Assessment of early response biomarkers in relation to long-term survival in patients with HER2-negative breast cancer receiving neoadjuvant chemotherapy plus bevacizumab: Results from the Phase II PROMIX trial.

Pathologic complete response (pCR) is a predictor for favorable outcome after neoadjuvant treatment in early breast cancer. Modulation of gene expression may also provide early readouts of biological activity and prognosis, offering the possibility for timely response-guided treatment adjustment. The role of early transcriptional changes in predicting response to neoadjuvant chemotherapy plus bevacizumab was investigated. One-hundred-and-fifty patients with large, operable and locally advanced HER2-negative breast cancer received epirubicin and docetaxel, with the addition of bevacizumab. Patients underwent tumor biopsies at baseline, after Cycle 2 and at the time of surgery. The primary end point, pCR, and its relation with the secondary endpoints event-free survival (EFS), overall survival (OS) and gene expression profiles, are reported. The pCR rate was 13% (95% CI 8.6-20.2), with significantly more pCRs among triple-negative [28% (95% CI 14.8-45.4)] than among hormone receptor positive (HR+) tumors [9% (95% CI 4.6-16.3); (OR = 3.9 [CI = 1.5-10.3])]. pCR rates were not associated with EFS or OS. PAM50 subtypes significantly changed after Cycle 2 (p = 0.03) and an index of absolute changes in PAM50 correlations between these time-points was associated with EFS [HR = 0.62 (CI = 0.3-1.1)]. In univariable analyses, signatures for angiogenesis, proliferation, estrogen receptor signaling, invasion and metastasis, and immune response, measured after Cycle 2, were associated with pCR in HR+ tumors. Evaluation of changes in molecular subtypes and other signatures early in the course of neoadjuvant treatment may be predictive of pCR and EFS. These factors may help guide further treatment and should be considered when designing neoadjuvant trials.

The Impact of a Hepatobiliary Multidisciplinary Team Assessment in Patients with Colorectal Cancer Liver Metastases: A Population-Based Study.

BACKGROUND: Assessing patients with colorectal cancer liver metastases (CRCLM) by a liver multidisciplinary team (MDT) results in higher resection rates and improved survival. The aim of this study was to evaluate the potentially improved resection rate in a defined cohort if all patients with CRCLM were evaluated by a liver MDT. PATIENTS AND METHODS: A retrospective analysis of patients diagnosed with colorectal cancer during 2008 in the greater Stockholm region was conducted. All patients with liver metastases (LM), detected during 5-year follow-up, were re-evaluated at a fictive liver MDT in which previous imaging studies, tumor characteristics, medical history, and patients' own treatment preferences were presented. Treatment decisions for each patient were compared to the original management. Odds ratios (ORs) and 95% confidence intervals were estimated for factors associated with referral to the liver MDT. RESULTS: Of 272 patients diagnosed with LM, 102 patients were discussed at an original liver MDT and 69 patients were eventually resected. At the fictive liver MDT, a further 22 patients were considered as resectable/potentially resectable, none previously assessed by a hepatobiliary surgeon. Factors influencing referral to liver MDT were age (OR 3.12, 1.72-5.65), American Society of Anaesthesiologists (ASA) score (OR 0.34, 0.18-0.63; ASA 2 vs. ASA 3), and number of LM (OR 0.10, 0.04-0.22; 1-5 LM vs. >10 LM), while gender (p = .194) and treatment at a teaching hospital (p = .838) were not. CONCLUSION: A meaningful number of patients with liver metastases are not managed according to best available evidence and the potential for higher resection rates is substantial. IMPLICATIONS FOR PRACTICE: Patients with liver metastatic colorectal cancer who are assessed at a hepatobiliary multidisciplinary meeting achieve higher resection rates and improved survival. Unfortunately, patients who may benefit from resection are not always properly referred. In this study, the potential improved resection rate was assessed by re-evaluating all patients with liver metastases from a population-based cohort, including patients with extrahepatic metastases and accounting for comorbidity and patients' own preferences towards treatment. An additional 12.9% of the patients were found to be potentially resectable. The results highlight the importance of all patients being evaluated in the setting of a hepatobiliary multidisciplinary meeting.

The Late Effects of Cancer Treatment on Female Fertility and the Current Status of Fertility Preservation-A Narrative Review.

Fertility counseling should be offered to all individuals of young reproductive age early in the patient's trajectory following a cancer diagnosis. Systemic cancer treatment and radiotherapy often have an inherent gonadotoxic effect with the potential to induce permanent infertility and premature ovarian failure. For the best chances to preserve a patient's fertility potential and to improve future quality of life, fertility preservation methods should be applied before cancer treatment initiation, thus multidisciplinary team-work and timely referral to reproductive medicine centers specialized in fertility preservation is recommended. We aim to review the current clinical possibilities for fertility preservation and summarize how infertility, as a late effect of gonadotoxic treatment, affects the growing population of young female cancer survivors.

Survival Outcomes, Digital TILs, and On-treatment PET/CT During Neoadjuvant Therapy for HER2-positive Breast Cancer: Results from the Randomized PREDIX HER2 Trial.

PURPOSE: PREDIX HER2 is a randomized Phase II trial that compared neoadjuvant docetaxel, trastuzumab, and pertuzumab (THP) with trastuzumab emtansine (T-DM1) for HER2-positive breast cancer. Rates of pathologic complete response (pCR) did not differ between the two groups. Here, we present the survival outcomes from PREDIX HER2 and investigate metabolic response and tumor-infiltrating lymphocytes (TIL) as prognostic factors. PATIENTS AND METHODS: In total, 202 patients with HER2-positive breast cancer were enrolled and 197 patients received six cycles of either THP or T-DM1. Secondary endpoints included event-free survival (EFS), recurrence-free survival (RFS), and overall survival (OS). Assessment with PET/CT was performed at baseline, after two and six treatment cycles. TILs were assessed manually at baseline biopsies, while image-based evaluation of TILs [digital TILs (DTIL)] was performed in digitized full-face sections. RESULTS: After a median follow-up of 5.21 years, there was no difference between the two treatment groups in terms of EFS [HR = 1.26; 95% confidence interval (CI), 0.54-2.91], RFS (HR = 0.69; 95% CI, 0.24-1.93), or OS (HR = 0.52; 95% CI, 0.09-2.82). Higher SUVmax at cycle 2 (C2) predicted lower pCR (ORadj = 0.65; 95% CI, 0.48-0.87; P = 0.005) and worse EFS (HRadj = 1.27; 95% CI, 1.12-1.41; P < 0.001). Baseline TILs and DTILs provided additional prognostic information to clinical parameters and C2 SUVmax. CONCLUSIONS: Long-term outcomes following neoadjuvant T-DM1 were similar to neoadjuvant THP. SUVmax after two cycles of neoadjuvant therapy for HER2-positive breast cancer may be an independent predictor of both short- and long-term outcomes. Combined assessment with TILs may facilitate early selection of poor responders for alternative treatment strategies.

Relapse Rates and Disease-Specific Mortality Following Procedures for Fertility Preservation at Time of Breast Cancer Diagnosis.

Importance: Breast cancer (BC) is the most common indication for fertility preservation (FP) in women of reproductive age. Procedures for FP often include hormonal stimulation, but current data are scarce regarding whether using hormonal stimulation for FP is associated with any deterioration in BC prognosis. Objective: To investigate the risk of disease-specific mortality and relapse in women who underwent FP with or without hormonal stimulation compared with women who did not at time of BC diagnosis. Design, Setting, and Participants: This Swedish nationwide prospective cohort study was conducted to assess the safety of hormonal and nonhormonal FP procedures indicated by BC in Sweden from January 1, 1994, through June 30, 2017. Women were identified from any of the regional FP programs located at Swedish university hospitals. A total of 425 women were found to have undergone FP, and 850 population comparators who had not undergone FP were sampled from regional BC registers and matched on age, calendar period of diagnosis, and region. Relapse-free survival was assessed in a subcohort of 241 women who underwent FP and 482 women who had not, with complete data. Nationwide demographic and health care registers provided data on outcome, disease- and treatment-related variables, and socioeconomic characteristics. Data analyses were performed between November 2021 and March 2022 and completed in June 2022. Main Outcomes and Measures: Relapse and disease-specific mortality after a diagnosis of BC. Results: The final study population included 1275 women (mean [SD] age, 32.9 [3.8] years) at the time of BC diagnosis. After stratification by the matching variables age, calendar period, and region, and adjustment for country of birth, education, parity at diagnosis, tumor size, number of lymph node metastases, and estrogen receptor status, disease-specific mortality was similar in women who underwent hormonal FP (adjusted hazard ratio [aHR], 0.59; 95% CI, 0.32-1.09), women who underwent nonhormonal FP (aHR, 0.51; 95% CI, 0.20-1.29), and women who were not exposed to FP (reference). In a subcohort with detailed data on relapse, adjusted rate of disease-specific mortality and relapse were also similar among the groups who underwent hormonal FP (aHR, 0.81; 95% CI, 0.49-1.37), underwent nonhormonal FP (aHR, 0.75; 95% CI, 0.35-1.62), and were not exposed to FP (reference). Conclusions and Relevance: In this cohort study, FP with or without hormonal stimulation was not associated with any increased risk of relapse or disease-specific mortality in women with BC. Results of this study provide much needed additional evidence on the safety of FP procedures in women with BC and may influence current health care practice to the benefit of young women with BC who wish to preserve their fertility.

Age-specific trends of survival in metastatic breast cancer: 26 years longitudinal data from a population-based cancer registry in Stockholm, Sweden.

Treatment of metastatic breast cancer (MBC) has evolved during the last decades but it is largely unknown whether this has led to improved survival in the general MBC population. Based on the regional, population-based breast cancer registry, we identified 5,463 patients diagnosed with MBC in Stockholm County during 1979-2004. Patients were divided into five cohorts based on the year of first MBC diagnosis and observed and relative survival were compared across the cohorts after adjustment for potential confounders. A significant trend of better survival over time was demonstrated for patients 60 years or younger (P < 0.001, by log-rank test for trend), but not for older patients (P = 0.12) or for the whole MBC population (P = 0.13). The adjusted observed survival of patients ≤ 60 years was significantly improved in the 2000-2004 cohort (P < 0.001, hazard ratio = 0.7, 95% confidence interval = 0.58-0.84), corresponding to a clinically significant increase of median survival with more than 3 months and absolute increase of 5-year survival with 8% or more compared to previous periods. Similarly, relative survival analysis indicated a 31% decreased mortality for the younger subpopulation in the 2000-2004 cohort (P < 0.001). Systemic adjuvant treatment was a negative prognostic factor after distant recurrence. Treatment advancements in MBC are not reflected by better survival for the whole MBC population. An improvement is only observed after the year 2000 and is restricted to younger patients.

Neoadjuvant Trastuzumab, Pertuzumab, and Docetaxel vs Trastuzumab Emtansine in Patients With ERBB2-Positive Breast Cancer: A Phase 2 Randomized Clinical Trial.

Importance: Trastuzumab emtansine (T-DM1) is presently approved for treatment of advanced breast cancer and after incomplete response to neoadjuvant therapy, but the potential of T-DM1 as monotherapy is so far unknown. Objective: To assess pathologic complete response (pCR) to standard neoadjuvant therapy of combination docetaxel, trastuzumab, and pertuzumab (DTP) vs T-DM1 monotherapy in patients with ERBB2 (formerly HER2)-positive breast cancer. Design, Setting, and Participants: This randomized phase 2 trial, conducted at 9 sites in Sweden, enrolled 202 patients between December 1, 2014, and October 31, 2018. Participants were 18 years or older, with ERBB2-positive tumors larger than 20 mm and/or verified lymph node metastases. Analysis was performed on an intention-to-treat basis. Interventions: Patients were randomized to receive 6 cycles of DTP (standard group) or T-DM1 (investigational group). Crossover was recommended at lack of response or occurrence of intolerable toxic effects. Assessment with fluorine 18-labeled fluorodeoxyglucose (18F-FDG) positron emission tomography combined with computed tomography (PET-CT) was performed at baseline and after 2 and 6 treatment cycles. Main Outcome and Measures: Pathologic complete response, defined as ypT0 or Tis ypN0. Secondary end points were clinical and radiologic objective response; event-free survival, invasive disease-free survival, distant disease-free survival, and overall survival; safety; health-related quality of life (HRQoL); functional and biological tumor characteristics; and frequency of breast-conserving surgery. Results: Overall, 202 patients were randomized; 197 (99 women in the standard group [median age, 51 years (range, 26-73 years)] and 98 women in the investigational group [median age, 53 years (range, 28-74 years)]) were evaluable for the primary end point. Pathologic complete response was achieved in 45 patients in the standard group (45.5%; 95% CI 35.4%-55.8%) and 43 patients in the investigational group (43.9%; 95% CI 33.9%-54.3%). The difference was not statistically significant (P = .82). In a subgroup analysis, the pCR rate was higher in hormone receptor-negative tumors than in hormone receptor-positive tumors in both treatment groups (45 of 72 [62.5%] vs 45 of 125 [36.0%]). Three patients in the T-DM1 group experienced progression during therapy. In an exploratory analysis, tumor-infiltrating lymphocytes at 10% or more (median) estimated pCR significantly (odds ratio, 2.76; 95% CI, 1.42-5.36; P = .003). Response evaluation with 18F-FDG PET-CT revealed a relative decrease of maximum standardized uptake value by equal to or greater than 68.7% (median) was associated with pCR (odds ratio, 6.74, 95% CI, 2.75-16.51; P < .001). Conclusions and Relevance: In this study, treatment with standard neoadjuvant combination DTP was equal to T-DM1. Trial Registrations: ClinicalTrials.gov Identifier: NCT02568839; EudraCT number: 2014-000808-10.

Five-Year Results of the Preoperative Accelerated Partial Breast Irradiation (PAPBI) Trial.

PURPOSE: In this multicenter phase 2 feasibility study, we investigated the impact of preoperative accelerated partial breast irradiation (PAPBI) on local control, breast fibrosis, and cosmetic outcome. METHODS AND MATERIALS: Women aged >60 years with an invasive, unifocal (mammography and magnetic resonance imaging), nonlobular adenocarcinoma of the breast were treated with PAPBI. Six weeks after radiation therapy, a wide local excision was performed. Radiation therapy consisted of 10 × 4 Gy (2010-2013) or 5 × 6 Gy (after 2013) to the tumor (gross target volume) with a 25 mm margin (20 mm from gross target volume to clinical target volume, 5 mm planning target volume). RESULTS: One hundred thirty-three patients treated between 2010 and 2016 were analyzed with a median follow-up of 5.0 years (0.9-8.8 years). Seventy-eight (59%) patients were treated with 10 × 4 Gy in 2 weeks and 55 (41%) patients with 5 × 6 Gy in 1 week. Eighteen postoperative complications (14%) occurred in 15 patients (11%). The proportion of patients with no to mild fibrosis in the treated part of the breast at 2 years and later time points was around 90%. Cosmesis improved over time in several patients: excellent to good cosmetic score as rated by the physician was 68% at 6 months and 92% at 5 years. Seventy-seven percent (6 months) to 82% (5 years) of patients were "satisfied" or "very satisfied" with their cosmetic outcome. Three recurrences were detected in the biopsy track and 1 recurrence in the ipsilateral breast. CONCLUSIONS: PAPBI is a feasible method with a low postoperative complication rate, limited fibrosis, and good to excellent cosmetic outcome. The local recurrence rate was 3% at 5 years; however, no local recurrences were observed since removal of the needle biopsy track.

Dynamic evaluation of the immune infiltrate and immune function genes as predictive markers for neoadjuvant chemotherapy in hormone receptor positive, HER2 negative breast cancer.

Gene expression (GE) signatures and Tumor Infiltrating Lymphocytes (TIL) enumeration are predictive for response to neoadjuvant chemotherapy in HR- and in HER2+ breast cancer, but data are conflicting in HR+/HER2- disease. This study aimed to explore their predictive value in this subset, measured both at baseline and after short exposure to chemotherapy. Specifically, the PROMIX phase 2 trial enrolled patients with locally advanced HER2- BC to receive six cycles of epirubicin and docetaxel, plus bevacizumab during cycles 3-6. Patients underwent tumor biopsies at baseline and after cycle 2 for GE profiling and enumeration of TIL, FOXP3+ T-cells and CD163+ macrophages. An immune related gene module and the quantification of the immune infiltrate were analyzed for association with pathologic complete response (pCR), decrease in tumor size and disease-free survival (DFS). Of the 150 patients enrolled in PROMIX, 113 were HR+/HER2-. Baseline GE and immune cell enumeration data were available from 71 patients, while data after 2 cycles of chemotherapy were available from 41. At baseline, only GE was statistically significantly associated with higher pCR rates (OR 2.29, 95% CI 1.05 - 5.38, p = 0.037) and decrease in tumor size (r = 0.25, p = 0.047). In contrast, longitudinal data indicate that both GE (r = 0.54, p<0.001) and TIL abundance (p = 0.009) are stronger predictors for the reduction of tumor size, while low FOXP3+ was statistically significantly associated with an improved DFS (p = 0.027). In conclusion, GE analysis, TIL and FOXP3+ enumeration after short-term exposure to chemotherapy carry important predictive information in HR+/HER2- breast cancer at the neoadjuvant setting.

First results of the preoperative accelerated partial breast irradiation (PAPBI) trial.

BACKGROUND AND PURPOSE: The aim of this study is to assess the toxicity and cosmetic outcome of preoperative accelerated partial breast irradiation (PAPBI) for breast cancer patients with low risk on local recurrence. MATERIAL AND METHODS: Women aged ⩾60years with an invasive, unifocal ⩽3cm on MRI, (non-lobular) adenocarcinoma of the breast and a negative sentinel node received PAPBI (40Gray in 10 fractions over 2 weeks). Six weeks after radiotherapy a wide local excision was performed. RESULTS: 70 patients with a median follow-up of 23 months (3-44 months) were evaluated. The overall postoperative infection rate was 11%. At 1, 2 and 3 years of follow-up respectively 89%, 98% and 100% of patients had no or mild induration-fibrosis. Fibrosis was only found in a small volume of the breast. The global cosmetic outcome was good to excellent in 77% at 6 months to 100% at 3 years. Two patients developed a local recurrence. CONCLUSION: Our first results show limited fibrosis in a small volume and good to excellent cosmetic outcome. In selected patients, preoperative radiotherapy appears to be a good option for breast conserving therapy.