Factors influencing acute and late toxicity in the era of adjuvant hypofractionated breast radiotherapy

PurposeTo evaluate toxicity in breast cancer patients treated with anthracycline and taxane based chemotherapy and whole breast hypofractionated radiotherapy, and to identify the risk factors for toxicity.Methods and materials537 early breast cancer patients receiving hypofractionated radiotherapy after conservative surgery were enrolled from April 2009 to December 2014, in an Italian cancer institute. The dose was 42.4 Gy in 16 daily fractions, 2.65 Gy per fraction. The boost to the tumor bed was administered only in grade III breast cancer patients and in patients with close or positive margins. Acute and late toxicity were prospectively assessed during and after radiotherapy according to RTOG scale. The impact of patients clinical characteristics, performed treatments and dose inhomogeneities on the occurrence of an higher level of acute skin toxicity and late fibrosis has been evaluated by univariate and multivariate analysis.ResultsThe mean age was 74 (range 46–91 yrs). 27% of patients received boost. 22% of cases (n = 119) received also chemotherapy. The median follow-up was 32 months.G1 and G2/G3 acute skin toxicity were 61.3% and 20.5% and G1 and G2/G3 late fibrosis 12.6% and 4.3% respectively.Chemotherapy (p = 0.04), diabetes (p = 0.04) and boost administration (p < 0.01) were found to be statistically significant on the occurrence of late fibrosis, but a multivariate analysis did not show any factors connected. The boost administration (p < 0.01), the breast volume (p = 0.05), dose inhomogeneities (p < 0.01) and boost volume (p = 0.04) were found to be statistically significant as concerns the occurrence of acute skin reaction at the univariate analysis, but only the boost administration (p = 0.02), at multivariate analysis.ConclusionsThe results of our study, according to the large randomized trials, confirmed that hypofractionated whole breast irradiation is safe, and only the boost administration seems to be an important predictor for toxicity. Chemotherapy does not impact on acute and late skin toxicity.     

Outcomes of intraoperative radiotherapy for early-stage breast cancer: Experience from a multidisciplinary breast oncology program

BackgroundIntraoperative radiotherapy (IORT) was implemented at our institution for early stage breast cancer patients including those with geographic or medical co-morbidity limitations to whole breast radiation therapy (WBRT).MethodsRetrospective review of patients (n = 127) who underwent IORT from 2009 to 2016 for breast cancer. Demographics, pathology, toxicity, and recurrences were ascertained.ResultsThe median age was 67 years (interquartile range: 62–73). At median follow-up (49.6 months), 5 patients (4%) had ipsilateral breast tumor recurrence with median time to recurrence of 36.8 months. Acute and late grade ≥3 skin toxicities were observed in 3.1% and 4.7% of patients, respectively. A subset (n = 7) who received prior ipsilateral WBRT was found to have no subsequent local recurrence, one case of acute grade 3 skin toxicity, and no late toxicity.ConclusionsIORT is a safe and effective alternative to whole breast radiotherapy, and serves as a suitable alternative to completion mastectomy in locally recurrent breast cancer.     

Accelerated hypofractionated adjuvant whole breast radiotherapy with concomitant photon boost after conserving surgery for early stage breast cancer: a prospective evaluation on 463 patients

The current standard therapeutic option for early stage breast cancer (EBC) employs a multimodality treatment approach including conservative surgery, radiotherapy, chemotherapy, and hormone therapy. The most common adjuvant radiotherapeutic strategy consists of external beam radiation therapy (EBRT) delivered to the whole breast using 1.8-2 Gy fractions given five times a week, up to a total dose of 45-50 Gy over a period of 5 weeks. In recent years, altered schedules employing larger dose per fraction delivered in fewer treatment sessions over a shorter overall treatment time began to be explored. We herein present clinical data on accelerated hypofractionated adjuvant whole-breast radiotherapy delivered on a daily basis for a total treatment time of 20 fractions. Between February 2005 and June 2009, a total of 463 patients underwent hypofractionated accelerated adjuvant radiation after conservative surgery for early breast cancer (pathological stage pTis, pT1 or pT2, pN0-N1). The basic course of radiotherapy consisted of 45 Gy, to the whole breast in 20 fractions with 2.25 Gy/fraction; an additional daily boost dose of 0.25 Gy was concomitantly delivered, to the lumpectomy cavity, for an additional total dose of 5 Gy. The cumulative nominal dose was 50 Gy. At follow-up, patients were examined at 3 and 6 months after the end of radiotherapy and twice a year afterward. Toxicity was scored according to the Common Terminology Criteria for Adverse Events, using the Radiation Therapy Oncology Group /European Organization for Research and Treatment of Cancer toxicity scale. Cosmetic results were assessed in agreement with the Harvard criteria. All the 463 patients treated with the accelerated hypofractionated adjuvant whole-breast radiotherapy schedule achieved at least 6 months' follow-up and subsequently were considered for the present analysis. With a median follow-up of 27 months, 5-year DFS is 93.1%. Only three patients experienced disease recurrence: two of them with an axillary nodal relapse; one patient with systemic spread. No local relapse occurred. No major toxicities (grade 3 or more) were detected during follow-up. Only 2% of the patients experienced grade 3 skin toxicity at the very end of the radiotherapy course. Cosmetic result was assessed and scored at 6 months, 1 year, 2 years: 100% of patients showed excellent or good cosmetic result. The explored accelerated hypofractionated adjuvant radiotherapeutic approach for early breast cancer with concomitant photon boost seems to be feasible providing consistent clinical results with excellent short-to-medium-term toxicity profile.     

Accelerated partial breast irradiation with 3-dimensional conformal and image-guided intensity-modulated radiotherapy following breast conserving surgery – 7-Year results of a phase II trial

PurposeTo present the 7-year results of accelerated partial breast irradiation (APBI) using three-dimensional conformal (3D-CRT) and image-guided intensity-modulated radiotherapy (IG-IMRT) following breast-conserving surgery (BCS).Patients and methodsBetween 2006 and 2014, 104 patients were treated with APBI given by means of 3D-CRT using 3–5 non-coplanar, isocentric wedged fields, or IG-IMRT using kV-CBCT. The total dose of APBI was 36.9 Gy (9 × 4.1 Gy) using twice-a-day fractionation. Survival results, side effects and cosmetic results were assessed.ResultsAt a median follow-up of 90 months three (2.9%) local recurrences, one (0.9%) regional recurrence and two (1.9%) distant metastases were observed. The 7-year local (LRFS), recurrence free survival was 98.9%. The 7-year disease-free (DFS), metastases free (MFS) and overall survival (OS) was 94.8%, 97.9% and 94.8%, respectively. Late side effects included G1 skin toxicity in 15 (14.4%), G1, G2, and G3 fibrosis in 26 (25%), 3 (2.9%) and 1 (0.9%) patients respectively. Asymptomatic (G1) fat necrosis occurred in 10 (9.6%) patients. No ≥ G2 or higher late side effects occurred with IMRT. The rate of excellent/good and fair/poor cosmetic results was 93.2% and 6.8%, respectively.Conclusion7-year results of APBI with 3D-CRT and IG-IMRT are encouraging. Toxicity profile and local tumor control are comparable to other series using multicatheter interstitial brachytherapy. Therefore, these external beam APBI techniques are valid alternatives to whole breast irradiation and brachytherapy based APBI.     

Hypofractionation with simultaneous integrated boost after breast-conserving surgery: Long term results of two phase-II trials

PurposeTo analyze long-term results of two multicenter prospective single-arm trials (ARO-2010-01 and ARO-2013-04) investigating adjuvant hypofractionated radiotherapy (HF) with simultaneous integrated boost (SIB) after breast-conserving surgery (BCS).MethodsEligible patients had histopathologically confirmed unifocal breast cancer planned for whole breast irradiation plus boost radiotherapy to the tumor bed. In both studies, a total dose of 40 Gy was applied to the whole breast and of 48 Gy to the tumor bed in 16 fractions of 2.5 and 3.0 Gy. Radiotherapy could be given either as three-dimensional conformal radiotherapy (3D-CRT) or as intensity-modulated radiotherapy (IMRT). The primary study objectives were feasibility and security within an observation period of six months. The current investigation focuses on long-term efficacy and toxicities.ResultsBetween 2011 and 2014, both trials enrolled 300 patients in total. Data from 274 of these patients could be used for the current analysis. The median follow-up time was 60 months and the 5-year disease-free survival 92.1%. Three patients suffered a local recurrence (after 36–72 months) while a regional recurrence occurred in one patient (after 17 months). The 5-year local control rate in the breast was 99.6%. 63.5% of all patients did not report any late radiation-related toxicity, 28.5% reported grade 1 and 7.3% grade 2 toxicities. The highest late toxicity was grade 3 in 2 women (0.7%, telangiectasia and lymphedema of the breast).ConclusionOur analysis demonstrates favorable efficacy and low rates of long-term side effects of HF with SIB after BCS. Randomized controlled phase III trials are ongoing.     

Prognosis of selected triple negative apocrine breast cancer patients who did not receive adjuvant chemotherapy

BackgroundTriple negative breast cancer encompasses several biological entities with different outcomes and is a priority to identify which patients require more treatment to reduce the risk of recurrence and which patients need less treatment.Patients and methodsAmong the 210 women with first primary invasive apocrine non metastatic breast cancer operated on between January 1998 and December 2016 at the European Institute Oncology, Milan, we identified 24 patients with a pT1-pT2, node-negative, triple negative subtype and Ki-67 ≤ 20% who did not receive adjuvant chemotherapy (CT). We compared the outcome of this cohort with a similar group of 24 patients with ductal tumors who received adjuvant chemotherapy, matched by pathological stage and biological features and also with a similar group of 12 patients with apocrine tumors who received adjuvant chemotherapy.ResultsThe median age was 64 and 61 years in the apocrine (w/o CT) and ductal group, respectively. The median value of Ki-67 expression was 12% in the apocrine group (w/o CT) and 16% in the ductal group (p < 0.001). After a median follow-up of 7.5 years, no patients in the apocrine group (w/o CT) experienced a breast cancer related event compared with 4 events in the ductal carcinoma group (Gray test p-value = 0.11).ConclusionsThe outcome of selected apocrine triple negative breast cancer patients who did not received adjuvant chemotherapy is excellent and supports a treatment de-escalation. Multicenter projects focusing on the possibility of avoiding adjuvant chemotherapy in selected subtypes of triple negative breast cancers with favorable outcome are warranted.     

Effective Local Control and Long-Term Survival in Patients with T4 Locally Advanced Breast Cancer Treated with Breast Conservation Therapy

Background: The presence of skin involvement has been accepted as a relative contraindication to breast preservation because it is believed to be associated with an increased local failure rate. This study was conducted to assess the outcome of a carefully selected group of patients who presented with breast cancer involving the skin and who had breast conservation therapy (BCT) following neoadjuvant chemotherapy.Methods: Between 1987 and 1999, 33 patients with stage IIIB or IIIC breast cancer completed treatment consisting of four cycles of neoadjuvant chemotherapy, lumpectomy, radiation therapy, and consolidative chemotherapy. Clinicopathologic factors were analyzed and patients were followed for locoregional and distant recurrence.Results: Initial median tumor size was 7 cm. All patients had skin involvement, defined as erythema, skin edema, direct skin invasion, ulceration, or peau dorange. Following chemotherapy, median pathologic tumor size was 2 cm. Complete resolution of skin changes occurred in 29 patients (88%). At median follow-up time of 91 months in surviving patients, 26 patients (79%) were alive without evidence of disease. The 5-year, disease-free survival rate was 70%, and the 5-year overall survival rate was 78%. The actuarial ipsilateral breast cancer recurrence rate was 6% at 5 years.Conclusions: Patients who present with T4 breast cancer who experience tumor shrinkage and resolution of skin changes with neoadjuvant chemotherapy represent a select group of patients who can have BCT. These patients have favorable rates of long-term local control and survival. Mastectomy is not mandatory for all patients with breast cancer who present with skin involvement.Presented at the 57^th Annual Society for Surgical Oncology Cancer Symposium in New York City, New York, March 18–21, 2004     

The efficacy and safety of hypofractionated radiotherapy with concurrent anti‐HER‐2 therapy following breast‐conserving therapy for breast cancer

The purpose of this study was to report rates and severities of radiation‐related toxicities and analyze disease‐control outcomes in patients who have received hypofractionated whole breast radiation (HF) with concurrent trastuzumab with or without pertuzumab. We conducted a retrospective cohort study including women with stage I‐III HER2‐positive breast cancer who received HF at the University of Pennsylvania between 1/2005 and 5/2018 with concurrent trastuzumab with or without pertuzumab. Fractionation was 266 cGy daily to a total dose of 4256 cGy with or without a sequential tumor bed boost. Eighty patients were included in the cohort with a median follow‐up time of 21.44 months. There was one grade 3 acute toxicity (fatigue) and no grade 3 late toxicities. 91% and 25% of patients experienced grade 1‐2 acute and late skin reactions, respectively. An excellent‐good cosmetic outcome was reported by 74% and 95% of patients and physicians, respectively. No patients experienced tumor recurrences, and the only death was due to a secondary cause. These results suggest that hypofractionated whole breast radiation administered concurrently with anti‐HER‐2 therapies is efficacious and has acceptable toxicity in early‐stage breast cancer patients treated with lumpectomy. Continued follow‐up is warranted to evaluate long‐term outcomes.     

Management of the axilla following neoadjuvant chemotherapy for breast cancer- A change in practice

ObjectivesChemotherapy in the neo adjuvant setting has allowed downsizing of breast tumours thus allowing patients to benefit from breast conservation surgery. The effect of neoadjuvant chemotherapy (NAC) has also been observed in the axilla but most units are still treating the axilla with axillary lymph node dissection (ALND).Materials and methodsA prospective database of breast cancer patients receiving NAC between 2007 and 2016 at a single breast unit was reviewed. The management of the axilla and outcomes was studied.Results165 patients received NAC, 123 (74.5%) were clinically/radiologically node positive and 42 were negative. Median age was 50 years. 26.7% had triple negative disease and 34.5% were HER2 positive. 56/123 (45.5%) patients with positive nodes at the outset responded completely to NAC. 40 patients with positive nodes pre-NAC had post NAC SLNB with 37 requiring adjuvant radiotherapy only. 83/123 went directly to ALND post NAC and of these 27 were node negative and therefore may be considered to have had an unnecessary ALND. Overall mortality was 20.6% (34), local recurrence in the breast or mastectomy scar was 3.6% (6) but there was no recurrence in the axilla (0/165) with a median follow up of 67 months.ConclusionThere is no clear evidence for management of the axilla post NAC. We have used best available evidence to change our practice over the years and our results should encourage others to de-escalate treatment of the axilla in line with the recently published multidisciplinary guidance on axillary surgery following neoadjuvant chemotherapy.     

Primary systemic treatment and concomitant low dose radiotherapy for breast cancer: Final results of a prospective phase II study

BackgroundTo evaluate the efficacy of preoperative low dose fractionated radiotherapy (LD-FRT) and chemotherapy in breast cancer.Materials and methodsPatients with stage IIA–IIIA breast cancer, received LD-FRT (0.40 Gy bid, on day 1 and 2, for 6 cycles) to primary tumor volume and concurrent chemotherapy with non-pegylated liposomal anthracycline and docetaxel. Pathological response was assessed by Mandard Tumor Regression Grade (TRG). We evaluated the pathological major response rate (PMRR) as TRG1 and TRG2. The expected outcome was a PMRR of 60%. The accrual was determined by the single proportion powered analysis (α = 0.05, power = 0.8).ResultsTwentyone patients were enrolled. No grade 2–4 acute skin and hematological toxicity was observed. TRG1 was obtained in 3 patients (14.3%), TRG2 in 4 patients (19%). The PMRR was 33.3%; it does not concur with the expected result, but is similar to that of chemotherapy alone. According to molecular subtype, 2/11 luminal A patients and 4/6 luminal B patients obtained a PMRR to preoperative treatment (35.3%); 1/4 basal like patients reported TRG1 (25%).ConclusionsLD-FRT concomitant with primary systemic treatment has a good toxicity profile. The response rate is consistent with that of chemotherapy alone, and suggests different interactions between low dose radiotherapy and molecular subtypes. Additional investigations are planned.     

Does immediate breast reconstruction compromise the delivery of adjuvant chemotherapy?

BackgroundImmediate breast reconstruction (IBR) provides psychological benefit to many early breast cancer patients however concerns persist regarding its potential impact on chemotherapy delivery. We investigated the association between IBR, complications and adjuvant chemotherapy delivery.MethodRetrospective analysis of patients in an academic breast service, who underwent mastectomy, with or without reconstruction, and received adjuvant chemotherapy.ResultsComparisons were made between 107 patients who received IBR and 113 who received mastectomy alone. Those receiving IBR were on average younger, with lower body mass index (BMI) and better prognoses. Overall complication rates were comparable (mastectomy alone: 45.1% versus IBR: 35.5%, p = 0.2). There was more return to surgery in the IBR group with 11.5% of tissue expanders requiring removal, whilst more seromas occurred in the mastectomy group. There was no significant difference in the median time to chemotherapy.ConclusionWe found no evidence that IBR compromised the delivery of adjuvant chemotherapy, although there was a significant incidence of implant infection.     

Immediate breast reconstruction for stage III breast cancer using transverse rectus abdominis musculocutaneous (TRAM) flap

Background: The management of stage III breast cancer is challenging; it often includes multimodal treatment with systemic therapy and/or radiation therapy and surgery. Immediate breast reconstruction has not traditionally been performed in these patients. We review the results of immediate transverse rectus abdominis musculocutaneous (TRAM) flap in 21 patients treated for stage III breast cancer. Methods: Data have been collected retrospectively on 21 patients diagnosed with stage III breast cancer between 1987 and 1994. All patients had mastectomy and immediate TRAM reconstruction. Thirteen patients received primary systemic therapy, 10 patients received postoperative consolidation radiotherapy to the operative site, and 3 patients received preoperative radiation. Results: Mean follow-up for the group was 26 months. Two patients died with disseminated disease: neither of them developed local disease recurrence in the operative site; 82% of the patients followed for at least two years are free of disease. Sixty-two percent of the patients received preoperative chemotherapy, the remaining patients received postoperative multiagent chemotherapy and/or radiation therapy. Two of the patients received autologous bone marrow transplants after their adjuvant therapy. Ten patients had postoperative radiotherapy for consolidation; three patients received preoperative radiation. Conclusions: Immediate TRAM reconstruction for stage III breast cancer is not associated with a delay in adjuvant therapy or an increased risk of local relapse. It facilitates wide resection of involved skin without skin grafting. Radiation therapy can be delivered to the reconstructed breast when indicated without difficulty. Breast reconstruction facilitates surgical resection of stage III breast cancer with primary closure and should be considered if the patient desires immediate breast reconstruction.Results of this study were presented at the 48th Annual Cancer Symposium of The Society of Surgical Oncology, Boston, Massachusetts, March 23–26, 1995.     

Breast cancer in women aging 35 years old and younger: The Egyptian National Cancer Institute (NCI) experience

ObjectiveThe aim is to identify the epidemiological and clinicopathological features associated with young breast cancer (BC) patients and to discuss factors affecting tumor recurrence and DFS.Patients & methodsA retrospective analysis was conducted based on medical records from young females patients aged ≤35 years with pathologically confirmed primary breast cancer treated during 2008–2010 at NCI. Cases with non invasive cancer and non carcinoma histology are excluded.ResultsOf the 5408 cases diagnosed with breast cancer, 554 were young. Four hundred & fifty eight patients representing 9.2% were within our inclusion criteria. Almost half of the patients (45.9%) presented with stage III. Axillary nodes involvement was in 63.9%, 83.3% were grade 2. More than one quarter of tumors was hormone receptors negative (28.8%) & Her2 was over-expressed in 30%. Mastectomy was offered in 72% while conservative breast surgery in 26%, 69.2% received chemotherapy either adjuvant, neoadjuvant or both, 82.5% received adjuvant radiotherapy, 68.6% received hormonal therapy. Metastatic disease developed in 51.3%, with 31% having more than one site of metastases. After a median follow up period of 66 months, the median DFS of patients was 60 months. The median DFS was significantly shorter among patients with positive lymph nodes (P < 0.0001), ER negative disease (P = 0.045) and stage III disease (P < 0.0001).ConclusionBreast cancer in young women is aggressive from the time of diagnosis. Our results provide baseline data of young BC in the Middle East & North Africa region; thus, contributing to future epidemiological and hospital-based researches.     

Outcome of small invasive breast cancer with no axillary lymph node involvement

Abstract: The prognosis and need or not for adjuvant therapy in patients with small breast tumors (≤1 cm N0) is the subject of controversy as regards the clinical benefit obtained, toxicity, and the economical costs generated. A retrospective analysis was made of 238 patients with early‐stage breast cancer (pT1 ≤ 1 cm N0M0) diagnosed between January 1993 and May 2008. As regards the systemic adjuvant treatments provided, (a) 122 (51%) received no treatment, (b) 102 (43%) received hormone therapy, (c) 9 (4%) chemotherapy, and (d) 5 (2%) received both hormone therapy and chemotherapy. An analysis was made of disease‐free survival (DFS) and breast cancer‐specific survival in our series of patients, and of their correlation to clinicopathological factors (age, tumor size, histological grade, estrogen receptor (ER) expression, HER‐2 overexpression, and systemic adjuvant therapy). The median follow‐up of this cohort was 63 months (range 5–145). Some type of relapse was recorded in 4.2% of the patients (six patients presented local recurrence in all cases subjected to rescue treatment with surgery and/or radiotherapy, three patients developed distant metastases, and one patient presented a resected local recurrence followed by systemic relapse). The 5 year DFS was 96%, and the 5 year breast cancer‐specific survival was 99.6%. A univariate analysis was made of the clinicopathological variables and their association to DFS. None of the variables was seen to be significantly correlated to shorter DSF except for an association between HER‐2 overexpression and poor outcome borderline significance (p = 0.07). The prognosis of our pT1 ≤ 1 cm N0M0 tumors was excellent, although the absence of systemic adjuvant therapy in one‐half of the patients.     

Late effects of adjuvant chemotherapy adumbrate dormancy complexity in breast cancer

BackgroundDormant avascular micrometastases and single, or small groups of, non-proliferating cells are currently assumed to explain the multipeak dynamics of distant metastases (DM) following primary breast cancer surgical removal.MethodsThe hazard rate pattern for DM was analysed in 1518 premenopausal node-positive patients, enrolled in a series of randomized clinical trials on early breast cancer, which were carried out in Italy and Belgium. Patients underwent surgery alone (n = 397) or surgery plus adjuvant chemotherapy (n = 1121) and the minimal follow up was 15 years.ResultsThe DM hazard rate for patients undergoing surgery alone displayed two early sharp peaks at 9 and 33 months, a wide intermediate one spanning from about 50 to 90 months and a late peak at 115–120 months. Adjuvant chemotherapy was associated with a prominent reduction of the two early peaks leaving a residual one at about 18 months and a reduction of the intermediate peak leaving two small peaks at about 50 and 80 months. The late peak remained unchanged.ConclusionsPresent results reveal the ability of adjuvant chemotherapy to reduce not only the rate of early relapses, but also the rate of intermediate relapses at about the sixth year of follow up. Adjuvant chemotherapy is not impacting on the development of metastases underlying the late peak detected at the tenth year. These findings suggest the existence of a previously unknown dormancy state that, at the primary tumour surgical removal, results in evolving chemo-sensitive metastatic processes, and, moreover, of a later chemo-refractory dormancy state.     

The Impact of Intermediate Time between Chemotherapy and Hypofractionated Radiotherapy to the Radiation Induced Skin Toxicity for Breast Adjuvant Treatment

To evaluate the impact of intermediate time between chemotherapy and radiotherapy (ITCR) to skin toxicity for a hypofractionated irradiation schedule. Forty‐four patients with stage I–II invasive breast cancer receiving postoperative radiotherapy (RT) after lumpectomy and axillary dissection were studied. All patients received RT with 6 MV linear accelerator (LINAC) with a total tumor dose of 53 Gy (Equivalent dose‐EQD2‐ 60 Gy), 2.65 Gy per fraction, in 20 fractions. All patients received six cycles of cyclophosphamide methotrexate fluorouracil chemotherapy i.v. every 21 days. Acute and late effects and cosmetic results were assessed using the European Organization for Research and Treatment of Cancer and Radiation Therapy Oncology Group (EORTC/RTOG) Rating System. The mean follow‐up was 7 years. The spearman rho test showed that there was a significant correlation between short ITCR and acute skin toxicity 3 months post RT, by means of acute radiation induced morbidity. None of the related late‐toxicity parameters was correlated with the ITCR. However, there was significantly higher acute toxicity when the ITCR was less than 20 days (p < 0.05). We may suggest that when a hypofractionated irradiation schedule is used for breast cancer patients, then the ITCR should be more than 20 days from chemotherapy.     

Validation of the AJCC 8th prognostic system for breast cancer in an Asian healthcare setting

AimsWe aim to validate the AJCC 8th edition prognostic staging system for breast cancer in an Asian setting.MethodsClinico-pathologic information and cancer-specific survival (CSS) outcomes of 6287 stage I to III patients with invasive breast cancer who underwent upfront surgery at SingHealth institutions in Singapore from 2006 to 2014 were analyzed. Survival distributions for the different staging systems were estimated by the Kaplan-Meier method and compared using the log-rank tests. Multivariable Cox proportional hazards models were used, with Akaike Information Criterion (AIC) and Harrell's Concordance Index (C-index) to compare both staging systems.Among patients with positive hormone-receptor status, 84.8% received endocrine therapy. Among the cohort, 60.3% of received chemotherapy; 82.1% of node positive patients received chemotherapy and 86.0% of HER2-enriched patients in whom chemotherapy was also indicated received adjuvant HER2-targeted therapy. Ninety-seven percent of patients received anthracyclines and/or taxanes containing chemotherapy regime.ResultsThe median follow up was 64 months. 2921 patients (46.5%) were discordant between the anatomic and prognostic systems of which 363 (5.8%) were upstaged and 2558 (40.7%) were down-staged. For all patients, stages in both the prognostic and anatomic systems were discriminating for 5-year CSS. Controlling for age, ethnicity and receipt of chemotherapy, the prognostic staging system model (AIC = 7538.87, C = 0.79) presented slightly better explanation and concordance of survival times than the anatomic staging system model (AIC = 7607.31, C = 0.77).ConclusionThe prognostic staging system was better than the anatomic staging system in predicting outcomes but the anatomic system remains relevant due to its ease of use.     

The Changing Role of Gene-Expression Profiling in the Era of De-escalating Adjuvant Chemotherapy in Early-Stage Breast Cancer

Purpose

We assessed the recent trends in the administration of adjuvant chemotherapy thereby evaluating the role of the 70-gene signature (70-GS) testing in decision-making in the systemic treatment of patients with lymph node negative (N0) and lymph node positive (N+) breast cancer.

Methods

Patients with a national guideline directed indication for 70-GS use treated between 2013 and 2016 were selected from the Netherlands Cancer Registry. Time trends in the administration of adjuvant chemotherapy were evaluated within guideline- and age-delineated subgroups. The influence of the 70-GS on chemotherapy use was assessed with logistic regression.

Results

During the study period, the overall administration of adjuvant chemotherapy decreased from 49 to 23% and 70-GS use increased from 24 to 51%. The 70-GS was not associated with a decreased likelihood for N0 patients to receive chemotherapy (odds ratio [OR] 1.0; 95% confidence interval [CI] 0.86–1.17), as the proportion of N0 patients who received chemotherapy in the absence of 70-GS use decreased during the study period. In patients with N1a disease, 70-GS testing was associated with a decreased likelihood to receive chemotherapy (OR 0.21; 95% CI 0.15–0.29). In patients < 50 years and 50–59 years of age, 70-GS use was associated with a consistent lower proportion of patients receiving chemotherapy throughout the study period (OR 0.17; 95% CI 0.13–0.23 and OR 0.53; 95% CI 0.43–0.65, respectively).

Conclusions

In this population-based study, the administration of adjuvant chemotherapy in ER+ breast cancer strongly declined. For node-positive and younger patients, 70-GS use was associated with a decreased probability for patients to receive adjuvant chemotherapy.

     

Randomized Multicentric Study of Perioperative Chemotherapy With Mitoxantrone in Early Breast Cancer

Background: To confirm the hypothesis that reducing the interval between surgery and adjuvant chemotherapy could improve prognosis, a randomized multicentric study of adjuvant perioperative chemotherapy (POC) in breast cancer was initiated.Methods: A total of 552 patients were randomized to evaluate whether the addition of POC to standard adjuvant treatment significantly improved outcome. Patients were stratified according to menopausal status, with 362 patients in the postmenopausal group and 192 patients in the premenopausal group. Premenopausal women with positive axillary nodes, negative hormonal receptors, or grade 3 tumors received adjuvant mitoxantrone-based chemotherapy. Node-negative premenopausal patients with grade 1 or 2 tumors expressing hormonal receptors received no standard adjuvant treatment. All postmenopausal women received hormonal therapy (tamoxifen 20 mg/day for 3 years). The perioperative regimen was a 14 mg/m² mitoxantrone infusion at the end of tumor excision.Results: With a median follow-up of 6.1 years, this study showed no significant advantage of POC on overall survival, disease-free survival, or metastasis-free survival for the total cohort or for the premenopausal and postmenopausal groups.Conclusions:POC was a safe procedure in this study. However, the addition of POC to standard adjuvant treatment offered no benefit in breast cancer adjuvant treatment.     

Safety and Clinical Evaluation of Dual Inhibition with Pertuzumab and Trastuzumab Biosimilar SB3 in HER2-Positive Breast Cancer Patients

BackgroundThe addition of trastuzumab to standard chemotherapy has improved survival in patients with HER2-positive breast cancer in neoadjuvant, adjuvant, and metastatic settings. In higher tumor stages, the addition of pertuzumab is now a standard of care and associated with a favorable toxicity profile. We evaluated the safety and efficacy of the trastuzumab biosimilar SB3 in combination with pertuzumab in HER2-positive breast cancer patients.MethodsSeventy-eight patients with HER2-positive breast cancer treated at the Division of Oncology at the Medical University of Graz were included. Summary measures are reported as medians (25th to 75th percentile) for continuous variables and as absolute frequencies (%) for count data.ResultsThirty-five patients received a median of 4 (3–7) cycles of trastuzumab biosimilar SB3 plus pertuzumab. All patients had a normal baseline left ventricular ejection fraction (LVEF; >50%) prior to the initiation of SB3 plus pertuzumab treatment with a median LVEF of 60% (60–65). Twenty-one patients had a median absolute LVEF decline of 1% (−5 to 0). Two patients (5.7%) had a LVEF reduction ≤50%, but none ≥10%. There were no unexpected adverse events. Twenty-two of 35 patients (63%) were treated with trastuzumab biosimilar SB3 and pertuzumab in the neoadjuvant setting and 11 patients (50%) achieved a pathological complete response. The safety and the efficacy in this setting was comparable to the trastuzumab plus pertuzumab combination in neoadjuvantly treated matched samples.ConclusionIn this series of HER2-positive breast cancer patients, the combination of SB3 plus pertuzumab was consistent with the known safety and efficacy profile of trastuzumab and pertuzumab combination.