between surgical groups after adjusting for known prognostic factors. Surgical extent appears to be less important for distant relapse or death from breast cancer than completeness of excision or, where appropriate, chest-wall radiotherapy. Acknowledgements Data collection/analysis funded by CRUK (grants:A7572,A11699,C1275/A15956). Sponsored by UHS NHS Foundation Trust. Citation Format: Maishman T, Cutress RI, Hernandez A, Gerty S, Copson ER, Durcan L, Eccles DM. Local recurrence in young women with invasive breast cancer; the prospective study of outcomes in sporadic and hereditary breast cancer (POSH) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD6-02.

Local Recurrence and Breast Oncological Surgery in Young Women With Breast Cancer: The POSH Observational Cohort Study.

To assess clinical and surgical factors affecting local recurrence and survival in young breast cancer patients in the Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH). Emerging data suggest young age is a predictor of increased local recurrence. POSH is a prospective cohort of 3024 women of 18 to 40 years with breast cancer. Cohort characteristics were grouped by mastectomy or BCS. Endpoints were local-recurrence interval (LRI), distant disease-free interval (DDFI), and overall survival (OS); described using cumulative-hazard and Kaplan-Meier plots and multivariable analyses by Flexible Parametric and Cox regression models. Mastectomy was performed in 1464 patients and breast-conserving surgery (BCS) in 1395. Patients undergoing mastectomy had larger tumors and higher proportions of positive family history, estrogen receptor+, progesterone receptor+, and/or human epidermal growth factor receptor 2+ tumors. Local events accounted for 15% of recurrences. LRI by surgical type varied over time with LRI similar at 18 months (1.0% vs 1.0%, P = 0.348) but higher for BCS at 5 and 10 years (5.3% vs 2.6%, P < 0.001; and 11.7% vs 4.9%, P < 0.001, respectively). Similar results were found in the adjusted model. Conversely, distant-metastases and deaths were lower for BCS but not after adjusting for prognostic factors. After mastectomy chest-wall radiotherapy was associated with improved LRI (hazard ratio, HR = 0.46, P = 0.015). Positive surgical margins, and development of local recurrence predicted for reduced DDFI (HR = 0.50, P < 0.001; and HR = 0.29, P = 0.001, respectively). Surgical extent appears less important for DDFI than completeness of excision or, where appropriate, chest-wall radiotherapy. Despite higher local-recurrence rates for BCS, surgical type does not influence DDFI or OS after adjusting for known prognostic factors in young breast cancer patients.

Trastuzumab re-treatment following adjuvant trastuzumab and the importance of distant disease-free interval: the HERA trial experience.

This retrospective analysis conducted using data from patients enrolled onto the Herceptin Adjuvant has two objectives: The first is to evaluate the impact of the time interval between the end of adjuvant trastuzumab and distant recurrence (TDRI) upon overall survival (OS). The second is to describe the duration of trastuzumab-based regimens in the metastatic setting for patients previously treated with adjuvant trastuzumab. The first objective included 187 patients treated with adjuvant trastuzumab and diagnosed with distant recurrence at 4-year median follow-up. The second objective included data from questionnaires sent to investigators retreating patients with trastuzumab upon distant recurrence: 144 of 156 questionnaires were returned (93%), and 90 patients were selected based on available clinical information and consent for subsequent studies. There was no statistically significant relationship between TDRI following 1 year of adjuvant trastuzumab and OS from distant recurrence: hazard ratio 0.991, p=0.46. The median OS from distant recurrence was numerically longer among patients with a TDRI of ≥12months (n=103) than <12months (n=84) but not statistically significant (23.7 vs. 17.8months, p=0.47). The median duration of first-line trastuzumab-based regimens for patients previously treated with adjuvant trastuzumab and diagnosed with distant disease recurrence was 8.8months (n=88). This retrospective, exploratory study suggests that TDRI did not impact on OS measured from distant recurrence. We argue that prospective collection of treatment information beyond disease progression should be included in future clinical studies.

Obesity and the outcome of young breast cancer patients in the UK: the POSH study

BackgroundObese breast cancer patients have a poorer prognosis than non-obese patients. We examined data from a large prospective cohort study to explore the associations of obesity with tumour pathology, treatment and outcome in young British breast cancer patients receiving modern oncological treatments. Patients and methodsA total of 2956 patients aged ≤40 at breast cancer diagnosis were recruited from 126 UK hospitals from 2001 to 2007. Height and weight were measured at registration. Tumour pathology and treatment details were collected. Follow-up data were collected at 6, 12 months, and annually. ResultsA total of 2843 eligible patients (96.2%) had a body mass index (BMI) recorded: 1526 (53.7%) were under/healthy-weight (U/H, BMI <25 kg/m2), 784 (27.6%) were overweight (ov, BMI ≥25 to <30), and 533 (18.7%) were obese (ob, BMI ≥30). The median tumour size was significantly higher in obese and overweight patients than U/H patients (Ob 26mm versus U/H 20mm, P < 0.001; Ov 24mm versus U/H 20mm, P < 0.001). Obese and overweight patients had significantly more grade 3 tumours (63.9% versus 59.0%, P = 0.048; Ov 63.6% versus U/H 59.0% P = 0.034) and node-positive tumours (Ob 54.6% versus U/H 49.0%, P = 0.027; Ov 54.2% versus U/H 49%, P = 0.019) than U/H patients. Obese patients had more ER/PR/HER2-negative tumours than healthy-weight patients (25.0% versus 18.3%, P = 0.001). Eight-year overall survival (OS) and distant disease-free interval (DDFI) were significantly lower in obese patients than healthy-weight patients [OS: hazard ratio (HR) 1.65, P < 0.001; DDFI: HR 1.44, P < 0.001]. Multivariable analyses adjusting for tumour grade, size, nodal, and HER2 status indicated that obesity was a significant independent predictor of OS and DDFI in patients with ER-positive disease. ConclusionsYoung obese breast cancer patients present with adverse tumour characteristics. Despite adjustment for this, obesity still independently predicts DDFI and OS.

Correlation of BRAF and NRAS mutation status with outcome, site of distant metastasis and response to chemotherapy in metastatic melanoma.

Background:The prognostic significance of BRAF and NRAS mutations in metastatic melanoma patients remains uncertain, with several studies reporting conflicting results, often biased by the inclusion of patients treated with BRAF and MEK (MAPK) inhibitors. We therefore interrogated a historical cohort of patients free of the confounding influence of MAPK inhibitor therapy.Methods:Patients with available archival tissue first diagnosed with metastatic melanoma between 2002 and 2006 were analysed. Mutational analysis was performed using the OncoCarta Panel. Patient characteristics, treatment outcome and survival were correlated with BRAF/NRAS mutation status.Results:In 193 patients, 92 (48%) melanomas were BRAF-mutant, 39 (20%) were NRAS-mutant and 62 (32%) were wild-type for BRAF/NRAS mutations (wt). There was no difference in response to chemotherapy based on mutation status (35–37%). The distant disease-free interval (DDFI) was significantly shorter in patients with wt melanoma (27.9 months vs 35.1 for BRAF and 49.1 for NRAS) although this was not significant in multivariate analysis. Survival from stage IV melanoma diagnosis was not significantly different based on mutation status. The DDFI was significantly shorter in patients with BRAFV600K/R versus BRAFV600E melanoma in univariate and multivariate analyses.Conclusions:BRAF and NRAS mutation status does not influence survival in metastatic melanoma.

Outcomes of palliative weekly low-dose gemcitabine-Cisplatin chemotherapy in anthracycline- and taxane- pretreated metastatic breast cancer patients.

PurposeThe combination of gemcitabine and cisplatin (GP) has been shown to be safe and efficacious for patients with metastatic breast cancer (MBC), pretreated with anthracyclines and taxanes. We assessed the efficacy and safety of weekly low-dose GP in patients with MBC.MethodsWe collected clinicopathological data from MBC patients who had been treated with gemcitabine, 800 mg/m2 plus cisplatin, 30 mg/m2 intravenously, on days 1 and 8 every 3 weeks, between January 2001 and November 2011 in Korea.ResultsThe analysis included 294 patients previously treated anthracycline-xand taxane-based chemotherapies prior to GP (median age, 48 years [range, 28-78 years]; median follow-up duration, 63.9 months). Seventeen patients (5.8%) discontinued GP because of toxicities. The median progression-free survival (PFS) was 3.9 months (95% confidence interval [CI], 3.394.4 months) and the median overall survival (OS) was 27.7 months (95% CI, 17.6-37.8 months) months. Statistically significant factors for PFS were performance status (Eastern Cooperative Oncology Group, ≥2 vs. <2; hazard ratio [HR], 1.37; 95% CI, 1.02-1.85; p=0.037), distant disease-free interval (DDFI; ≤2 years vs. >2 years; HR, 1.66; 95% CI, 1.28-1.95, p<0.001), time interval from the diagnosis of metastasis to GP therapy (≤1 year vs. >1 year; HR, 1.48; 95% CI, 1.13-1.95, p<0.001), and presence of brain metastasis (HR, 1.47; 95% CI, 1.03-2.10; p=0.031). Similarly, DDFI (≤2 years vs. >2 years; HR, 2.07; 95% CI, 1.36-3.14; p<0.001) and the presence of brain metastasis (HR, 2.14; 95% CI, 1.27-3.61; p=0.004) were important factors for OS after GP treatment.ConclusionWeekly low-dose GP chemotherapy appears safe and effective for heavily pretreated MBC patients.

Abstract P2-15-04: Trastuzumab re-treatment following adjuvant trastuzumab and the importance of distant disease-free interval: The HERA trial experience

Abstract Background: Trastuzumab (T) forms the backbone of the current first-line treatment of advanced HER2+ breast cancer. In the present study we sought to evaluate the impact of the time interval between the end of adjuvant trastuzumab and distant recurrence (TDRI), upon a) overall survival (OS), b) the duration of trastuzumab-based regimens (T) in the advanced setting. Patients &amp; Methods: a) The first hypothesis involved 187 pts on HERA treated with adjuvant T and diagnosed with distant recurrence after the scheduled treatment period of 1 year at 4 years median follow-up. The impact of TDRI on OS from distant recurrence was evaluated in a Cox model adjusted for tumor size, nodal and hormone receptor status at time of enrollment into the HERA trial. b) The second hypothesis involved 90 patients retreated with T in the metastatic setting. A questionnaire was sent to investigators retreating pts with T upon distant recurrence; 144 of 156 questionnaires were returned (93%), and 90 pts were selected based on available clinical information and consent for subsequent studies (14 pts were randomized to observation and received adjuvant trastuzumab after crossover). Results: a) There was no statistically significant relationship between TDRI following 1yT and OS from distant recurrence: HR 0.99, p = 0.46; HR 0.99, p = 0.27 from the stratified and unadjusted Cox proportional hazard models, respectively. The median OS from distant recurrence was numerically longer among pts with a TDRI of ≥ 12 months (n = 103) than &amp;lt; 12 months (n = 84) but not statistically significant (23.7 vs. 17.8 months, p = 0.47). b) The median duration of T-based regimens for metastatic disease was 8.8 months (n = 88), 9.4 months in the ER+ cohort (n = 36) and 8.8 months in the ER- cohort (n = 52); (n = 2, missing). Sites of first distant recurrence and subsequent disease progression for the 90 pts were hierarchically distributed as below. First distant recurrence n (%)Subsequent progression n (%)CNS6 (6.7%)22 (24.4%)Visceral45 (50.0%)39 (43.3%)Skeletal25 (27.8%)9 (10.0%)Soft Tissue14 (15.6%)9 (10.0%)No event-11 (12.2%) Conclusions: In the HERA trial, TDRI following 1yT did not impact on OS from distant recurrence in pts experiencing distant disease recurrence. This may be due to the benefit of anti-HER2 regimens in subsequent lines of therapy. Although our sample size is limited, the present analysis suggests that pts experiencing a shorter interval (≤ 12 months) from the end of adjuvant trastuzumab to distant recurrence derive similar benefit from trastuzumab-containing regimens in the metastatic setting when compared to the cohort with an interval &amp;gt; 12 months. CNS relapse in HER2-postive breast cancer remains a clinical problem. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-15-04.

Prospective Observational Study of Breast Cancer Treatment Outcomes for UK Women Aged 18–40 Years at Diagnosis: The POSH Study

Breast cancer at a young age is associated with poor prognosis. The Prospective Study of Outcomes in Sporadic and Hereditary Breast Cancer (POSH) was designed to investigate factors affecting prognosis in this patient group. Between 2000 and 2008, 2956 patients aged 40 years or younger were recruited to a UK multicenter prospective observational cohort study (POSH). Details of tumor pathology, disease stage, treatment received, and outcome were recorded. Overall survival (OS) and distant disease-free interval (DDFI) were assessed using Kaplan-Meier curves. All statistical tests were two-sided. Median age of patients was 36 years. Median tumor diameter was 22 mm, and 50% of patients had positive lymph nodes; 59% of tumors were grade 3, 33.7% were estrogen receptor (ER) negative, and 24% were human epidermal growth factor receptor 2 (HER2) positive. Five-year OS was higher for patients with ER-positive than ER-negative tumors (85.0%, 95% confidence interval [CI] = 83.2% to 86.7% vs 75.7%, 95% CI = 72.8% to 78.4%; P < .001), but by eight years, survival was almost equal. The eight-year OS of patients with ER-positive tumors was similar to that of patients with ER-negative tumors in both HER2-positive and HER2-negative subgroups. The flexible parametric survival model for OS shows that the risk of death increases steadily over time for patients with ER-positive tumors in contrast to patients with ER-negative tumors, where risk of death peaked at two years. These results confirm the increased frequency of ER-negative tumors and early relapse in young patients and also demonstrate the equally poor longer-term outlook of young patients who have ER-positive tumors with HER2-negative or -positive disease.

Long-term prognostic performance of Ki67 rate in early stage, pT1-pT2, pN0, invasive breast carcinoma.

BackgroundMolecular signatures may become of use in clinical practice to assess the prognosis of breast cancers. However, although international consensus conferences sustain the use of these new markers in the near future, concerns remain about their degree of discordance and cost-effectiveness in different international settings. The present study aims to validate Ki67 as prognostic factor in a large cohort of early-stage (pT1–pT2, pN0) breast cancer patients.Methods456 patients treated in 1995–1996 were identified in the Institut Curie database. Ki67 (MIB1) was retrospectively assessed by immunohistochemistry for all cases. The prognostic value of this index was compared to that of histological grade (HG), Estrogen receptor (ER) and HER2 status. Distant disease free interval, loco-regional recurrence, time-lapse from first metastatic diagnosis to death were analyzed.ResultsAll 456 patients were treated by lumpectomy plus axillary dissection and radiotherapy. 27 patients (5.9%) received systemic treatment. Tumors were classified as HG1 in 35%, HG2 in 42% and HG3 in 23% of cases. ER was expressed in 86% of the tumors, HER2 in 5% and 14% were triple negative. The median follow-up was 151 [5–191] months. Distant and loco-regional disease recurrences were observed in 16% and 18%, respectively. High (>20%) Ki67 rate [HR = 3 (1.8–4.8), p<10e−06] and HG3 [HR = 4.4 (2.2–8.6), p = 0.00002] were associated with an increased rate of distant relapse. In multivariate analysis, the Ki67 remained the only significant prognostic factor in the subgroups of ER positive HER2 negative [HR = 2.6 (1.5–4.6), p = 0.0006] and ER positive HER2 negative HG2 tumors [HR = 2.2 (1.01–4.8), p = 0.04].ConclusionsWe validate the prognosis value of the Ki67 rate in small size node negative breast cancer. We conclude that Ki67 is a potential cost-effective decision marker for adjuvant therapy in early-stage HG2, pT1–pT2, pN0, breast cancers.

P5-19-14: Platinum-Based Chemotherapy in Triple-Negative Breast Cancer.

Abstract Background: There is increasing evidence that DNA repair defects characteristic of BRCA1-related cancers and triple negative breast cancer (TNBC) confer sensitivity to certain chemotherapeutic agents, such as platinums. However, prospective and retrospective studies comparing the efficacy of these agents versus conventional treatment in TNBC are lacking. The aim of this study was to evaluate the efficacy of platinum-based chemotherapy (PBC) in metastatic TNBC in terms of median duration of treatment and overall-survival (OS) and compare it to patients treated with conventional chemotherapy. Methods: We performed a retrospective chart review of patients with metastatic TNBC who received PBC from January 2007 to June 2010 treated at the Sunnybrook Odette Cancer Center and the Ottawa Hospital Cancer Centre. This cohort was compared to a control group that included metastatic TNBC treated with conventional agents that included anthracyclines, taxanes, capecitabine, and vinorelbine. Results: A total of 166 metastatic TNBC patients were analyzed: 60 treated with PBC and 106 managed with conventional treatment. Median age at diagnosis was 48 years and distant disease-free interval was 26 months (m) for both groups. Patients on both groups had multiple sites of metastases at diagnosis of recurrence than a single site of metastasis (69% for both groups). Of the 60 patients treated with PBC, 90% received a combination regimen, most commonly weekly cisplatin plus gemcitabine in 37% of patients and cisplatin plus vinorelbine in 17% of patients. The median number of cycles delivered was 4 (1-24). 33% received the PBC as first-line treatment, 38% as second-line, 18% as third-line, 7% as fourth line, and 3% as fifth-line. Only 8 patients (5%) discontinued PBC secondary to toxicity. The median time on treatment in first, second and third-line therapy was longer for the PBC group compared to the conventional group (5 vs. 2 m, p=0.108; 5 vs. 2 m, p=0.01; and 4 vs. 1 m, p=0.026). Patients treated with PBC had a longer OS compared to those managed conventionally (16 vs. 10 m, p=0.039). Conclusions: PBC appears to improve clinical outcomes in patients with metastatic TNBC compared to those treated with conventional chemotherapy regimens. Although this is a retrospective study with its obvious limitations, it adds to the growing body of literature, suggesting the benefit of PBC in TNBC. Prospective trials are needed to confirm its benefit in order to integrate it as part of the routine management of these patients. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-19-14.

Platinum-based chemotherapy in triple-negative breast cancer.

1090 Background: There is increasing evidence that DNA repair defects characteristic of BRCA1-related cancers and triple negative breast cancer (TNBC) confer sensitivity to certain chemotherapeutic agents, such as platinums. However, prospective and retrospective studies comparing the efficacy of these agents versus conventional treatment in TNBC are lacking. The aim of this study was to evaluate the efficacy of platinum-based chemotherapy (PBC) in metastatic TNBC in terms of median duration of treatment and overall-survival (OS) and compare it to patients treated with conventional chemotherapy. Methods: We performed a retrospective chart review of patients with metastatic TNBC who received PBC from January 2007 to June 2010 treated at the Sunnybrook Odette Cancer Center. A case-control study was designed, with 3 controls per case matched by age, comprising metastatic TNBC treated with conventional agents. Results: A total of 116 patients were analyzed: 29 treated with PBC and 87 managed with conventional treatment. Median age at diagnosis was 47 years and distant disease-free interval was 27 months (m) for both groups. Patients treated with PBC had more sites of disease (100% vs. 70%, p<0.0001) and a worse performance status (ECOG 2 21% vs. 6%, p=0.034), respectively. Of the 29 patients treated with PBC, 79% received a combination regimen, most commonly weekly cisplatin and gemcitabine in 62% of patients. The median number of cycles delivered was 4 (2-11). 31% received PBC as first-line treatment, 35% as second-line, 28% as third-line and 7% as fifth-line. Only 2 patients discontinued PBC secondary to toxicity. The median time on treatment in first, second and third-line therapy was longer for the PBC group (5 vs. 2 m, p=0.225; 3 vs. 2 m, p=0.063; and 4 vs. 1 m, p=0.009). Patients treated with PBC had a longer OS compared to those managed conventionally (18 vs. 13 m, p=0.025). Conclusions: PBC appears to improve clinical outcomes in patients with metastatic TNBC compared to those treated with conventional chemotherapy regimens. Although this is a retrospective study with its obvious limitations, it adds to the growing body of literature, suggesting the benefit of PBC in TNBC. Prospective trials are needed to confirm this benefit.