Case 6

How would a patient with ER/PR negative, and Her2v negative (triple negative) be treated?

A breast cancer patient without the estrogen or progesterone receptor cannot be treated with SERMS, aromatase inhibitors, or the like since the tumor does not have the pharmacologic target of the drug or the tumor is not dependent on the hormones for progression. Likewise, trastuzumab cannot be used since the tumor lacks Her2v. For these patients, classic chemotherapeutics (doxorubicin, cisplatin, cyclophosphamide, etc.) would be employed and will be discussed in both hematology and oncology courses.

What is the risk of cancer in intraductal papillomas?

A two- and threefold risk of breast cancer for solitary and multiple papillomas, respectively, but the risk is increased further if atypical ductal hyperplasia is present, 5- to 7-fold.

What are the risk factors for prostate cancer?

A. Age (Most frequently diagnosed among men aged 65-74) B. African-American racial background. Prostate cancer is more common in black than white or Hispanic men. In addition to higher incidence rates, the age of onset in African American men is earlier than for comparative groups. C. Genetics D. Diet E. Obesity. There is a small but statistically significant association between obesity and prostate cancer incidence. More importantly, there is a clear relationship between obesity and disease aggressiveness, with an increase in both biochemical recurrence rate following treatment and prostate cancer-specific mortality.

What are the microscopic hallmarks of prostate cancer?

A. Malignant glands are irregular and haphazardly arranged B. Lined by a single layer of cuboidal to low columnar cells C. Nuclei are large and characteristically have one or more prominent nucleoli

Compare and contrast the MOA of the endocrine agents, by class, used in the treatment of breast cancer.

All endocrine agents target either estrogen or testosterone to inhibit cancer growth. Each of these agents go about this general mechanism differently. Selective estrogen receptor modulators (SERMs), such as tamoxifen, bind to the estrogen receptor, competitively inhibiting estrogen to bind. Depending on the tissue expression of the estrogen receptor, will determine the effect. If tamoxifen binds to ER on the breast of CNS, it acts as an antagonist - no cell growth. If tamoxifen binds to ER on the bone, endometrium or CV system, it acts as an agonist - cell growth. ER down regulators, such as fulvestrant, bind to the estrogen receptor, competitively inhibiting estrogen from binding (similar to SERMs), however it does not have any agonist activity. Aromatase inhibitors, such as anastrozole, inhibits the enzyme aromatase from converting androstenedione to estrone and testosterone to estradiol (or put more simply, less testosterone and estrogen are produced). LHRH (or GnRH) agonists, such as goserelin and leuprolide, decrease the release of FSH and LH through negative feedback on the hypothalamus, inhibiting the production of estrogen, progesterone and testosterone.

What is the role of androgens in the pathogenesis of prostate cancer?

Androgens play an important role in the transformation and growth of prostate cancer cells. Prostate cancer contains both androgen-dependent and androgen-independent malignant cells. For those cells that are androgen dependent, a critical level of androgen is required to activate a sufficient number of androgen receptors (ARs) so that transcription of death-signaling (pro-apoptotic) genes is repressed. Further, disease progression has been related to a number of genetic abnormalities that affect the AR and other molecules that are involved in the regulation of cell survival and apoptosis.

What drugs can be used to alleviate the tumor flare (caused by the LH surge with LHRH agonists)?

Another class of drugs, the antiandrogens (bicalutamide) can be used to combat the LH surge when LHRH agonists like goserelin are initiated.

What is the mechanism of action, indications, and side effects of degarelix? How does this compare with goserelin or histrelin?

Basically, degarelix produces the same outcome as goserelin in the management of prostate cancer. It reduces testosterone's proliferative effects on the prostate by antagonizing LHRH receptors on the pituitary to reduce LH secretion towards the testes. It essentially skips the tumor flare step (LH surge).

What is the prognostic importance of this mucinous subtype?

Better prognosis compared to invasive ductal carcinoma of NST

What is the prognostic importance of this tubular subtype?

Better prognosis compared to invasive ductal carcinoma of NST

Why would castration recurrence occur and what drugs can be used to treat this?

Castration (chemical) recurrence implies testosterone can be coming from another source (not the tumor itself). So the typical LH pathway aforementioned will have little effect. For this type of prostate cancer, we have abiraterone, an inhibitor of CYP17, the enzyme responsible for converting progesterone to androstenedione (an immediate precursor to testosterone). Also, enzalutamide is an androgen (testosterone) receptor antagonist. Both of these drugs would severely reduce the testosterone effect on the proliferation of the prostate.

What are the morphologic hallmarks of tubular carcinoma?

Discreet, angulated tubules in over 90% of the tumor, lined by a single layer of epithelial cells with apical snouts often visible.

What are the morphologic hallmarks of lobular carcinoma in situ?

Distention of involved lobules by a dyshesive, uniform proliferation of round cells with eccentric cytoplasm. The cells are uniform with no pleomorphism.

What are the characteristics of EGF and its EGFR/HER receptors?

Epidermal growth factor is a polypeptide hormone that is responsible for cell growth, cell division and differentiation. It exerts its effects by binding to a cell-surface receptor, EGFR. EGFR is a family of 4 receptors, named HER1, 2, 3 and 4. All of them belong to the EGFR family of receptor tyrosine kinases (RTKs). Thus, by ligand binding, they dimerize and self-phosphorylate on Tyr residues. This event upregulates intracellular signaling pathways, including the MAPK pathway. ● EGFR is a dimer of HER1/HER1 ● HER2 has no ligand-binding capability, but can dimerize with any of the HERs and thus, upregulate signaling. It is a lways in an active form, thus dimerizing with itself can upregulate signaling without any growth factor present ● HER3 has no intracellular domain RTK, but pairing up with HER2 or other HERs, signaling is upregulated ● HER4 can also pair up with HER2 or other HERs

What are the morphologic hallmarks of ductal carcinoma in situ?

Epithelial cells proliferate within the ducts, and may extend into the lobular structures. The neoplastic cells may be large, pleomorphic, and often solid in growth pattern in high-grade DCIS or small and regular, showing polarization around architectural structures, such as micropapillae and cribriform spaces in low-grade DCIS. No invasion is seen into the stroma.

What are the prognostic and predictive tests routinely performed in the initial diagnosis of breast cancer?

Estrogen and progesterone receptor expression and HER2 overexpression or amplification.

What is the mechanism of action of Herceptin?

Herceptin (Trastuzumab) 1. mab - monoclonal antibody 2. Binds with high affinity to the HER2 3. Blocks signal transduction 4. Enhances HER2 endocytosis and lysosomal degradation by cells 5. Activates immune system for removal of abnormal cells 6. Prevents DNA repair 7. Causes cancer cell death 8. Shrinks tumor

What is the risk of breast cancer for a patient with fibrocystic changes?

None

What is the prognostic importance of this medullary subtype?

Favorable compared to invasive ductal carcinoma of NST

What are the clinical indications for LHRH agonists?

Female and male infertility, diagnosis of delayed puberty, ovarian overstimulation, endometriosis, leiomyomas (uterine fibroids), breast and prostate cancer.

What are the pathologic hallmarks of fibroadenoma?

Fibroadenomas are well-defined, round or ovoid masses, 1 to 3 cm, but rarely much larger. They are often gray with no true capsule and have a rubbery, often lobulated cut surface with slit-like spaces. Microscopically, the stromal component is loosely cellular, lacking cytologic atypia, and the epithelial component is composed of compressed duct structures or tubules with epithelial and myoepithelial layers.

What are the morphologic hallmarks of invasive ductal carcinoma of no special type?

Firm masses with stellate infiltrative borders. Microscopically, the NST tumors show variable combinations of morphology, which prevent allocation to a special type. Consequently, pushing and infiltrative margins are seen, sometimes in the same lesion, together with trabecular, sheetlike, acinar, and nesting morphologies. The tumor cells show a variable degree of differentiation. The stroma can be desmoplastic or collagenous or there may be minimal stroma.

Which of the LHRH agonists can be used for the treatment of breast cancer or prostate cancer? Which can only be used for prostate cancer?

Goserelin and Leuprolide can be used in either men (prostate cancer) or women (breast cancer). Histrelin and triptorelin can only be used for the treatment of prostate cancer. Histrelin, however, may be used for treatment of uterine fibroids.

What are the morphologic hallmarks of medullary carcinoma?

Grossly, usually well-defined and circumscribed with gray/tan cut surface. Microscopic findings are a syncytial growth pattern in >75% of the tumor, an absence of glandular structures, a moderate/marked lymphoplasmacytic infiltrate and marked (score 3) nuclear pleomorphism.

What are the morphologic hallmarks of invasive lobular carcinoma?

Grossly, varies from firm, gray, well-circumscribed mass to poorly defined thickening. The classical microscopic findings include cells showing a dyshesive pattern of infiltration, often in single file llinear arrays, with oval nuclei, minimal cytoplasm, and intracytoplasmic lumina. LCIS present in 66% of cases.

What are the pathologic hallmarks of fibrocystic change?

Grossly, fibrosis with blue-dome or clear cysts; microscopic findings include stromal fibrosis, dilated/ectatic ducts with cyst formation, apocrine metaplasia, and mild usual epithelial hyperplasia without atypia.

What are the consequences of HER2 overexpression?

HER2 protein is overexpressed in approximately 15% of breast cancers. In HER2+ breast cancers, the HER2 gene is amplified by 2-fold to 20-fold in each tumor cell nucleus relative to the number of copies of chromosome 17. Amplification of the HER2 gene drives HER2 protein overexpression. The resulting increase in the number of receptors at the tumor cell surface (as many as 2 million HER2 molecules per cell instead of the normal 20,000 per cell) promotes receptor activation, leading to signaling, excessive cellular division and the formation of tumors. Added to the effect is that HER2 can form homodimers when overexpressed and thus activates the signaling pathway without EGF binding. Because HER2 requires no ligand, and is thus always in an a ctive configuration, HER2-positive (HER2+) breast cancer is considered an aggressive cancer.

What type of receptor is Her2v and what does it do?

HER2v is a transmembrane receptor of the epidermal growth factor receptor family. These receptors are tyrosine kinases. Activation of Her2 results in cell signalling of a growth-promoting phenotype involving the MAPK and mTOR pathways; which are major pathways in cancer biology. In breast (and a few other) cancers, overexpression of Her2v is found in approximately one quarter of breast tumors and is associated with a poor prognosis.

What are some clinical indications for histrelin?

Histrelin can be used for the treatment of prostate cancer (NOT breast cancer). It can also be used for the treatment of uterine fbroids, central precocious puberty in children, and has been implemented in protocols for transgender children/youth.

What are the typical clinical features seen in prostate cancer?

It is rare for patients to present because of symptoms attributable to prostate cancer. Most prostate cancers are detected in the localized stage by an elevated serum prostate specific antigen test leading to biopsy and pathological confirmation. But among the six percent of patients whose prostate cancer is metastatic at the time of diagnosis, bone pain may be the presenting symptom. Bone is the predominant site of disseminated prostate cancer, and pain is the most common manifestation of bone metastases. Other symptoms with metastatic disease may include weight loss, weakness or pain due to spinal cord compression, pain due to pathologic fractures, fatigue caused by anemia, or renal/urinary symptoms.

What is lapatinib? How is it administered?

Lapatinib is an orally administered, small molecule tyrosine kinase inhibitor for Her2v+ breast (and gastric) tumors. This drug has a different binding site than trastuzumab and is used for refractory breast cancer patients who have become unresponsive to trastuzumab therapy. This drug may be combined with other "classic" chemotherapy agents like taxanes or anthracyclines.

What are the cellular changes induced by ligand-binding to HER receptors?

Ligand binding to HER initiates a signal transduction cascade that results in a variety of biochemical changes within the cell, including: ● a rise in intracellular calcium levels ● increased glycolysis and protein synthesis ● increases in the expression of certain genes, including the EGFR gene itself ● that ultimately lead to DNA synthesis and cell proliferation (a mitogenic response) Signaling events result in: ● Cell division ● Cell survival ● Mobility and invasion ● Neovascularization (all hallmarks of cancer cells)

What two classes of drugs inhibit Her2v?

Monoclonal antibodies and small molecule tyrosine kinase inhibitors are two drug classes that can inhibit Her2v signalling. Monoclonal antibodies end with the suffix -mab; while tyrosine kinase inhibitors end with the suffix -nib. The name distinction also comes from the fact that monoclonal antibodies are recombinant IgG antibodies and are large structurally. Small molecule tyrosine kinase inhibitors are smaller (compared to IgG) and are not protein in origin, but organic molecules.

When looking at a family history, what are the signs of inherited breast cancer?

Multiple family members with breast and ovarian cancer, usually at younger age, bilateral breast cancer, male breast cancer, prostate cancer (at a young age) and pancreatic cancer.

How does phyllodes tumor differ clinically and morphologically from fibroadenoma?

Phyllodes tumor most commonly occurs in an older age group (50s versus 20s-30s in fibroadenomas), is more rapidly growing, and is associated with recurrences and, rarely, malignant transformation. Phyllodes tumors differ microscopically by having more cellular stroma lined by an epithelial and myoepithelial bilayer, forming leaflike structures. They also may show malignant features characterized by overgrowth of markedly atypical stromal cells with abundant mitoses (>10 per 10 high-power fields) and specific heterologous sarcomatous elements may be seen.

What are the side effects associated with LHRH agonists, such as goserelin or leuprolide?

Sweating, hot flashes, depression, tumor flare (transient), and QT prolongation are common in men and women taking these drugs.

A premenopausal ER+ breast cancer patient with osteoporosis is being treated with tamoxifen. When speaking to this patient, what types of side effects would you tell her about?

SERMs, such as tamoxifen, increase the risk of endometrial cancer, ischemic stroke and blood clots. Hot flashes, nausea & vomiting, hair loss and vision problems are also common.

A post-menopausal breast cancer patient is being treated with Fulvestrant .What side effects are associated with this chemotherapy that you would tell the patient about?

Since this drug is an IM injection, she may experience injection site pain and muscle aches. She may also experience hot flashes, headache, urticaria and angioedema.

What are the techniques by which the HER2 (gene or protein) can be identified and quantitated?

Standard HER2 tests measure how many copies of the HER2 gene are present in tumor cells or how many HER2 receptors are on the surface of tumor cells; either method is appropriate for determining HER2 status. Both are FDA-approved. ● Fluorescence in situ Hybridization (FISH) — a gene-based diagnostic test used to identify the number of HER2 genes per cell. The ratio of the HER2 genes to a reference gene, such as CEP17 (chromosome enumeration probe 17) can also be calculated. ● Immunohistochemistry (IHC) — a protein-based diagnostic test used to identify overexpression of the HER2 protein. The amount of HER2 protein that is present in a tumor is determined by a lab test and a score from 0 to 3+ (which is a highly positive score) is assigned.

What is the role of fusion of the androgen-regulated gene TMPRSS2 and the ETS transcription family members (ERG, ETV1) in prostate cancer?

TMPRSS2-ERG fusions have a diagnostic role as they are found in nearly one half of prostate-specific antigen (PSA)-screened prostate cancer patients and are absent in biopsies from benign lesions, but, more importantly, these fusions show a high correlation with disease recurrence after surgery for localized prostate cancer.

In addition to BRCA1/2, what other genes are associated with inherited breast cancer?

TP53, PTEN, CHD1 and STK11

For the LHRH agonists, what is the target tissue?

Target tissue is the pituitary gland to reduce the secretion of LH and FSH

What is the function of the BRCA1/2 genes?

The BRCA1/2 genes are both tumor suppressor genes

What is the most characteristic pathologic finding with inflammatory breast carcinoma and is it necessary for the diagnosis?

The classic histologic finding in IBC on biopsy of affected skin is dermal lymphatic invasion by tumor cells. The absence of dermal lymphatic invasion does not exclude a diagnosis of inflammatory carcinoma in patients who clinically have the characteristic mammary skin changes and demonstrate invasive carcinoma in the underlying breast.

What is the most common site of metastasis in prostate cancer and its typical appearance?

The most common site for metastasis is bone, especially involving the axial skeleton. Prostatic cancer metastases typically appear osteoblastic (≈factors produced by tumor cells signal to the bone to make extra bone matrix which results in rigid, thickened, inflexible bone being formed) and radiographically appear as more opaque compared to surrounding bone.

What is the basis or the "surge" of LH after initiation of LHRH agonists?

The surge in LH comes from the fact that the pituitary gland is overstimulated with LHRH agonist at the LHRH receptor. This pulse of activation on the pituitary causes an surge of LH to leave the pituitary gland and have effects on the testes (or ovaries) which causes a testosterone (or estrogen) surge on the prostate (or uterus). However, the surge is short-lived, and the heightened stimulation of the pituitary receptors is shut down to reduce the LH effects on the testes/ovaries to reduce testosterone/estrogen secretion. This is a classic example, where intense activation actually produces the opposite effect whereby the system cannot reset and the net result is inhibition of a pathway or shutting down a process. The analogy would be akin to plugging in too many electronics and tripping the circuit breaker.

A post-menopausal early-stage breast cancer patient comes into the office with another bone fracture. What chemotherapy is being administered to this patient and what can be added to her regimen to prevent future bone fractures?

This patient is on an aromatase inhibitor. One of the side effects of aromatase inhibitors is loss of bone density, making a patient more prone to bone fractures. Co-administration of bisphosphonates can used to used to help with this side effect.

How is trastuzumab administered? Why?

Trastuzumab is a monoclonal antibody and has to be administered IV. It cannot be administered orally as gastric acid from the stomach will denature the tertiary structure of the molecule and render it inactive.

What side effects are associated with trastuzumab?

Trastuzumab is associated with infusion reactions (fever, chills, nausea, vomiting) that may stem from the diluents and stabilizers packaged in the drug. EGFR is also an embryonic protein that is expressed during fetal development and administration of this drug to a pregnant woman results in embryo lethality. Trastuzumab can also negatively affect the heart which can be problematic if the patient is also given anthracycline chemotherapy as part of add-on therapy. Common reactions include fatigue and headache. There can be lung manifestations as well as low white blood cell counts.

What are the pathologic hallmarks of intraductal papilloma?

Typically well-circumscribed tumors composed of multiple branching papillae lined by myoepithelium and epithelium, with varying degrees of epithelial proliferation ranging from usual to atypical ductal hyperplasia.

What are the morphologic hallmarks of mucinous carcinoma?

Well-defined mass with a gelatinous cut surface. Microscopic findings are nests or trabeculae of neoplastic cells within lakes of mucin. Tumor cells show mild or moderate nuclear pleomorphism.