Estrogen receptor positive operable breast cancer: does menopausal status impact on HER2 and progesterone receptor status?

Purpose

The objective of the present study was to determine whether progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2) status differs by menopausal status in estrogen receptor (ER)-positive breast cancers.

Patients and methods

We retrospectively analyzed the clinicopathological data of 588 with operable ER⁺ breast cancers patients. ER, HER2 and PgR expression in the tumor specimens were examined by immunohistochemistry. The relationship between different variables was assessed by Pearson’s χ² and Fisher’s exact probability tests in univariate analyses. Logistic regression was used for multivariate analyses of relationship between HER2 expression and selected clinicopathological characteristics. Maximum likelihood estimates of the odds ratio (OR) were obtained and 95% confidence intervals (CI) were calculated.

Results

In the postmenopausal women with ER⁺ tumors, HER2 was independently inversely associated with PgR expression (P = 0.017; OR 3.02; 95% CI 1.22–7.49). An ER⁺/PgR⁻ tumor was 3.02 times more likely to express HER2 than an ER⁺/PgR⁺ tumor in the postmenopausal women. However, an ER⁺ tumor in the premenopausal patients failed to show an independent relationship between HER2 and PgR.

Conclusion

Menopausal status played a very important role in determining HER2 and PgR status in ER⁺ breast cancer patients. HER2 was independently inversely associated with PgR only in the postmenopausal women with ER⁺ breast cancers but not in the premenopausal ones.     

The MAGIC survey in hormone receptor positive (HR+), HER2-negative (HER2−) breast cancer: When might multigene assays be of value?

BackgroundA modest proportion of patients with early stage hormone receptor-positive (HR+), HER2-negative (HER2−) breast cancer benefit from adjuvant chemotherapy. Traditionally, treatment recommendations are based on clinical/pathologic criteria that are not predictive of chemotherapy benefit. Multigene assays provide prognostic and predictive information that can help to make more informed treatment decisions. The MAGIC survey evaluated international differences in treatment recommendations, how traditional parameters are used for making treatment choices, and for which patients treating physicians feel most uncertain about their decisions.MethodsThe MAGIC survey captured respondents' demographics, practice patterns, relevance of traditional parameters for treatment decisions, and use of or interest in using multigene assays. Using this information, a predictive model was created to simulate treatment recommendations for 672 patient profiles.ResultsThe survey was completed by 911 respondents (879 clinicians, 32 pathologists) from 52 countries. Chemo-endocrine therapy was recommended more often than endocrine therapy alone, but there was substantial heterogeneity in treatment recommendations in 52% of the patient profiles; approximately every fourth physician provided a different treatment recommendation. The majority of physicians indicated they wanted to use multigene assays clinically. Lack of reimbursement/availability were the main reasons for non-usage.ConclusionsThe survey reveals substantial heterogeneity in treatment recommendations. Physicians have uncertainty in treatment recommendations in a high proportion of patients with intermediate risk features using traditional parameters. In HR+, HER2− patients with early disease the findings highlight the need for additional markers that are both prognostic and predictive of chemotherapy benefit that may support more-informed treatment decisions.     

Is a breast MRI possible and indicated in case of suspicion of breast cancer during lactation?

The paper tries to answer two questions: the safety of the injection of gadolinium during breastfeeding; the value of a breast MRI in the nursing mother if breast cancer is suspected. Recent Anglo-Saxon publications are in favour of continued breastfeeding following the injection of gadolinium. In fact, only a minute quantity of contrast product passes into the mother's milk, much less than the threshold recommended in paediatrics in the infant. However, a suspension of lactation for 24 h after the injection of gadolinium chelate is still recommended in France. The literature is poor as regards the contribution of the MRI during lactation, although the data indicates that the MRI is contributory, in spite of the physiological changes in the breast during this period. In fact, all of the lesions have been visualised and correctly classified according to the BI-RADS classification by the ACR¹. However, the semiology is specific and has to be known.     

Hormonal receptor status,Ki-67 and HER2 expression: Prognostic value in the recurrence of ductal carcinoma in situ of the breast?

PurposeLocal recurrence is considered a major concern in patients diagnosed with ductal carcinoma in situ (DCIS), as its invasive occurrence is associated with high rates of distant disease and mortality. This study aims to assess the possible correlation of hormonal receptor status, Ki-67 and HER2 expression with recurrence rates in women with DCIS, taking also into account the potential prognostic effects of grade and age at diagnosis.Methods230 consecutive patients with DCIS were included in this study. Invasive and non-invasive recurrence events were recorded, as a total. Clinicopathological information, as well as PR positivity, ER positivity, HER2 positivity and ki-67 expression were analyzed. Multivariable Cox regression analysis was performed, examining the risk factors for recurrence.ResultsRecurrence was noted in 17.8% of cases; the median follow-up was 44 months. Higher grade (adjusted HR = 1.72, 95%CI: 1.06–2.78), age at diagnosis (adjusted HR = 0.60, 95%CI: 0.43–0.83), Ki-67 expression (adjusted HR = 1.78, 95%CI: 1.11–2.88), and type of administered treatment were independently associated with increased recurrence rates. Recurrence rates were not significantly associated with ER, PR status or HER2 expression.ConclusionIn addition to high grade, administered treatment and younger age at diagnosis, high Ki-67 expression seems to be independently associated with increased likelihood of recurrence in patients with DCIS. Future studies with additional molecular markers seem necessary to further improve the identification of high-risk patients for DCIS recurrence.     

Is sarcopenia a missed factor in the management of patients with metastatic breast cancer?

BackgroundSarcopenia has emerged as an important parameter to predict outcomes and treatment toxicity. However, limited data are available to assess sarcopenia prevalence in metastatic breast cancer and to evaluate its management.MethodsThe SCAN study was a cross-sectional multicenter French study that aimed to estimate sarcopenia prevalence in a real-life sample of metastatic cancer patients. Sarcopenia was identified by low muscle mass (estimated from the skeletal muscle index at the third lumbar, via computed tomography) and low muscle strength (defined by handgrip strength). Three populations were distinguished based on EWGSOP criteria: a sarcopenic group with low muscle mass AND strength, a pre-sarcopenic group with low muscle mass OR strength and a normal group with high muscle mass AND strength.ResultsAmong 766 included patients, 139 patients with breast cancer and median age of 61.2 years (29.9–97.8 years) were evaluable; 29.5% were sarcopenic and 41.0% were pre-sarcopenic. Sarcopenic patients were older (P < 0.01), had a worse PS-score (P < 0.05), and a higher number of metastatic sites (P < 0.01), the majority being hepatic and bone. A moderate agreement between the oncologist's diagnosis and sarcopenia evaluation by muscle mass and strength was recognized (Cohen's kappa = 0.45). No associations were found between sarcopenia and adverse event occurrence in the 12 patients for whom these were reported. Sarcopenic patients were underdiagnosed and nutritional care and physical activity were less proposed.ConclusionIt is necessary to evaluate sarcopenia due to its impact on patient prognosis, and its utility in guiding patient management in metastatic breast cancer.     

Is there a case for anti-HER2 therapy without chemotherapy in early breast cancer?

Trastuzumab in combination with chemotherapy is now standard of care for patients with early HER2-positive cancers larger than 1 cm. Some patients however may not need or simply may not want chemotherapy with its associated toxicities. For example patients with small (<1 cm.Tla.b) node-negative (NO) HER2-positive cancers were largely excluded from all the large randomized adjuvant trastuzumab trials on the basis of perceived excellent prognosis, yet recently several retrospective studies have suggested that this is not always the case and more active adjuvant treatment including anti-HER2 therapy may be warranted. Subset analysis of one trastuzumab trial (HERA) demonstrated that patients with 1-2 cm cancers derived at least as much clinical benefit from 1-year of adjuvant trastuzumab with chemotherapy as the overall cohort and 2 retrospective audits have confirmed this. Anti-HER2 therapy including both trastuzumab and lapatinib alone has established clinical efficacy in metastatic disease, with response rates of up to 35% and with some long term remissions. Combination anti-HER2 therapy with trastuzumab/lapatinib and with trastuzumab/pertuzumab have also been shown to have efficacy as second line treatment inpatients after trastuzumab. Trastuzumab and Lapatinib have each been shown to improve time to progression and response rate when given with anastrazole and letrozole respectively as first line treatment for metastatic ER-positive HER2-positive disease. In neoadjuvant trials the combination of trastuzumab and pertuzumab without chemotherapy have achieved pathological complete remission rates in a significant minority of patients, suggesting that a subgroup exists for whom anti-HER2 therapy alone may be as effective as with additional chemotherapy. Trials and prospective studies are now warranted to investigate this issue further in selected patients and these must be accompanied by tissue collection to try to identify predictive biomarkers. Meanwhile there is already enough circumstantial evidence to justify anti-HER2 therapy alone in selected patients for whom chemotherapy is contraindicated.     

Is OSNA better than imprint cytology for intraoperative diagnosis of cancer involvement of axillary sentinel node in breast cancer?

ObjectiveThe study aim was to establish Sensitivity, Specificity, Positive Predictive Value, Negative Predictive Value (NPV), and Accuracy Values of both imprint cytology (IC) and the OSNA assay for intraoperative assessment of axillary sentinel node (SN) cancer involvement in breast cancer. Specifically, we wished to find out if true positive and false negative results of IC were associated to axillary lymphadenectomy (ALND). Also, we addressed a comparative cost analysis between techniques.Methods244 patients treated for breast cancer in the Breast Unit of Hospital Germans Trias i Pujol from 2011 to 2015 were prospectively included. A transversal, consecutive design was applied to assess IC compared to the reference test (OSNA). Inclusion criteria were: T1 and T2 tumors with negative nodes, both clinically and on ultrasound.ResultsSensitivity of IC for macrometastases was 70%. The NPV of IC for macrometastases was 95,75%. Accuracy of IC was 96,12%. In the comparative cost analysis, the release time of results for OSNA doubled that of IC and was associated with an increased cost of € 370.ConclusionsIC has been stated as a good technique for intraoperative cancer involvement SN with high sensitivity and NPV compared to the OSNA assay. It allows keeping the whole node tissue and thus the possibility of improved histopathological evaluation, which can be useful for adjuvant, and offers the advantage of being less time consuming. Cost analysis shows a higher cost for OSNA, which may exceed the benefit of sorting out false negatives from IC.     

Does the 21-gene recurrence score have clinical utility in HR+/HER2+ breast cancer?

The 21-gene recurrence score assay has been validated as a predictive biomarker in early-stage HR+ and HER2-breast cancer. It is not indicated for use in HER2+ disease based on national guidelines. In this study, we assessed the value of 21-gene recurrence score (RS), or OncotypeDX (ODX), testing in HR+/HER2+ breast cancer.We used the National Cancer Database to identify patients with stages I-II, HR+/HER2+ breast cancer who received multi-gene testing with ODX. We then explored the prognostic and predictive value of this biomarker through various forms of survival modeling.ODX testing was performed in n = 5,280 patients. N = 2,678 patients (50.7%) had a RS < 26, while n = 2,602 (49.3%) had a RS ≥26. In Kaplan-Meier survival modeling for patients with recurrence scores <26, there was no significant difference in overall survival (p = 0.445) between patients receiving different systemic treatment regimens. However, when recurrence scores were ≥26, there was a statistically-significant difference in overall survival between systemic treatment regimens (p < 0.001). 5-year overall survival was highest (97.4%) for patients receiving triple therapy (anti-HER2 with chemotherapy and endocrine therapy), followed by those receiving dual therapy with endocrine and anti-HER2 (96.7%), and endocrine with chemotherapy (94.9%). Patients receiving endocrine therapy alone exhibited the lowest 5-year overall survival (88.5%).ResultsAnalysis from this large national cancer registry suggests that multigene testing may have predictive value in treatment selection for patients with early-stage, HR+/HER2+ breast cancer. Prospective trials are warranted to identify subgroups of patients with HR+/HER2+ breast cancer who can be spared anti-HER2 treatments and cytotoxic chemotherapy.     

Axillary ultrasound for preoperative nodal staging in breast cancer patients: Is it of added value?

BackgroundNew insights show that an axillary lymph node dissection (ALND) may not always be indicated for metastases detected by ultrasound (pathologically proven). This study investigated whether axillary ultrasound accurately predicts pN0, pN1 and pN2–pN3 status.MethodsData were retrospectively collected from all consecutive patients with invasive breast cancer who underwent (primary) surgery between 2008 and 2012. False negative percentages and negative predictive values (NPVs) for sonographic nodal staging were calculated for all patients and again for cT1–2 patients treated by breast conserving therapy (BCT).ResultsA total of 577 axillary ultrasounds were included. After negative ultrasound findings (cN0), pathology showed pN2–pN3 disease in 4.4% of these cases, with an NPV of 95.5% (93.4–97.1%). When cN1 (1–3 suspicious nodes) was predicted, pathology showed pN2–pN3 disease in 41.2%, with an NPV of 58.5% (44.2–71.5%).In the subgroup of patients with cT1–2 breast cancer that were treated by BCT, pathology showed pN2–pN3 disease in 2.3% after negative ultrasound findings (cN0), with an NPV of 97.7% (94.9–99.0%). When cN1 was predicted (n = 12), pathology showed pN2–pN3 disease in 50.0%, with an NPV of 50.0% (22.3–77.9%). A direct ALND was performed in these 12 cN1 cases; pathology showed six patients with pN1 (three patients with one and three with two macrometastases) and six with pN2–pN3 disease (4, 5, 11, 13, 16 or 22 macrometastases, respectively).ConclusionIn conclusion, a negative axillary ultrasound generally excludes the presence of pN2–pN3 disease. An axillary ultrasound cannot accurately differentiate between pN1 and pN2–pN3. It could be argued that the standard performance of an axillary ultrasound in breast cancer patients is questionable; multidisciplinary discussion could guide decisions on the use of axillary ultrasound for the individual patient.     

Trastuzumab therapy in Australia: Which patients with HER2+ metastatic breast cancer are assessed for cardiac function?

PurposeTo manage the potential trastuzumab mediated cardiotoxicity, clinical guidelines recommend pre-treatment cardiac function assessment and 3-monthly reassessment during therapy. This study examined rates of cardiac function assessment and predictors of assessment among patients receiving trastuzumab for HER2+ metastatic breast cancer treatment in routine clinical care.MethodsOur cohort comprised 3418 women receiving trastuzumab for HER2+ metastatic breast cancer under Australia's nationally funded Herceptin Program (2001–2010). We examined rates of pre-treatment and during-treatment assessment. We used logistic regression and zero-inflated Poisson regression to examine predictors of pre-treatment and during-treatment assessment respectively.Results37.7% of patients were assessed pre-treatment, 50.4% during therapy, and 26.4% both before and during therapy. Among patients assessed for cardiac function, reassessment occurred regularly (median of 3.9 months). History of cardiovascular conditions and prior anthracycline use predicted pre-treatment assessment (OR = 1.32, 95% CI: 1.08–1.61; OR = 1.23, 95% CI: 1.05–1.44 respectively). Concurrent trastuzumab and taxane use, exposure to anthracyclines, and older age predicted during-treatment assessment (IRR = 1.17, 95% CI: 1.06–1.29; IRR = 1.12, 95% CI: 1.02–1.23; and IRR = 1.05, 95% CI: 1.01–1.09 respectively). Patients with multi-morbidities were less likely to receive during-treatment assessment.ConclusionOver the last decade, cardiac function assessment in a large cohort of patients receiving trastuzumab was not consistent with guideline recommendations. The association between cardiac monitoring and risk factors for cardiac dysfunction suggest clinicians are triaging patients prior to implementing cardiac assessment. Efforts are needed to identify barriers to implementing current guidelines for cardiac monitoring in metastatic breast cancer patients undergoing trastuzumab treatment, particularly those with multi-morbidities.     

Prognosis of HER2-positive pregnancy-associated breast cancer: Analysis from the French CALG (Cancer Associé à La Grossesse) network

IntroductionThe prevalence of pregnancy-associated breast cancer is increasing. HER2-positive breast cancers typically have a poor prognosis. The objective of our study was to compare the prognosis of patients with HER2-positive breast cancer diagnosed during pregnancy (HER2-positive BCP) to young women diagnosed with HER2-positive breast cancer outside of pregnancy (HER2 non-BCP).MethodsData of patients managed for invasive breast carcinoma between January 2005 and 2020 were retrospectively collected from the database of Tenon University Hospital (Paris, France), part of the “Cancer lié à la Grossesse” network.ResultsFifty-one patients with HER2-positive BCP were matched on age at diagnosis with 51 HER2-positive non-BCP patients. Locally advanced disease with axillary lymph node involvement were frequent. Tumors were frequently aggressive with high grade (p = 0.57) and high Ki67 (p = 0.15). Among the HER2-positive BCP patients, the mean term at diagnosis was 19.3 week of gestation (WG). Eighty-four percent of the patients continued their pregnancy with a mean term at delivery of 34.2WG. Chemotherapy modalities differed between the two groups: neoadjuvant chemotherapy was more frequent in the HER2-positive BCP group (p = 0.03) and adjuvant chemotherapy more frequent in the HER2 non-BCP group (p = 0.009). The recurrence rate was 10% (n = 5) and 18% (n = 9) in the HER2-positive BCP and HER2 non-BCP groups, respectively, p = 0.25. Breast cancer-free survival was poorer in the HER2-positive BCP group with earlier recurrence, p = 0.008. No difference in type of recurrence was found between the groups (p = 0.58).ConclusionThis matched case-control study implies that patients with HER2-positive BCP still have a poorer prognosis than non-pregnant HER-positive patients.     

Is there a role for microsurgery in the prevention of arm lymphedema secondary to breast cancer treatment?

The secondary lymphedema of the upper limb (post-mastectomy lymphedema) has an incidence, in patients who underwent axillary lymphadenectomy for breast cancer, between 5 to 25%, up to 40% after radiotherapic treatment. We studied 50 patients treated for breast cancer. The patients were divided in two groups of 25 each, comparable for age, sex, pathology and treatment and followed up to 5 years after operation for breast. One group of 25 patients was controlled only clinically (physical examination, water volumetry) at 1-3-6 months and 1-3-5 years from breast cancer treatment. The other group of 25 patients was followed also by lymphatic scintigraphy performed pre-operatively and after 1-3-6 months and 1-3-5 years from operation. In the first group, followed only clinically, lymphedema appeared in 9 patients after a period variable from 1 week to 2 years, with highest incidence between 3 and 6 months. In the second group of 25 patients, the preventive therapeutic protocol allowed to have a clinically evident arm lymphedema only in 2 patients. The comparison of the two groups of 25 patients proved a statistically significant difference in the appearance of arm secondary lymphedema (p = 0.01, using Fisher's exact test). The diagnostic and therapeutic preventive procedures allow to reduce the incidence rate of lymphedema significantly, in comparison with patients who did not undergo this protocol of prevention.     

Do all patients with HER2 positive breast cancer require one year of adjuvant trastuzumab? A systematic review and meta-analysis

One year of adjuvant trastuzumab is considered the standard treatment for patients with HER2 positive breast cancer. However, a shorter duration of trastuzumab may be associated with reduced costs and side effects. Results from randomized trials with diverse non-inferiority margins comparing one year to a shorter duration of adjuvant trastuzumab are not consistent and have not been systematically reviewed using a non-inferiority meta-analysis approach.We conducted a systematic review and meta-analysis of randomized trials to assess whether a shorter duration of adjuvant trastuzumab was non-inferior to one year of treatment or not. The non-inferiority margin for the meta-analysis was pre-defined as the median of the margins of all the trials included. Data of 11,376 patients from 5 trials were analyzed. Non-inferiority margins in included studies varied from 1.15 to 1.53 with median of 1.29 for HR of DFS. A shorter duration of trastuzumab was non-inferior to one year of therapy for DFS (HR 1.13, 95%CI 1.03–1.24) but inconclusive for OS (HR 1.14, 95%CI 1.00–1.30). In a subgroup analysis for DFS outcome, shorter therapy was non-inferior in patients with ER positive disease (HR 1.10, 95%CI 0.95–1.28) and those with sequential therapy (HR 0.97, 95%CI 0.75–1.27) and when the duration of treatment was 6 months (HR 1.09, 95%CI 0.98–1.22). Although a shorter duration of adjuvant trastuzumab was non-inferior to one year of therapy for DFS in patients with HER2 positive breast cancer based on our HR margin of 1.29, any benefit of a shorter duration comes at a loss of efficacy with an increase in absolute risk up to 3.9% for 5 year DFS. Whether the potential increased risk is clinically acceptable for the benefits of a shorter duration remains debatable.