Management of metastatic breast cancer

Systemic treatment almost certainly prolongs the median survival of women with metastatic breast cancer, and it may prolong the survival of a small number of patients substantially. Even with conventional therapy, 10% or more patients may live into the second decade after recurrence. However, the disease cannot be eradicated, and the primary goal of treatment remains palliation and improvement of the quality of life. Because of the great variability in the pattern and course of the disease from one patient to another, therapy should be selected judiciously to maximize response and minimize toxicity. In some clinical situations, such as pathologic fractures and brain metastases, local therapies alone, such as surgery or irradiation, are the treatments of choice. Patients who will respond to endocrine therapy are well defined, and all patients with the characteristics of an endocrine responder deserve a chance at palliation with this modality alone because of its limited toxicity. A number of new forms of endocrine therapy with more specific targets at estrogen and progesterone receptor sites are now in clinical trials. When used appropriately, chemotherapy significantly improves patient quality of life despite its toxicity. No drug combinations, schedules, or doses have been shown to prolong survival or provide better net palliation than classic CMF (oral cyclophosphamide with intravenous methotrexate and 5-fluorouracil) or CAF (intravenous cyclophosphamide, doxorubicin, and 5-fluorouracil). Treatment with these combinations in excess of 6 to 9 months provides only marginal additional benefits and no survival advantage. The role of high dose chemotherapy with autologous bone marrow transplantation remains a promising area of investigation, but the available survival data are entirely compatible with the possibility that this modality will eventually prove inferior to conventional therapy. Many new cytotoxic agents with unique mechanisms of action are currently under investigation, including taxol, taxotere, Topotecan, and amonafide. Taxol may be the most promising therapy now available for patients whose disease has become refractory to doxorubicin. Biologic therapies using monoclonal antibodies against a specific oncogene or its product have entered clinical trials, and novel drug delivery systems using liposomes are under evaluation.

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Resumen El tratamiento sistémico casi ciertamente prolonga la supervivencia media de las mujeres con cáncer mamario metastásico y logra prolongar la sobrevida de un muy pequeño número de pacientes en forma muy sustancial. Aún con terapia convencional, 10% o más de las pacientes sobreviven hasta la segunda década después de una recurrencia. Sin embargo, la enfermedad no puede ser erradicada y el objetivo primario del tratamiento sigue siendo paliativo para mejorar la calidad de vida. Teniendo en cuenta la gran variabilidad del patrón y de la evolución de la enfermedad entre una y otra paciente, la terapia debe ser cuidadosamente seleccionada a fin de lograr la máxima respuesta y minimizar la toxicidad. En algunas situaciones clínicas, tales como las fracturas patológicas y las metástasis cerebrales, las solas modalidades de terapia local, tales como la cirugía o la irradiación, constituyen los tratamientos de elección. Las pacientes que puedan responder a la terapia endocrina están bien definidas, y todas las pacientes con las características de ser una de las que responda al manejo endocrino merece la oportunidad de paliación con esta modalidad, en virtud de su limitada toxicidad. Variadas y nuevas formas de terapia endocrina con miras más específicas en cuanto a receptores de estrógeno y de progesterona se encuentran en ensayo. Cuando la quimioterapia es utilizada en forma apropiada, ésta mejora significativamente la calidad de vida a pesar de su toxicidad. Ninguna combinación de drogas, programas o dosificaciones ha demonstrado prolongar la sobrevida o lograr mejor paliación que el régimen clásico CMF (ciclofosfamida oral con metotrexato IV y 5-fluorouracilo). El tratamiento con estas combinaciones por más de 6–9 meses provee apenas beneficios adicionales marginales y ninguna ventaja en cuanto a sobrevida. El papel de la quimioterapia de altas dosis con trasplante autólogo de médula ósea permanece como una promisoria área de investigación, pero la información sobre supervivencia hasta ahora disponible es enteramente compatible con la posibilidad de que esta modalidad llegue a demostrar ser inferior a la terapia convencional. Muchos nuevos agentes citotóxicos con mecanismos de acción únicos están siendo investigados en la actualidad. Estos incluyen el taxol, el taxotere, el Topotecan y el amonafide. El taxol puede ser la forma más promisoria de terapia actualmente disponible para pacientes cuya enfermedad se ha hecho resistente a la doxorubicina. Las terapias biológicas usando anticuerpos monoclonales contra un oncogene específico o su producto han ingresado a los ensayos clínicos y novedosos sistemas de administración de drogas, utilizando liposomas, también se hallan en proceso de investigación.

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Résumé Le traitement par voie systémique prolonge la survie médiane des patientes ayant un cancer métastatique du sein et peut également prolonger, sans doute, la survie d'un petit nombre d'autres patientes quel que soit le dégréé de sévérité de la maladie. Même avec une thérapeutique conventionnelle, 10% ou plus des patientes peuvent espérer survivre plus de 10 ans après leur récidive. La maladie ne peut, dans ce cas cependant, être enrayée et le but de la thérapeutique restera palliatif et d'améliorer la qualité de vie. En raison de la grande variabilité du type et de l'évolutivité de la maladie d'une patiente à l'autre, chaque protocole thérapeutique se doit d'être élaboré de façon à maximaliser la réponse tout en minimisant la toxicité. Dans certaines situations cliniques, telles les fractures pathologiques ou les métastases cérébrales, les thérapeutiques locales, telles la chirurgie ou l'irradiation, sont de modalités thérapeutiques de choix. On connaît aussi une catégorie de patientes qui répondent bien au traitement hormonal, qui devraient toutes être traitées par cette modalité étant donnée le peu de toxicité. Un certain nombre de ces traitements hormonaux sont actuellement l'objet d'essais thérapeutiques. Utilisée judicieusement la chimiothérapie améliore de façon significative la qualité de vie, et ce souvent, malgré sa toxicité. Aucune combinaison de médicaments ni de régimes ou de doses ne se sont montrés plus efficaces pour prolonger la survie ou améliorer le confort mieux que la classique association CMF (cyclophosphamide per os, methotrexate et 5-Fluorouracil par voie intraveineuse) ou la CAF (cyclophosphamide, doxorubicine, 5-fluorouracil par voie intraveineuse). Un traitement par ces combinaisons pendant plus de 6–9 mois n'apporte guère d'avantages, sans prolonger la survie pour autant. Le rôle de la chimiothérapie à hautes doses combinée avec la greffe de moelle osseuse était une voie prometteuse mais pour le moment, il semble exister de preuves en faveur de son infériorìté par rapport aux traitements conventionnels. D'autres nouvelles substances cytotoxiques, faisant intervenir d'uniques mécanismes d'actions, sont actuellement en cours d'évaluation. Ces nouveaux médicaments comprennent le taxol, le taxotère, le Topotécane, et l'amonafide. Le taxol est probablement celuì qui a le plus d'intérêt, semble-t'il, e cas de résistance à la doxorubicine. Des traitements biologiques, utilisant des anticorps spécifiques dirigés contre tel on tel oncogèn ou son produit, ainsi que de nouveaux systèmes d'apport des médicaments sont également au stade d'évaluation clinique.

     

Ulcerative paraneoplastic dermatomyositis secondary to metastatic breast cancer

A 40-year-old Chinese-American woman with breast carcinoma metastatic to her lungs presented with a 3-month history of erosions on her inner thighs (Figure 1) and medial left shoulder. Faint livedo reticularis was evident on her legs as well. She had difficulty in walking and raising her shoulders. Her cutaneous examination was also notable for cuticular erythema (Figure 2) and mild periorbital erythema and edema. She had no systemic or rheumatologic complaints other than some difficulty in swallowing. Her blood chemistry values were notable for a creatinine kinase of 564 IU/L (5-200 IU/L), alanine aminotransferase 161 U/L (0-40 U/L) and aspartate aminotransferase 93 U/L (0-40 U/L), and an antinuclear antibody titer of 1:2560. Other blood chemistries and antibody serologies (anti-Jo-1, anti-Mi-2 and other anti-tRNA synthetase, anti-Ro/SSA, anti-U1RNP, anti-PM/Scl, and anti-Ku) were within normal limits. A biopsy specimen was obtained from an area of intact skin close to a right thigh ulceration that showed subtle vacuolar alteration at the dermo-epidermal junction with occasional necrotic keratinocyte (Figure 3). Melanophages and telangiectases were present. Within the subcutis there was fibrin deposition and neutrophils. A diagnosis of dermatomyositis was made. The patient received oral prednisone 20 mg three times a day, and her ulcerations resolved. Her creatinine kinase, alanine aminotransferase, and aspartate aminotransferase values returned to normal over the course of 3 weeks, but her antinuclear antibody was unchanged. Radiographic studies concurrently noted that her breast cancer had recurred in her lungs; plans were made to treat her with chemotherapy. The patient was lost to close follow-up, but it was learned that her erosions had reoccurred while her prednisone was tapered and resolved when her dosage of prednisone was increased.     

Bisphosphonates in the treatment of metastatic breast cancer

The skeleton is the most common site of metastatic disease in breast cancer and the most common site of first distant relapse. Bone metastases in breast cancer are the source of considerable morbidity, including severe pain, pathological fractures, need for radiotherapy or surgery, and hypercalcemia. Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption, and it is well known that breast cancer cells in bone can stimulate osteoclast formation and activity leading to the release of growth factors and cytokines, which will further stimulate cancer cell growth and their secretion of osteolytic factors. We are thus typically dealing with a vicious cycle, as the bone resorption-induced release of growth factors from the bone matrix will stimulate breast cancer cell growth (probably mainly by IGFs) and the production of the osteolytic factor PTHrP (probably mainly by TGF- but also by extracellular calcium). Clodronate, but not the aminobisphosphonates, can be metabolized to an ATP analog that is toxic for osteoclasts. Nitrogen-containing bisphosphonates, such as pamidronate, ibandronate, and zoledronate, interfere with the mevalonate pathway that is crucial to maintain cell membrane integrity. The net result, regardless of the mechanism, is osteoclast apoptosis, notably through the induction of caspase-3. Bisphosphonates are now the standard treatment for cancer hypercalcemia. Repeated bisphosphonate infusions also exert clinically relevant analgesic effects in at least one half of the patients with metastatic bone pain. Most importantly, prolonged administration of bisphosphonates (for at least 1 year) reduces the frequency of morbid skeletal events by 30–40% in breast cancer metastatic to bone and in up to 50% in patients with multiple myeloma. Newer bisphosphonates, such as ibandronate and zoledronate, will simplify the current therapeutic schemes and improve the cost-effectiveness ratio, and they have the potential to improve the therapeutic efficacy, at least in patients with aggressive osteolytic disease or in the adjuvant setting.     

Bisphosphonate use in metastatic breast cancer

Skeletal metastatic disease affects more than 70% of patients with breast cancer. These patients frequently demonstrate a prolonged survival with high morbidity. Hypercalcemia, bone pain, and fracture with potential neurologic compromise represent the major morbidity of skeletal metastases. The management of skeletal metastases in breast cancer revolves around the consequences of bone destruction. The lytic destruction of bone is a result of increased osteoclastic activity, prompting the use of bisphosphonates, which reduce osteoclastic activity and inhibit bone resorption. Their use has become the first line of therapy in hypercalcemia of malignancy. Studies with oral clodronate demonstrate efficacy in palliation of bone pain, reduction in analgesic use and of skeletal-related events, and reduction of hypercalcemia. Pamidronate is a second-generation aminobisphosphonate with a potent inhibition of osteoclastic activity and superior results, which can be demonstrated with IV rather than oral administration. This review intended to highlight the current published data on IV pamidronate use in patients with advanced skeletal metastases. Included are large, multi-institutional, prospective, randomized, blinded and nonblinded, controlled trials carried out through the Aredia Multinational Cooperative Group, and a well-designed, nonblinded, controlled trial with uniform crossover from a single institution. The studies are complementary, and each highlights questions and directions of study that are either currently under investigation or still require the development of well-designed studies. Protocol 19 of the Aredia Breast Cancer Study Group produced a large database to establish the safety and efficacy of long-term IV pamidronate use, expanding the treatment and follow-up of the original study patients over 2 years. Significantly fewer skeletal complications were noted in the pamidronate group, which was maintained for the 2 years of study. The treatment was given in conjunction with IV cytotoxic therapy and, consequently, the pamidronate-specific benefit may be partially obscured by the palliative effects of cytotoxic therapy. The trial by Conte is similarly affected with the use of concomitant chemotherapy. Significant data were accrued, however, to reflect both the efficacy and safety of this therapeutic regimen. The use of a blinded controlled trial has been criticized in this population of patients, and the Conte trial overcame this issue by using a nonblind controlled design and subsequent blinded extramural review.The data supporting prolonged PD allow speculation on the use of bisphosphonates to prevent further disease formation or prevent skeletal metastases in an adjunctive setting. The adjuvant use of bisphosphonates in the prevention of skeletal metastases is currently in a trial development phase with consideration of the use of more potent, third-generation IV bisphosphonates or oral clodronate. The issue of length of treatment is unclear, with data suggesting that a protective effect is lost after therapy is discontinued. Long-term use would favor an oral and more cost-effective and quality-of-life-effective route of administration.Evidence for dose responsiveness prompted the use of higher-dose, single-agent, and prolonged therapy. The trial by Coleman et al reflects these study modifications and further advances our knowledge of the metabolic response of bisphosphonates charted with the clinical and qualitative subjective response to treatment. This study helps to elucidate a population of patients with bone metastases, which are more likely to respond, and a method of clinically monitoring response to treatment through the more cost-effective and reproducible ELISAs of bone metabolism. Although higher doses of IV pamidronate were not more effective in obtaining greater rates of subjective response, ELISAs did demonstrate effective bone resorptive activity. A decrease in the incremental change in subjective scoring was seen over time despite objective evidence of bone resorption. Consequently, this prompts the question of whether a third-generation bisphosphonate—such as zoledronate, with a potency that has been demonstrated to be greater than 100 times that of second-generation bisphosphonates—could affect an improved or sustained, subjective clinical benefit. Studies might also be designed to elucidate and overcome mechanisms of bisphosphonate resistance. The development and utilization of agents to affect non-osteoclastic-mediated mechanisms of bone destruction could lead to a greater subjective response when used in conjunction or independently of bisphosphonates. Certainly the results of these studies highlight the multifactorial process associated with subjective and clinical skeletal-related events. The long-term survival of patients with skeletal metastases and the associated morbidity underscore the crucial, beneficial, palliative effects of the bisphosphonates in breast cancer. The potential for long-term use in both the metastatic and adjunctive settings should prompt the addition of formal cost-benefit analyses to future prospective study designs.     

Stereotactic radiotherapy in metastatic breast cancer

The treatment of metastatic breast cancer is largely focused on systemic therapy. However, over the past decades, there has been growing interest in the use of metastasis-directed therapy in selected cases presenting with an oligometastatic phenotype, i.e. low disease burden with a more indolent biology. Identification of the oligometastatic breast cancer population has, so far, proven elusive. Stereotactic radiotherapy offers an effective, non-invasive approach to ablate metastatic disease both in the brain and in extra-cranial settings. The advent of advanced imaging techniques for target definition, along with the ability to achieve highly conformal dose deposition with steep dose fall-off, enable safe implementation of extreme hypofractionated and single fraction regimens with ablative intent. There is growing evidence that radiation-based treatments are more cost-effective when compared to other ablative modalities. This article provides preliminary evidence that metastasis-direct ablation, with advanced radiotherapy techniques, may play an important role in the management of metastatic breast cancer patients, potentially improving clinical outcomes with minimal toxicity. However, prospective randomized controlled trials are needed to further the understanding of the interaction between systemic therapy and ablative irradiation. Additionally, research in genomic and molecular profiling is needed to characterize metastatic breast cancer patients who will most likely benefit from such combined treatment approaches.     

The variability of estrogen receptors in metastatic breast cancer.

Estrogen receptor protein (ERP) concentrations were determined by the sucrose diffusion method in primary tumors and one or more metastases in twenty-nine patients with breast cancer. Concurrence of ERP concentrations between primaries and at least some metastases was found in 76 per cent of cases. Multiple metastases were assayed in ten cases, three of which demonstrated highly variable concentrations. It was concluded that clinically significant differences in ERP concentrations often exist between primary breast cancers and their metastases as well as between different metastases from the same tumor, accounting for the lack of responsiveness of some ERP-"positive" tumors and for mixed responses to hormonal or endocrine therapy. Assay of an isolated metastasis may be no more reliable in predicting overall patient benefit from therapy than assay of the primary itself.     

Impact of age at diagnosis of metastatic breast cancer on overall survival in the real-life ESME metastatic breast cancer cohort

BackgroundYoung age is a poor prognostic factor in early stage breast cancer (BC) but its value is less established in metastatic BC (MBC). We evaluated the impact of age at MBC diagnosis on overall survival (OS) across three age groups (<40, 40 to 60 and > 60 years(y)).MethodsESME MBC database is a national cohort, collecting retrospective data from 18 participating French cancer centers between January 01, 2008 and December 31, 2014.ResultsAmong 14 403 women included, 1077 (7.5%), 6436 (44.7%) and 6890 (47.8%) pts were <40, 40–60 and > 60 y respectively. Pts <40 had significantly more aggressive presentations than other age groups: more frequent HER2+ (25.7 vs 15.3% in >60y) and triple negative subtypes (27.4 vs 14.6% in >60y), and more frequent visceral involvement (36.3 vs 29.8% in >60y). At a median follow-up of 48 months, median OS differed across age groups: 38.8, 38.4 and 35.6 months for pts <40, 40–60 and > 60y, respectively (p < 0.0001). Compared to pts <40y, older pts had a statistically significant higher risk of death (all causes of death included), although of limited clinical value (HR = 1.1, IC 95%:1.01–1.20). There was a significant trend for better OS in pts <40y with HER2+ and luminal diseases. A possible explanation is a greater use of anti-Her2 therapies as first-line treatments: 86.6, 81.9 and 74.9% for pts <40, 40–60 and > 60y, respectively (p < 0.0001).ConclusionAlthough young age seems associated with more aggressive presentations at diagnosis of MBC, it has no deleterious effect on OS in this large series.     

The pattern of vertebral involvement in metastatic vertebral breast cancer

The spine is a common site of bony metastasis. To date, studies have not identified the initial site and pattern of vertebral metastasis in a homogeneous group of patients. Twenty-seven magnetic resonance imaging studies performed on 25 patients with metastatic vertebral breast cancer were reviewed retrospectively. The location and extent of metastatic vertebral involvement were determined. The vertebral body is the most frequent initial site of metastatic seeding. Although radiographically an absent pedicle is often the first sign of metastatic disease, involvement of the pedicle is by direct extension from either the vertebral body or the posterior elements and is therefore a late occurrence in the disease process.     

Clinical management of metastatic breast cancer.

The physician treating the patient with recurrent or metastatic breast cancer has a number of available therapeutic options. Various clinical and laboratory factors play a role in the decision process for the choice of the initial and subsequent treatments for such patients. The strategies for palliative therapy are reviewed along with estimates of potential benefits of the various modalities.     

Immunohistochemical diagnosis of a case of metastatic prostate cancer to breast

Bilateral breast mass was found in a 71-year-old male who had been placed on estrogen therapy for stage D2 prostatic adenocarcinoma. Microscopically the mass contained adenocarcinoma morphologically similar to that of the prostate, but the differential diagnosis was impossible between metastatic prostatic carcinoma and primary breast carcinoma. Formalin-paraffin sections of both tumors were stained positively by PSA (prostatic specific antigen) and PAP (prostatic acid phosphatase) using B-SA (biotin-streptavidin) system technique and prostatic origin of the breast mass was confirmed. Prostatic origin for metastatic carcinoma in the breast is are with only 30 reported cases in the literature including 5 Japanese cases. In most of them the diagnosis of the breast lesion as prostatic carcinoma has been made on morphologic and clinical grounds only. Accurate diagnosis is important for the prognosis of the patient, and immunohistochemical method is useful for he diagnosis of breast carcinoma metastasized from prostatic origin.     

Immunohistologic diagnosis of 2 cases of metastatic prostate cancer to breast

We report 2 cases of primary prostatic carcinoma with subsequent carcinomatous lesions in the breast. Prostatic origin of these carcinomas was confirmed by immunocytochemical demonstration of prostatic acid phosphatase and prostate specific antigen within paraffin sections. Previously, only 20 cases of prostatic carcinoma metastatic to the breast have been reported in the literature. In most of these cases the designation of the breast lesion as prostatic carcinoma has been made on morphologic and clinical grounds only.