Axillary Management: How Much Is Too Much?

PURPOSE OF REVIEW: To review the current management of the axilla in breast cancer. RECENT FINDINGS: Axillary dissection is no longer indicated in patients with clinically node-negative axilla with 1-2 positive sentinel lymph nodes following upfront surgery or in patients with clinically node-negative axilla following neoadjuvant chemotherapy. Breast cancer has evolved away from routine axillary clearance to the less invasive sentinel lymph node biopsy to now complete omission of axillary sampling in select patients. We will review the most salient evidence that has shaped these practice changes over the last three decades. Current practice controversies are especially relevant for elderly populations and those receiving neoadjuvant therapy. Ongoing clinical trials will provide data to further guide breast cancer surgical management.

Racial disparities in disease-specific mortality and surgical management of patients with ductal carcinoma in situ with microinvasion.

BACKGROUND AND OBJECTIVES: Given persistent racial disparities in breast cancer outcomes, this study explores racial differences in disease-specific mortality and surgical management among patients with microinvasive ductal carcinoma in situ (DCIS-MI). METHODS: The Surveillance, Epidemiology, and End Results Program was queried for patients aged 18+ years with DCIS-MI between January 1, 2010 and December 31, 2018. The study cohort was divided into non-Hispanic Black (NHB) and non-Hispanic White (NHW) patients. Disease-specific mortality was evaluated using Cox proportional hazards models. RESULTS: A total of 3400 patients were identified, of which 569 (16.7%) were NHB and 2831 (83.3%) were NHW. Compared with NHW patients, NHB patients had more positive lymph nodes (7.6% vs. 3.9% p < 0.001). In addition, NHB women were more likely to undergo axillary lymph node dissection (6.0% vs. 3.8%, p = 0.044) and receive chemotherapy (11.8% vs. 7.2%, p < 0.001). There were no racial differences in breast surgery type (p = 0.168), reconstructive surgery (p = 0.362), or radiation therapy (p = 0.342). Overall, NHB patients had worse disease-specific mortality (adjusted hazard ratio 2.13, 95% confidence interval [CI]: 1.10-4.14) with mortality risks diverging from NHW women after 3 years (6 years rate ratio [RR] 2.12, 95% CI: 1.13-4.34; 9 years RR 2.32, 95% CI: 1.24-4.35). CONCLUSIONS: NHB women with DCIS-MI present with higher nodal disease burden and experience worse disease-specific mortality than NHW women.

An Image-Rich Educational Review of Breast Pain.

Breast pain is extremely common, occurring in 70% to 80% of women. Most cases of breast pain are from physiologic or benign causes, and patients should be reassured and offered treatment strategies to alleviate symptoms, often without diagnostic imaging. A complete clinical history and physical examination is key for distinguishing intrinsic breast pain from extramammary pain. Breast pain without other suspicious symptoms and with a negative history and physical examination result is rarely associated with malignancy, although it is a common reason for women to undergo diagnostic imaging. When breast imaging is indicated, guidelines according to the American College of Radiology Appropriateness Criteria should be followed as to whether mammography, US, or both are recommended. This review article summarizes the initial clinical evaluation of breast pain and evidence-based guidelines for imaging. Additionally, the article reviews cyclical and noncyclical breast pain and provides an image-rich discussion of the imaging presentation and management of benign and malignant breast pain etiologies.

Efficacy and safety of near-infrared fluorescence identification of the thoracic duct during left lateral neck dissection.

BACKGROUND: Thoracic duct leaks occur in up to 5% of left lateral neck dissections. No one imaging modality is routinely used to identify the thoracic duct intraoperatively. The goal of our study was to evaluate the efficacy and safety of indocyanine green lymphangiography for intraoperative identification of the thoracic duct compared to traditional methods using ambient and evaluate the optimal timing of indocyanine green administration. METHODS: We enrolled all patients who underwent left lateral neck dissection at our institution from 2018 to 2022 in this prospective clinical trial. After indocyanine green injection into the dorsum of the foot, we performed intraoperative imaging was performed with a near-infrared fluorescence camera. We reported the data using descriptive statistics. RESULTS: Of the 42 patients we enrolled, 14 had prior neck surgery, and 3 had prior external beam radiation. We visualized the thoracic duct with ambient light in 48% of patients and with near-infrared fluorescence visualization in 64%. In 17% of patients, we could identify the thoracic duct only using near-infrared fluorescence visualization, which occurred within 3 minutes of injection, and were required to re-dose 5 patients. We visualized the thoracic duct with near-infrared fluorescence in all patients with prior neck radiation and 77% of patients with prior neck surgery. One adverse reaction occurred (hypotension), and 5 intraoperative thoracic duct injuries occurred that were ligated. There with no chylous fistulas postoperatively. CONCLUSION: This trial demonstrates that near-infrared fluorescence identification of the thoracic duct is feasible and safe with indocyanine green lymphangiography, even in patients with prior neck surgery or radiation.

Low Hospital Volume Is Associated with Higher All-Cause Mortality in Black Women with Triple Negative Breast Cancer.

INTRODUCTION: This study examines the association between hospital volume and all-cause mortality in Black women with triple negative breast cancer (TNBC) who received surgery and chemotherapy. METHODS: Black women ages 18+ with stage I-III TNBC who received both surgery and chemotherapy were identified in the National Cancer Database (NCDB). Hospital volume was determined using the number of annual breast cancer cases divided by the number of years the hospital participated in the NCDB. Hospital annual volume quartiles ranged from Q1 (lowest) to Q4 (highest). Univariable analysis and multivariable logistic regression modeling with restricted cubic splines examined the effect of hospital volume on all-cause mortality. RESULTS: Sixteen thousand five hundred fifty-six patients met the study criteria. All-cause mortality incidence was lower at higher volume compared to lower volume hospitals Q1 24.1% (95% CI: 22.8 to 25.4), Q2 21.8% (95% CI: 20.5 to 23.1), Q3 20.9% (95% CI: 19.6 to 22.1), Q4 19.0% (95% CI: 17.7 to 20.1), p<0.001. On multivariable analysis, treatment at the highest hospital volume quartile was associated with a 21% reduction in the odds of death compared to the lowest quartile [Q4 Vs. Q1, OR=0.79 (95% CI: 0.67 to 0.92)]. For every 100-patient increase in annual volume, all-cause mortality was reduced by 4% [OR=0.96 (95% CI: 0.94 to 0.98)]. There was a significant linear dose-dependent relationship between increasing hospital volume and all-cause mortality. CONCLUSION: Black women treated at high-volume hospitals have lower all-cause mortality than those at low-volume hospitals. Future studies should examine the characteristics of high-volume hospitals associated with improved outcomes.

Trends in utilization of contralateral prophylactic mastectomy among different age, racial and ethnic groups.

Background: The use of contralateral prophylactic mastectomy (CPM) has increased over the last two decades with variations in the frequency of reconstruction. The objective of this cohort study is to elucidate the use of CPM and reconstruction among underrepresented racial and ethnic groups and women over 65 years. Methods: Women over 18 years, diagnosed with stages I to III breast cancer who underwent mastectomy from 2004-2017 were identified in the National Cancer Database (NCDB) and grouped into CPM vs. non-CPM. Multivariable analyses were used to examine the associations between CPM and reconstruction with sociodemographic and clinical factors. Results: A total of 571,649 patients were identified. Patients who underwent CPM were under 50 years (45.9%), White (88.4%) and with private insurance (73.5%). On multivariable analysis, women over 65 years [odds ratio (OR): 0.18, P<0.001], non-White (Black, OR: 0.56, P<0.001) and without private insurance (uninsured, OR: 0.50, P<0.001) had decreased odds of CPM. Women over 65 years (OR: 0.11, P<0.001), non-White (Asian/Pacific Islander, OR: 0.58, P<0.001) and without private insurance (Medicaid, OR: 0.41, P<0.001) had decreased odds of reconstruction. Conclusions: Non-White women and women over the age of 65 years were less likely to have CPM or reconstruction than their White counterparts from 2004 to 2017. Research is needed to understand factors impacting decision-making.

Loss of TSC1 in secondary angiosarcoma of the breast.

Key Clinical Message: Post-radiation angiosarcoma of the breast is a rare complication associated with a poor prognosis. This case reports the first loss of function mutation in TSC1 in breast radiation-induced angiosarcoma and illustrates the utility of evaluating these markers to identify potential therapeutic targets. Abstract: Post-radiation angiosarcoma of the breast is rare and associated with a poor prognosis. This case presents the first loss of function mutation in TSC1 in breast radiation-induced angiosarcoma. Evaluation of these markers can aid in identifying potential therapeutic targets.

Examining racial differences in treatment and survival among patients with Paget's disease of the breast.

BACKGROUND: The objective of this study was to evaluate racial differences in treatment (ie, surgery, chemotherapy, and radiation) and survival among patients with Paget's disease of the breast in the Surveillance, Epidemiology and End Result program. METHODS: Women >18 years old diagnosed with localized or regional Paget's disease between January 1, 2010 to December 31, 2016 in the Surveillance, Epidemiology and End Result program were included. The cohort was divided into Black and White patients. Univariable analysis compared the groups. Using propensity score matching, Black and White patients were nearest matched (1:2) on age at diagnosis; Surveillance, Epidemiology and End Result summary stage; surgery; chemotherapy; and year of diagnosis. The log-rank test evaluated the matched sample's overall survival and disease-specific survival. RESULTS: Of the 1,181 patients, the racial distribution was 1,049 (88.8%) White and 132 (11.2%) Black. A higher percentage of Black women were Medicaid insured (Black 25.8% vs White 11.1%), lived in neighborhoods with low socioeconomic status (Black 53.0% vs White 25.4%), and had regional disease than White women (Black 41.7% vs White 29%). There were no racial differences in receipt of radiation therapy (P = .90), breast surgery (P = .23), or axillary surgery (P = .25). Black patients were more likely to receive chemotherapy (Black 34.8% vs White 26.3% P = .038). In the propensity matched cohort, Black patients had a worse overall survival (P < .005) and disease-specific survival (P = .05) than White patients. CONCLUSION: In this cohort of patients with Paget's disease, despite differences in sociodemographic factors, there were no disparities in locoregional treatment. However, on matched analysis, Black patients had a worse overall survival and disease-specific survival than their White counterparts.

Bilateral Paget's Disease of the Breast in a Patient with CHEK2 Mutation.

We report a case of a 53-year-old woman with a CHEK2 mutation who was found on histology to have bilateral incidental Paget's disease of the breast following bilateral prophylactic mastectomy.

Targeting PI3Kß alone and in combination with chemotherapy or immunotherapy in tumors with PTEN loss.

Background: PTEN-deficient tumors are dependent on PI3Kß activity, making PI3Kß a compelling target. We evaluated the efficacy of PI3Kß inhibitor AZD8186 on tumors with PTEN loss. Results: In vitro cell viability assay and immunoblotting demonstrated that PTEN loss was significantly correlated with AZD8186 sensitivity in triple negative breast cancer (TNBC) cell lines. Colony formation assay confirmed sensitivity of PTEN-deficient cell lines to AZD8186. AZD8186 inhibited PI3K signaling in PTEN loss TNBC cells. AZD8186 in combination with paclitaxel, eribulin had synergistic effects on growth inhibition in PTEN loss cells. AZD8186 promoted apoptosis in PTEN loss cells which was synergized by paclitaxel. In vivo, AZD8186 had limited activity as a single agent, but enhanced antitumor activity when combined with paclitaxel in MDA-MB-436 and MDA-MB-468 cell-line xenografts. AZD8186 significantly enhanced antitumor efficacy of anti-PD1 antibodies in the PTEN-deficient BP murine melanoma xenograft model, but not in the PTEN-wild-type CT26 xenograft model. Methods: In vitro, cell proliferation and colony formation assays were performed to determine cell sensitivity to AZD8186. Immunoblotting was performed to assess PTEN expression and PI3K signaling activity. FACS was performed to evaluate apoptosis. In vivo, antitumor efficacy of AZD8186 and its combinations were evaluated. Conclusions: AZD8186 has single agent efficacy in PTEN-deficient TNBC cell lines in vitro, but has limited single agent efficacy in vivo. However, AZD8186 has enhanced efficacy when combined with paclitaxel and anti-PD1 in vivo. Further study is needed to determine optimal combination therapies for PTEN-deficient solid tumors.

TAK228 enhances antitumor activity of eribulin in triple negative breast cancer.

Background: Phosphatase and tensin homologue deleted from chromosome 10 (PTEN) negatively regulates the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway. Triple negative breast cancers (TNBC) are often PTEN-deficient, making mTOR a compelling target. We evaluated the efficacy of catalytic mTOR inhibitor TAK228 alone and in combination with eribulin in TNBC. Results: Five of eight triple negative breast cell lines were sensitive to TAK228, independent of PIK3CA/PTEN status. Western blotting demonstrated inhibition of mTORC1/2 signaling as demonstrated by decreased phospho-AKT, phospho-S6 and phospho-4EBP1. In vitro, TAK228 was synergistic with eribulin in all eight TNBC cell lines. The combination of TAK228 and eribulin did not enhance apoptosis but increased G2/M growth arrest. In vivo, TAK228 led to modest growth inhibition in TNBC patient-derived xenografts (PDXs) with no tumor regression observed. In two TNBC PDXs with PTEN loss, one with intrinsic eribulin sensitivity, another eribulin resistance, TAK228 in combination with eribulin did not enhance in vivo efficacy. In a third PTEN-negative TNBC model, eribulin alone achieved disease stabilization, but the combination of TAK228 and eribulin led to significantly smaller tumor volumes compared to eribulin alone (p < 0.001). Methods: We tested in vitro efficacy of TAK228 in a panel of TNBC cell lines with cell proliferation assays. In vivo antitumor efficacy of TAK228 was evaluated alone and in combination with eribulin. Conclusion: TAK228 enhances the antitumor efficacy of eribulin in TNBC models in vitro, and enhanced in vivo activity in selected models. Further study is needed to determine the potential of this combination, and optimal patient selection strategies.

A mathematical model of sickle cell genome frequency in response to selective pressure from malaria.

Because of the relative prevalence of hereditary sickle cell disease and the auxiliary role of the sickle cell gene in reducing the mortality of malaria, it is believed that P. falciparum has exerted selection pressure on human populations to increase the prevalence of this otherwise detrimental gene. A model incorporating three genotypes and two age cohorts is used to test the hypothesis that higher death rates due to malaria can exert selective pressure to increase the prevalence of the sickle cell gene. The model displays selection pressure for the carrier gene in the presence of increasing malaria death rates for either adults or children, showing both higher final frequencies of the gene as well as shortened time to reach these frequencies.

A novel ALK rearrangement in an inflammatory myofibroblastic tumor in a neonate.

Inflammatory myofibroblastic tumors (IMTs) are uncommon lesions primarily affecting children and young adults. They have rarely been described in infants, with a very small number described in neonates. Structural rearrangements in the anaplastic large-cell lymphoma kinase gene (ALK) has contributed to our categorizing this lesion as a neoplasm. In addition, rearrangements of the ALK gene have been implicated in the pathogenicity of many other hematolymphoid and non-hematolymphoid tumors, typically involving 2p23 with different partners or with pericentric inversion. We report a previously undescribed cryptic deletion and intrachromosomal-insertional translocation of the 3'-region of the ALK gene from 2p23 to the 2q33-q35 in an IMT of a newborn patient with an apparently normal G-band karyotype of the tumor.

Photodynamic tumor eradication with a novel targetable photosensitizer: strong vascular effects and dependence on treatment repetition versus potentiation.

A novel pyropheophorbide-a (PPa) derivative, Ac-sPPp, was developed in our lab for targeted photodynamic therapy (PDT) and combination therapies. Its versatile peptide moiety, high water-solubility, amphiphilicity, and micellar aggregation allow efficient coupling to targeting moieties and convenient mixing with other therapeutics. Photosensitizer immunoconjugate (PIC) targeted PDT, using Ac-sPPp conjugated to therapeutic anti-epidermal growth factor receptor (EGFR) antibody cetuximab, and PDT + chemotherapy combination treatment, using Ac-sPPp mixed with stealth liposomal doxorubicin (Doxil), were investigated as promising strategies for potentiating PDT and improving target specificity. Passively targeted PDT with Ac-sPPp only or surfactant-solubilized PPa was also investigated for comparison. The A-431 human vulvar squamous cell carcinoma, xenografted in nude mice, was chosen as a tumor model because of its high EGFR expression and sensitivity to liposomal doxorubicin in vitro. Fluorescence imaging and PDT experiments showed that Ac-sPPp formulations circulated far longer and provided superior tumor contrast and superior tumor control compared to PPa. Strong PDT vascular effects were observed by laser Doppler imaging regardless of whether Ac-sPPp was passively or actively targeted. Passively targeted Ac-sPPp PDT gave equivalent or better tumor control than PIC-targeted PDT or PDT + Doxil combination therapy, and when treatments were repeated, it also yielded the highest cure rate.

Development of an ErbB-overexpressing A-431 optical reporting tumor xenograft model to assess targeted photodynamic therapy regimens.

To better assess the efficacy of erbB-targeted therapies, it would help to have optical reporting human tumor xenograft models that abundantly express erbB receptors. A-431 cells have frequently been used in erbB1-targeting studies, but a well-characterized optical reporting version of the cell line has not been readily available. In this study, optical reporting A-431 clones were developed that express both a fluorescent protein reporter (green, GFP; or red, RFP) and a bioluminescent reporter, firefly luciferase. Reporter genes were transduced into cells using commercial lentiviral vectors, and clonal selection was carried out using a series of procedures. A number of clones were isolated for further characterization. A GFP/luciferase clone, A-431/D4, and an RFP/luciferase clone, A-431/G4, were obtained that exhibit erbB1 expression levels and tumor growth kinetics similar to the parental cells. To demonstrate the utility of the optical reporting clones, A-431/G4 tumors were grown subcutaneously in nude mice and treated with vascular-targeted photodynamic therapy (PDT), which targets the angiogenic consequences of erbB signaling. The A-431/G4 tumor model permitted highly sensitive longitudinal monitoring of PDT treatment response using optical imaging. A-431/D4 and A-431/G4 optical reporting tumor models should also prove useful for assessing therapies that directly target the erbB1 receptor.