Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial.

BACKGROUND: HER2 mutations are targetable alterations in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). In the SUMMIT basket study, patients with HER2-mutant MBC received neratinib monotherapy, neratinib + fulvestrant, or neratinib + fulvestrant + trastuzumab (N + F + T). We report results from 71 patients with HR+, HER2-mutant MBC, including 21 (seven in each arm) from a randomized substudy of fulvestrant versus fulvestrant + trastuzumab (F + T) versus N + F + T. PATIENTS AND METHODS: Patients with HR+ HER2-negative MBC with activating HER2 mutation(s) and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy received N + F + T (oral neratinib 240 mg/day with loperamide prophylaxis, intramuscular fulvestrant 500 mg on days 1, 15, and 29 of cycle 1 then q4w, intravenous trastuzumab 8 mg/kg then 6 mg/kg q3w) or F + T or fulvestrant alone. Those whose disease progressed on F + T or fulvestrant could cross-over to N + F + T. Efficacy endpoints included investigator-assessed objective response rate (ORR), clinical benefit rate (RECIST v1.1), duration of response, and progression-free survival (PFS). Plasma and/or formalin-fixed paraffin-embedded tissue samples were collected at baseline; plasma was collected during and at end of treatment. Extracted DNA was analyzed by next-generation sequencing. RESULTS: ORR for 57 N + F + T-treated patients was 39% [95% confidence interval (CI) 26% to 52%); median PFS was 8.3 months (95% CI 6.0-15.1 months). No responses occurred in fulvestrant- or F + T-treated patients; responses in patients crossing over to N + F + T supported the requirement for neratinib in the triplet. Responses were observed in patients with ductal and lobular histology, 1 or ≥1 HER2 mutations, and co-occurring HER3 mutations. Longitudinal circulating tumor DNA sequencing revealed acquisition of additional HER2 alterations, and mutations in genes including PIK3CA, enabling further precision targeting and possible re-response. CONCLUSIONS: The benefit of N + F + T for HR+ HER2-mutant MBC after progression on CDK4/6is is clinically meaningful and, based on this study, N + F + T has been included in the National Comprehensive Cancer Network treatment guidelines. SUMMIT has improved our understanding of the translational implications of targeting HER2 mutations with neratinib-based therapy.

Evaluation of safety and efficacy of p53MVA vaccine combined with pembrolizumab in patients with advanced solid cancers.

BACKGROUND: Vaccination of cancer patients with p53-expressing modified vaccinia Ankara virus (p53MVA) has shown in our previous studies to activate p53-reactive T cells in peripheral blood but without immediate clinical benefit. We hypothesized that the immunological responses to p53MVA vaccine may require additional immune checkpoint blockade to achieve clinically beneficial levels. We therefore conducted a phase I trial evaluating the combination of p53MVA and pembrolizumab (anti-PD-1) in patients with advanced solid tumors. PATIENTS AND METHODS: Eleven patients with advanced breast, pancreatic, hepatocellular, or head and neck cancer received up to 3 triweekly vaccines in combination with pembrolizumab given concurrently and thereafter, alone at 3-week intervals until disease progression. The patients were assessed for toxicity and clinical response. Correlative studies analyzed p53-reactive T cells and profile of immune function gene expression. RESULTS: We observed clinical responses in 3/11 patients who remained with stable disease for 30, 32, and 49 weeks. Two of these patients showed increased frequencies and persistence of p53-reactive CD8+ T cells and elevation of expression of multiple immune response genes. Borderline or undetectable p53-specific T cell responses in 7/11 patients were related to no immediate clinical benefit. The first study patient had a grade 5 fatal myocarditis. After the study was amended for enhanced cardiac monitoring, no additional cardiac toxicities were noted. CONCLUSION: We have shown that the combination of p53MVA vaccine with pembrolizumab is feasible, safe, and may offer clinical benefit in select group of patients that should be identified through further studies.

Outcome after invasive local recurrence in patients with ductal carcinoma in situ of the breast.

PURPOSE: To detail the outcome, in terms of local recurrence, local invasive recurrence, distant recurrence, and breast cancer mortality for patients previously treated for ductal carcinoma in situ (DCIS). PATIENTS AND METHODS: Clinical, pathologic, and outcome data were collected prospectively for 707 patients with DCIS accrued from 1972 through June 1997. RESULTS: There were 74 local recurrences; 39 were noninvasive (DCIS) and 35 were invasive. Fifty-one percent of patients with invasive recurrences presented with stage 1 disease; the remainder presented with more advanced disease. Invasive local recurrence after mastectomy was a rare event that occurred in 0.8% of patients. Invasive recurrence after breast preservation was more common and occurred in 7.4% of patients. The 8-year probability of breast cancer mortality after breast preservation was 2.1%, a number that is likely to increase with longer follow-up. The 8-year breast cancer-specific mortality and distant-disease probability for the subgroup of 74 patients with locally recurrent disease was 8.8% and 20.8%, respectively. If only the 35 invasive recurrences are considered as events, the 8-year breast cancer-specific mortality and distant-disease probability was 14.4% and 27.1%, respectively. CONCLUSION: Invasive local recurrence after breast-preservation treatment for patients with DCIS is a serious event that converts patients with previous stage 0 disease to patients with disease that ranges from stage I to stage IV. These results, however, indicate that most DCIS patients with local recurrence can be salvaged.

Multidrug-resistant tuberculosis outbreak among transvestite sex workers, Buenos Aires, Argentina.

We describe the first outbreak of multidrug-resistant tuberculosis (MDR-TB) that occurred in Argentina among transvestite sex workers, and actions undertaken for its control. In Buenos Aires city, transmission was documented between 2001 and 2004 by conventional and molecular methods in a hotel where transvestites used to reside and work. The source case was traced back to 1998. Six secondary cases were diagnosed and treated. Thirty-two contacts were investigated. The outbreak strain had formerly caused nosocomial transmission in Rosario, a city 300 km from Buenos Aires. Our findings highlight the difficulties controlling MDR-TB in Argentina.

Development of a lesion resembling diabetic nephropathy in a renal homograft.

One month following a cadaver renal transplant for obstructive uropathy, a 27-year-old man developed diabetes mellitus. Two years later, marked proteinuria and decreased renal function were detected. Eight months later, a second decline in function occurred. Light microscopy of graft biopsy specimens obtained after each decline in renal function showed increased mesangial cells and matrix, thickening of Bowman capsule, and tubular atrophy with basement membrane thickening. Vascular changes, interstitial infiltrate, and fibrosis were not prominent. Electron microscopic studies of the second biopsy specimen confirmed the light microscopic changes; subepithelial dense deposits were also detected. Immunofluorescent studies of both biopsy specimens demonstrated linear staining of glomerular and tubular basement membranes and Bowman capsule for IgG and albumin. Antikidney antibodies were not detected in the patient's serum. These observations suggest development of the diffuse form of diabetic nephropathy in a renal homograft following steroid-induced diabetes mellitus.

Duct carcinoma in situ: 227 cases without microinvasion.

From 1979 to 1990, 227 patients with intraductal carcinomas (DCIS) without microinvasion were selectively treated; the least favourable (large lesions with involved biopsy margins) with mastectomy, the most favourable (small lesions with clear margins) with breast preservation. The preservation group was further subdivided into those who received radiation therapy (excision and radiation) and those who did not (excision alone). In the mastectomy group, there were 98 patients (43%) with an average lesional size of 3.3 cm; 41% had multifocal lesions, 15% had multicentric lesions. There has been one local invasive recurrence and no deaths. The 7-year actuarial disease-free survival is 98% with mastectomy. In the excision and radiation group, there were 103 patients (45%) with an average lesional size of 1.4 cm. 10 patients have had local recurrences (5 invasive and 5 noninvasive) one of whom has died. The 7-year actuarial disease-free survival is 84%, a statistically significant difference when excision and radiation is compared with mastectomy (P = 0.038). In the excision alone group, there were 26 patients (11%) with an average lesional size of 1.0 cm. There have been two local recurrences (8%), one of which was invasive and no deaths. The 7-year actuarial disease-free survival is 67%, but only 3 patients have been followed for more than 4 years. A total of 163 axillary node dissections were done; all were negative. Since DCIS without microinvasion rarely metastasizes to axillary lymph nodes, routine dissection should not be performed. Patients in this series with intraductal carcinoma treated with excision and radiation recurred locally at a statistically higher rate than those treated with mastectomy, in spite of the fact that those chosen for excision and radiation had clinically more favourable lesions. 6 of 12 (50%) local recurrences in conservatively treated patients were invasive. There was, however, no significant difference in overall survival in any subgroup regardless of treatment.

Ten-year results comparing mastectomy to excision and radiation therapy for ductal carcinoma in situ of the breast.

The 10-year results of 300 patients with ductal carcinoma in situ (DCIS) without microinvasion are reported; 167 treated with mastectomy and 133 treated with excision and radiation therapy. There was a significant difference in disease-free survival at 10 years, in favour of those treated with mastectomy, 98% versus 81% (P = 0.0004). Multivariate analysis confirmed nuclear grade as the only significant predictor of local recurrence (P = 0.02) or invasive local recurrence (P = 0.03) in patients with DCIS treated with excision and radiation therapy. There was no difference in breast cancer-specific survival or overall survival between the two treatment groups.

"Pseudosarcoma" of the larynx.

Polypoid epidermoid carcinoma of the larynx with a cellular, often atypical stroma has also been classified as pseudosarcoma, carcinosarcoma, pleomorphic carcinoma, or spindle cell sarcoma. The nature of the spindle-shaped stromal cells has clinical significance, but pathologists do not agree about the origin and potential of these cells. This paper describes two laryngeal tumors, one with an abundant osseous component in which light-microscopic, ultrastructural, and clinical features suggest the origin of these fusiform cells from reactive pluripotential mesenchyme. In a second case, atypical fusiform cells within the stroma show ultrastructural epithelial characteristics. These findings suggest a varied histogenesis for pseudosarcoma of the larynx and may explain divergent theories expressed in the literature.

Giant adrenal myelolipoma and testicular interstitial cell tumor in a man with congenital 21-hydroxylase deficiency.

The occurrence of a giant myelolipoma of the adrenal gland reported in a patient with congenital adrenal hyperplasia (21-hydroxylase deficiency). Associated significant findings include a massive proliferation of adrenocortical cells as an integral part of the myelolipoma and coincidental tumor of the interstitial cells of the testis. The clinical, radiologic, endocrinologic, and pathologic features of this case are correlated with a review of the literature. The additional myelolipomas are also reported here for the first time. Similar lesions have been induced experimentally in rats and provide further evidence suggesting a hyperplastic rather than a neoplastic nature for this complex lesion, at least in its earlier stages.

Nephrotoxicity of epinephrine-assisted venography.

A retrospective study was performed to determined the nephrotoxicity of epinephrine-assisted venography (EAV). The results showed an increase in the serum level of creatinine (sCr) up to five days after EAV in 67% of patients, in comparison with 16% in patients who had other types of renal angiography. Microscopic examination of renal specimens from patients who had undergone EAV showed vacuolization of the epithelial cells of the proximal tubules. Risk factors for acute renal failure that have been described in the literature were not statistically significant in this study. These findings suggest that EAV is a more nephrotoxic procedure than renal angiography without EAV.

Acute lymphoblastic leukemia with giant intracytoplasmic inclusions.

Leukemic cells of bone marrow and peripheral blood showing clusters of distinctive, large, uniform, rounded intracytoplasmic inclusions were found in a patient who had acute lymphoblastic leukemia. These membrane-bound inclusions ranged from 0.8 to 1.4 microgram in diameter and were clearly demonstrated on routinely stained preparations. Electron microscopy disclosed transitions between well-developed mitochondria and the electron-dense structures. The functional significance of these presumably altered mitochondria is uncertain. Whorled lamellar internal structures, in occasional fingerprintlike arrangements, may represent duplication of mitochondrial cristae and, functionally, may reflect increased metabolic rate or otherwise abnormal metabolism. Cytochemical studies demonstrated the presence of both periodic acid-Schiff positivity and nonspecific esterase activity in these inclusions, but no peroxidase or acid phosphatase was found. These findings support the lymphoid nature of the disorder. Immunologic surface membrane markers are consistent with this case being, as with the majority of acute lymphoblastic leukemias, of non-B, non-T cell type. Cytogenetic studies on cultured leukemic cells from bone marrow and peripheral blood showed a consistently abnormal karyotype associated with the presence of an XXY chromosomal constitution. Since no other tissues (e.g., dermal fibroblasts) were examined, the diagnosis of Klinefelter's syndrome cannot be confirmed. A causal relationship between the coexistence of the abnormal karyotype and the acute leukemia was not proven but was suspected.

Fine-needle aspiration of secondary neoplasms involving the salivary glands. A report of 36 cases.

Metastases or secondary deposits account for 16% of the malignant neoplasms involving the major salivary glands. A correct diagnosis of a secondary neoplasm is important to avoid unnecessary radical surgery and to guide further therapy. Fine-needle aspiration biopsy (FNAB) is an excellent noninvasive diagnostic tool for evaluating salivary gland lesions. We reviewed 36 secondary malignant salivary gland neoplasms evaluated by FNAB. Ancillary studies were performed in selected cases. Follow-up included clinical correlation and review of histologic material. For 4 adenocarcinomas, 4 squamous cell carcinomas, 1 undifferentiated carcinoma, 1 cutaneous basal cell carcinoma, 10 cutaneous melanomas including 1 desmoplastic variant, 3 osteosarcomas, 11 non-Hodgkin lymphomas, and 2 multiple myelomas, there was 1 false-negative FNAB result. The desmoplastic melanoma was interpreted as reactive lymphoid hyperplasia. A malignant diagnosis was given in all remaining cases except the secondary basal cell carcinoma, which was diagnosed as a neoplasm with basal cell features. FNAB is a reliable tool to differentiate hematologic malignant neoplasms and melanomas from other salivary gland neoplasms. A complete knowledge of the clinical history, review of previous pathologic materials, and, in some instances, the use of ancillary studies are crucial for recognizing solid malignant neoplasms secondarily involving the salivary glands.

Long-standing virilism in a woman with hyperplasia and neoplasia of ovarian lipidic cells.

A woman with bilateral hyperplasia of ovarian hilar cells, stromal lipidic cells (hyperthecosis), and unilateral adenoma of Leydig cells is described. Her clinical course was characterized by long-standing virilism with a recent exacerbation suggesting growth of a tumor from the hyperplastic stromal lipidic cells. Evidence for this hypothesis included similar light and electron microscopic features of the hyperplastic and neoplastic cells and identical patterns of secretion of steroid hormones. Comparison of the in vivo steroid biosynthesis of the hyperplastic lipidic cells with that of testicular Leydig cells showed several similarities. These included 1) secretion of 5 and delta 4 steroids; 2) greater secretion of the delta 4 hormones, progesterone and 17-hydroxyprogesterone, than of the delta 5 steroids, pregnenolone and 17-hydroxypregnenolone; 3) prominent secretion of testosterone but not androstenedione; and 4) limited secretion of estrogens, with estradiol as the principal estrogen. These findings support prior microscopic evidence that ovarian lipidic cells and testicular Leydig cells represent cells of common function and, likely, common origin.

Stereotaxic localization for fine-needle aspiration breast biopsy. Initial experience with 300 patients.

The efficacy of stereotaxic aspiration biopsy was evaluated in 300 consecutive patients with nonpalpable mammographic lesions. Sixty-eight patients (23%) had suspicious or malignant aspirates; all cases were proved malignant by subsequent examination of operative specimens. Two hundred sixteen patients (72%) had benign aspirates. Of these, 65 were confirmed by operation and 151 had subsequent mammography at 6- and 12-month intervals with no demonstrable mammographic change. In 10 instances (3%), the aspirates were atypical, and in six (2%), nondiagnostic. Biopsy specimens were obtained in all 16 instances, and eight were malignant. The sensitivity of stereotaxic breast aspiration for the diagnosis of cancer was 96%, and the specificity was 100%. Our experience confirms the efficacy of stereotaxic aspiration for the initial evaluation of mammographically detected, nonpalpable lesions.

Radiation therapy for intraductal carcinoma. Is it an equal alternative?

Of 213 consecutive patients with intraductal carcinoma, 109 were selectively treated with mastectomy and 104 with radiation therapy. There were eight local recurrences, seven in patients treated with radiation therapy and one in a patient treated with mastectomy. Histologically, there were 110 comedocarcinomas and 103 noncomedocarcinomas. Seven local recurrences occurred in patients with comedocarcinomas and one in a patient with a noncomedo tumor. Three (38%) of eight local recurrences (all comedo) were invasive. The 5-year actuarial survival for all subgroups was 100%. The median follow-up was 51 months. Intraductal carcinoma is unlikely to metastasize to axillary lymph nodes, and routine dissection is unnecessary. Ductal carcinoma in situ of the comedo variety is more aggressive and more likely to recur than its noncomedo counterpart. We currently view conservative therapy for patients with intraductal comedocarcinoma with caution.

Breast cancer in women after augmentation mammoplasty.

More than 1 million American women have undergone augmentation mammoplasty; 100,000 (10%) will develop or already have developed breast cancer. Between March 1981 and August 1986, 20 patients with previous augmentation mammoplasty were treated for breast carcinoma. All patients had unilateral infiltrating carcinomas and presented with a palpable mass. None of the cancers were occult (discovered mammographically). Thirteen patients (65%) had metastases to axillary lymph nodes. During the same period, 733 nonaugmented patients with breast cancer were treated: 207 (28%) had involved axillary nodes, 194 (26%) had in situ lesions, and 154 cancers (21%) were occult. Augmentation mammoplasty with sillicone-gel-filled implants reduces the ability of mammography, our best diagnostic tool, to visualize breast parenchyma. When compared with our own nonaugmented breast cancer population, augmented patients with breast cancer presented with more advanced disease; they had a higher percentage of invasive lesions and positive axillary nodes, resulting in a worsened prognosis.

Oncocytic renal tubular adenoma (so-called oncocytoma) in seventeen-year-old girl.

Renal tubular neoplasms (adenomas or adenocarcinomas) are rare in children or young adults. Herein, we report an oncocytic renal tubular adenoma (so-called oncocytoma) that was found in a seventeen-year-old girl. Preoperative evaluation included aspiration of this tumor, and we suggest that preoperative aspiration is an important procedure in the diagnosis and management of suspected renal tumors in children and young adults.

Primary carcinoid tumor of testis with metastasis.

A primary carcinoid tumor of the testis metastatic to one preaortic lymph node in a forty-three-year-old man is reported. The case was of great clinical interest not only because of the extreme rarity of testicular carcinoid with metastasis but also because of a coincidental bacterial endocarditis.

Papillary adenocarcinoma of ureter.

A well-differentiated papillary adenocarcinoma developed in a ureteral stump thirty-six years after nephrectomy and was associated with a combined transitional-epidermoid carcinoma in the urinary bladder. Carcinoma in a ureteral stump is not uncommon and should be suspected in patients with a ureteral stump and hematuria. The very rare adenocarcinoma of the ureter is typically papillary and is associated with urinary tract infection and stones. At present successful treatment requires the early identification and extirpation of the ureteral tumor and consideration of associated cancer elsewhere in the urinary tract.

Angiosarcoma of kidney.

We describe a forty-six-year-old man who died of disseminated angiosarcoma ten months after a radical nephrectomy and postoperative radiation therapy for a renal angiosarcoma. We found 3 other well-documented reports of renal angiosarcoma, all in men. Two of the 3 cases previously reported also had a rapidly fatal course with hematogenous spread of the neoplasm following nephrectomy. Angiosarcoma of the kidney, although rare, is apparently a highly malignant fatal neoplasm, and effective therapy remains unknown.